Uterine Cervix - Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

Chapter 69. Uterine Cervix

Akila N. Viswanathan

ANATOMY

The uterus is a hollow, thick-walled, pear-shaped, muscular organ located in the pelvis above the vagina, behind the bladder, and in front of the rectum (Fig. 69.1). On average, it is approximately 7 to 8 cm long, 5 to 7 cm wide, and 2 to 3 cm thick. The uterus is divided into the uterine corpus superiorly and the uterine cervix inferiorly, with the most superior part of the corpus also known as the fundus and the middle portion of the corpus known as the body. The fundus is located superior to the line joining the entrance of the fallopian tubes. The body of the uterus is enclosed between layers of the broad ligament and is freely mobile. The regions of the body where the fallopian tubes enter are called the cornua. The most inferior, slightly constricted, portion of the uterus is called the isthmus or lower uterine segment (LUS). The cervix rests inferior to the LUS.

The uterus is usually bent anteriorly (anteflexed) between the cervix and the uterine body. The entire uterine-cervix structure is normally bent anteriorly (anteverted) in the pelvis. The uterus is frequently posteriorly retroverted, especially in older women who have a small uterus. The wall of the uterus has three layers: the outer serosal layer; the middle myometrium, which is approximately 12 to 15 mm of muscle through which the main blood vessels and nerves flow; and the inner coat called the endometrium.

The cervix measures approximately 3 by 3 cm and is predominantly a fibrous organ. The cervix is divided into an upper or supravaginal portion, above the ring containing the endocervical canal, and the vaginal portion, projecting in the vaginal vault. Central in the rounded vaginal region is the external os, bounded by the anterior and posterior lips of the cervix, extending inward to the internal os, the endocervical canal, and endometrial canal.

The uterus is partially covered by peritoneum in its fundal portion and posteriorly; its anterior and lateral surfaces are related to the bladder and the broad ligaments, respectively. It is attached to the surrounding structures in the pelvis by two pairs of ligaments—the broad and the round ligaments. The broad ligament is a double layer of peritoneum extending from the lateral margin of the uterus to the lateral wall of the pelvis. It contains the fallopian tubes. The two layers of peritoneum forming the broad ligament enclose the parametrium as it reaches the uterus. Inferiorly, the broad ligament follows the plane of the pelvic floor and ends medially in the upper portion of the vagina.¹

The round ligament, a band of smooth muscle and connective tissue that contains small vessels and nerves, extends forward horizontally from its attachment in the anterolateral portion of the uterus to the lateral pelvic wall. The cord ascending from the lateral wall of the true pelvis crosses the pelvic brim and extends laterally to reach the abdominoinguinal ring, through which it leaves the abdomen to traverse the inguinal canal and terminates in the superficial fascia.

The uterosacral ligaments are paired supports for the lower uterus, extending from the uterus to the sacrum and running along the recto-uterine-peritoneal fields.¹ The cardinal ligaments, also called transverse cervical ligaments (Mackenrodt’s), are thickened connective tissue and fascia arising at the upper lateral margins of the cervix and inserting into the fascial covering of the pelvic diaphragm.

The uterus including the uterine cervix has a rich lymphatic network (Fig. 69.2) that drains principally into the paracervical lymph nodes; from there it goes to the external iliac (of which the obturator nodes are the innermost component) and the hypogastric lymph nodes. The pelvic lymphatics drain into the common iliac and the para-aortic lymph nodes. Lymphatics from the fundus pass laterally across the broad ligament continuous with those of the ovary, ascending along the ovarian vessels into the para-aortic lymph nodes. Some of the fundal lymphatics also drain into the common iliac lymph nodes. The main artery supplying the uterus is the uterine artery, which originates from the anterior division of the hypogastric artery.

EPIDEMIOLOGY

Over the last 80 years, the morbidity and mortality of locally advanced invasive cervical cancer has dramatically declined in the United States and Europe due to effective screening and treatment of preinvasive lesions.² In the United States 50% of women who develop cervical cancer have never been screened and another 10% have not been screened within the previous 5 years. However, in the last decade, incidence rates of invasive carcinoma have remained relatively constant. The American Cancer Society estimates that approximately 12,200 new cases of invasive carcinoma of the cervix arise in the United States and about 4,200 deaths will occur per year, in addition to >60,000 cases of carcinoma in situ.³

Worldwide, cervical cancer remains the most common gynecologic cancer and the third-most-common malignancy in women, with over 500,000 women globally developing this tumor and 233,000 dying of the disease every year.⁴ Unfortunately, it often affects young women, resulting in loss of the ability to bear future children. The larger societal impact from the death of young women in the prime of life and motherhood has not been measured.

In developing countries, cervical cancer is the leading cause of cancer-related death.² Cervical cancer is more common in areas where women have less access to screening, including parts of Asia, Africa, and Central and South America. Whether regional differences in predisposition to developing cervical cancer exist is debated because it is impossible to adequately correct for unknown and known confounders, such as socioeconomic status, access to health care, parity, smoking, presence of other infections, immune status, and other factors affecting host immunity such as nutritional status.⁵

FIGURE 69.1. Anatomy of the pelvis. (Asset provided by the Anatomical Chart Company Lexington, SC.)

Human Papilloma Virus

Estimates indicate that >90% of cervical cancers are related to the presence of human papilloma virus (HPV) and are contracted via sexual intercourse.⁶ HPV is a small, double-stranded DNA virus; HPV 16 and 18, as well as a long list of other, less frequent subtypes, including but not limited to HPV 31, 33, 35, 39, 45, 51, 52, 56, and 58, have been well characterized as causative agents for cervical cancer, with some geographic variation.⁷ The HPV genome integrates into the host cell chromosomes in cervical epithelial cells and codes for six early and two late open reading frame proteins, of which three (E5, E6, and E7) alter cellular proliferation. Two viral genes, E6 and E7, are typically expressed in HPV-positive cervical-cancer cells. The E6 protein inactivates the major tumor suppressor p53; this causes chromosomal instability, inhibits apoptosis, and activates telomerase. The E7 protein affects the retinoblastoma protein (Rb), resulting in a loss of regulation of the cell’s proliferation and immortalization.⁸

Although a high prevalence of HPV exists worldwide, peaking at ages 25 to 35 years, <15% of exposed women develop persistent infection that results in dysplasia,⁹ whereas the majority of women clear the infection within 2 years.¹⁰ Cervical cancer may develop 10 to 20 years after initial exposure to HPV. Social factors related to cervical cancer include those associated with HPV transmission, such as early age of first intercourse; a history of multiple sexual partners; a male partner with a history of multiple sexual partners; a large number of pregnancies;¹¹^,¹² and a history of sexually transmitted disease, including gonorrhea, chlamydia,¹³ herpes simplex virus II, and/or human immunodeficiency virus (HIV).¹⁴ A higher incidence of cervical cancer exists among women whose spouses are known or suspected to have had higher exposure to HPV¹⁵ or whose partners have a history of penile carcinoma.¹⁶^,¹⁷Whether circumcision may be protective to women is controversial¹⁸ because circumcision may be a surrogate for unknown factors related to HPV transmission.¹⁹

Chemical,²⁰ hormonal, or other carcinogens²¹ may be implicated in cervical cancer. An association between cervical carcinoma and oral contraceptive use has been reported but is considered controversial.²² Prenatal exposure to diethylstilbestrol (DES) is linked to the development of clear-cell adenocarcinoma, although the overall incidence is small (0.14 to 1.4 per 1,000 DES-exposed women).²³^–²⁵ Cigarette smoking may increase the risk of cervical cancer.²⁶ However, passive smoking may not be an independent factor in the absence of active smoking.²⁷ A review of >50 studies considers smoking a cofactor for HPV infection and carcinogenesis,²⁸ although one study does not confirm this.¹⁵ Current smoking (relative risk [RR] = 1.55) and younger age at HPV exposure (RR = 1.75) are considered risk factors among HIV-positive women.²⁹ Intrauterine device use may decrease cervical cancer risk, potentially through an increase in cellular immunity triggered by the device.³⁰

HPV Vaccination

The quadrivalent human papillomavirus recombinant vaccine for HPV types 6, 11, 16, and 18, first approved in the United States in 2006 for girls and women ages 9 to 26 years, is now available for boys ages 9 to 26 years, with the goal of eradicating HPV-related gynecologic, penile, anal, and oropharyngeal cancers. A second vaccine with strong immunogenicity to HPV types 16 and 18, approved for girls 9 to 25 years old, is more frequently administered in Europe. Although its development is a major advance in the prevention of cancer, vaccine implementation has been hindered worldwide by cost and access. With an increase in understanding and availability, the hope is that all children will be given a vaccine covering all subtypes in the future.

FIGURE 69.2. A: Lymph vessels and lymph nodes of the cervix and the body of the uterus. (Asset provided by the Anatomical Chart Company, Lexington, SC.) B: Three-dimensional reconstruction of location of pelvic and common iliac lymph nodes outlined on computed tomography scans in patients with carcinoma involving the distant vagina. Treatment portal is shown. C: The incidence of cervical cancer increased slightly in the U.S. from 2005–2010.

TABLE 69.1 INCIDENCE OF PELVIC NODE METASTASES IN CARCINOMA OF THE UTERINE CERVIX

TABLE 69.2 METASTASES TO PARA-AORTIC LYMPH NODES IN CARCINOMA OF THE UTERINE CERVIX

NATURAL HISTORY AND PATTERNS OF SPREAD

Squamous cell carcinoma of the uterine cervix usually originates at the squamous columnar junction (transformation zone) of the endocervical canal and the portio of the cervix.

Cellular transformation follows a stepwise progression from normal to higher levels of dysplasia. Of patients diagnosed with cervical intraepithelial neoplasia (CIN) type 1, 60% have regression of the lesion, and of those with CIN2, 40% regress. Higher levels of dysplasia are more likely to progress to cancer, particularly in the presence of cofactors such as smoking or impaired immunity. Although progression typically takes 10 to 20 years,³¹^,³² in some instances a rapid development of carcinoma may be associated with aggressive disease.

The development of a malignant phenotype results from cells that break through the basement membrane of the epithelium and invade the cervical stroma. Invasion may result in spread to pelvic lymph nodes or other, more distant sites.³³ If the cells are detected at this stage by a Papanicolaou (Pap) or thin preparation test, appropriate minimally invasive therapy may suffice. However, if the lesion progresses, it may present as a superficial ulceration or exophytic tumor in the ectocervix or with extensive infiltration of the endocervix. If untreated, the tumor may spread to the adjacent vaginal fornices, paracervical or parametrial tissues,³⁴ or adjacent organs, including the bladder, the rectum, or both. Landoni et al.³⁵ studied 230 patients with clinical stages IB and IIA tumors treated with radical hysterectomy with pelvic lymphadenectomy and noted that the tumor spread endocervically equally in all directions. Tumor extension into the vesicocervical ligament (anterior parametrium) was noted in 23% of cases, into the uterosacral ligaments (posterior parametrium) and the rectovaginal septum in approximately 15%, and into the parametria in 28% to 34% of cases. Paracervical extension was related to the depth of stromal invasion, tumor size, lymphatic invasion, and presence of lymph node metastasis.

Approximately 10% to 30% of patients with carcinoma of the uterine cervix have extension into the lower uterine segment and the endometrial cavity.³⁶ Decreased survival rates and a greater incidence of distant metastases were reported by Perez et al.³⁶ and Chao et al.³⁷ in patients with stromal endometrial invasion or replacement of normal endometrium by cervical carcinoma. Regional lymphatic or hematogenous spread may occur and increases with stage, although dissemination does not always follow an orderly sequence, and occasionally a small primary tumor may be seen infiltrating the pelvic lymph nodes, invading the bladder or rectum, or metastasizing distantly.

Both adjacent parametrial and pelvic lymph nodes may be involved. Girardi et al.³⁸ analyzed 359 radical hysterectomy specimens and found positive parametrial nodes in 280 patients (78%); the incidence of positive nodes was 11.4% in stage IB and 21.5% in stage IIB disease. With negative parametrial nodes, only 26% of patients had positive iliac lymph nodes, whereas 81% of patients with positive parametrial lymph nodes also had pelvic-node metastases. These data underscore the need to irradiate the parametrial tissues or carry out a complete bilateral pelvic lymphadenectomy with a radical hysterectomy in patients with invasive cervical carcinoma.

Spread of carcinoma of the cervix may progress to the obturator lymph nodes, considered a medial group of the external iliac chain, to other external iliac nodes, and to the hypogastric lymph nodes. From these, there may be tumor metastases to the common iliac or para-aortic lymph nodes.³⁹ The incidence of metastasis to pelvic or para-aortic lymph nodes for various stages of the disease is listed in Tables 69.1 and 69.2. In one study, pelvic lymph nodes were dissected in 225 patients with cervical carcinoma treated with radical hysterectomy; positive pelvic nodes were identified in 13 of 91 women (14.2%) with stages IB and IIA, 16 of 81 (19.8%) with stage IIB, and 11 of 40 (28%) with stage IIIB disease.⁴⁰ The most commonly involved groups were the parametrial, obturator, external iliac, and common iliac nodes (Fig. 69.3). Para-aortic lymph nodes were involved in 3 of 91 patients (3.3%) with stage IB or IIA tumors 4 cm or less and in 5 of 38 patients (13.1%) with stage IIB or III disease.

Spread through the venous plexus and the paracervical veins resulting in hematogenous dissemination, though infrequent, is relatively common with more advanced stages. In an analysis of 322 patients in whom distant metastases developed, the most frequently observed metastatic sites were the lung (21%), para-aortic lymph nodes (11%), abdominal cavity (8%), and supraclavicular lymph nodes (7%).⁴¹ Bone metastases occurred in 16% of patients, most commonly to the lumbar and thoracic spine (Table 69.3). Spinal epidural compression from metastatic tumor, often involving lumbar segments, can occur rarely,⁴² and metastasis to the brain and the heart have been reported, although it is unusual to have spread to the brain without evidence of pulmonary metastases already present,⁴³^,⁴⁴ even for small-cell carcinoma of the cervix.⁴⁵

FIGURE 69.3. Distribution of pelvic node metastases in 14 patients with stages IB to IIA cervical cancer, tumor size <4 cm (A), and 38 patients with locally advanced cervical cancer treated with neoadjuvant chemotherapy (B). (From Benedetti-Panici P, Maneschi F, Scambia G, et al. Lymphatic spread of cervical cancer: an anatomical and pathological study based on 225 radical hysterectomies with systematic pelvic and aortic lymphadenectomy. Gynecol Oncol 1996;62:19–24; with permission from Elsevier.)

PAP SMEAR SCREENING

The American College of Obstetrics and Gynecology guidelines published in 2009⁴⁶ state that Pap smear screening should begin at age 21 years and continue every 2 years until age 30 years; then, if there are three normal consecutive Pap smears and no history of CIN2, CIN3, DES exposure, or HIV infection and the woman is not otherwise immunocompromised, screening should be every 3 years. Women who have had a hysterectomy for benign reasons and have no history of high-grade squamous intraepithelial lesion may discontinue testing. Co-testing of the Pap smear with an HPV DNA test is appropriate for low-risk women older than age 30 years. If negative, rescreening is not required sooner than 3 years. Women who have been treated for CIN2 or CIN3 need annual screening for at least 20 years. Those who have had a hysterectomy and a history of CIN2/CIN3 should continue to undergo screening with annual pelvic exams.

When obtaining the Pap smear, special attention should be directed to not using a lubricating agent (warm water on the speculum will suffice), to obtaining good “scrapings” from the cervix and vaginal posterior fornix (without blood), and to using a small brush to obtain an endocervical sample. The patient should be instructed not to cleanse with a douche before the examination, and, if indicated, specimens should be obtained to check for trichomonas. If the cytologic smear shows atypia or mild dysplasia (class II), it should be repeated no sooner than 2 weeks after the initial test to allow representative cellular exfoliation to occur. Guidelines for reporting results of cervical and vaginal cytology were promulgated in 1988. The Bethesda system eliminated the classes of Pap cytology. The correlation between the cytologic diagnosis and subsequent histologic examination is >90%.⁴⁷ This system was modified in 1991 and in 2001.⁴⁸

TABLE 69.3 CARCINOMA OF THE UTERINE CERVIX (MALLINCKRODT INSTITUTE OF RADIOLOGY 1959–1986): ANATOMIC SITE OF FIRST METASTASIS

TABLE 69.4 DIAGNOSTIC WORKUP FOR CARCINOMA OF THE UTERINE CERVIX

CLINICAL PRESENTATION

Cervical cancer in the United States is most frequently identified during routine gynecologic examination. Intraepithelial or early invasive carcinoma of the cervix may be detected by cytologic smears before symptoms appear; Pap smear, colposcopy and biopsies, and HPV testing have high specificity and sensitivity. Visible lesions present with an exophytic mass or a barrel-shaped cervix due to an endocervical lesion. Patients may present complaining of metrorrhagia (intermenstrual bleeding), menorrhagia (heavier menstrual flow), or postcoital bleeding. If chronic bleeding occurs, the patient may complain of fatigue or other symptoms related to anemia.

In cases with more advanced disease, bowel obstruction, renal failure, foul-smelling serosanguinous or yellowish vaginal discharge, pelvic pain, flank and/or leg pain, rectal bleeding, obstipation, dysuria, hematuria, or persistent edema of lower extremities due to lymphatic/venous blockade by pelvic sidewall disease may occur. Pain in the pelvis or hypogastrium may be caused by tumor necrosis or associated pelvic inflammatory disease. In patients with pain in the lumbosacral area, the possibility of para-aortic lymph node involvement with extension into the lumbosacral roots or hydronephrosis should be considered.

DIAGNOSTIC WORKUP

When a patient presents with an abnormal smear or if abnormal squamous cells of undetermined significance (ASCUS) are detected but HPV status is negative, follow-up in 1 year is recommended. If the second smear reveals ASCUS, regardless of HPV status, colposcopy is recommended. When both ASCUS and HPV are present or adenocarcinoma in situ or a squamous intraepithelial lesion is identified, directed biopsies at the time of colposcopy should be carried out. Endocervical curettage may be performed except in pregnant women. If the biopsy results are negative, the procedure should be repeated in 6 months, and, if they are positive, a conization should be performed.

Patients who present with a clinically visible lesion should be jointly evaluated by the radiation and gynecologic oncologists. After obtaining a careful clinical history and performing a general physical examination, with attention to the inguinal and supraclavicular (nodal) areas, abdomen, and liver, a careful pelvic examination should be carried out with as little discomfort to the patient as possible without compromising the thoroughness of the evaluation.⁴⁹Pelvic examination should include inspection of the external genitalia, vagina, and uterine cervix, a rectal examination, and bimanual palpation of the pelvis. Pelvic examination under anesthesia is a universally accepted component in the evaluation and clinical staging of patients in order to provide a pain-free examination that allows a clearer estimation of parametrial or sidewall tumor extension. In countries in which magnetic resonance imaging (MRI) is available, this may be used to assist with assessing tumor extension beyond the lower cervix, and in many institutions it has replaced the examination under anesthesia. Cystoscopy or rectosigmoidoscopy should be performed in all patients with symptoms consistent with presence of a fistula of the urinary or lower gastrointestinal tract, patients with clinical stage IIB, III, or IVA disease who cannot undergo an MRI, or patients with an MRI suspicious for bladder or bowel invasion. The diagnostic procedures for carcinoma of the cervix are presented in Table 69.4.

Conization/Loop Excision

Conization involves a conical removal of a large portion of the ectocervix and endocervix. Cold knife cone biopsy specimens should always be obtained with a scalpel or other appropriate instrument. At least 50% of the endocervical canal should be removed without compromising the internal sphincter. Curettage of the remaining endocervical canal should be carried out.

Conization must be performed in the following situations: no gross lesion of the cervix is noted and an endocervical tumor is suspected; the entire lesion cannot be seen with the colposcope; diagnosis of microinvasive carcinoma is made on biopsy; discrepancies are found between the cytologic and the histologic appearances of the lesion; or the patient is not reliable for all necessary follow-up. With careful selection of patients who have a negative positron emission tomography (PET) scan and an MRI with a central lesion <2 cm in width, knife conization with lymphadenectomy may be considered for fertility preservation. Laser conization and loop diathermy excision are frequently done in an office setting as an alternative to conization; loop excision is less expensive and more reliable than laser conization.

Biopsy

Multiple punch biopsies of a grossly visible lesion should be adequate to confirm the diagnosis of invasive carcinoma. Specimens should be obtained from any suspect area and from all four quadrants of the cervix and from any suspect areas in the vagina. It is important to obtain tissue from the periphery of the lesion with some adjoining normal tissue; biopsy specimens from central ulcerated or necrotic areas may not be adequate for diagnosis. Dilation and curettage is not required if the biopsy confirms a diagnosis of invasive disease.

TABLE 69.5 COMPUTED TOMOGRAPHY AND POSITRON EMISSION TOMOGRAPHY IN THE EVALUATION OF PARA-AORTIC NODES

Laboratory Studies

For invasive carcinoma, patients should have the following laboratory studies: complete peripheral blood evaluation, including hemogram, white blood cell count, differential and platelet count; blood chemistry profile, with particular attention to blood urea nitrogen and creatinine; liver function values; and urinalysis.

Imaging Studies

In countries where three-dimensional (3D) imaging is not routinely available, patients with cervical cancer should have a chest radiograph to assess for lung metastases and an intravenous pyelogram (IVP) to determine whether hydronephrosis is present. The IVP in many countries has been replaced by computed tomography (CT) scan of the pelvis and abdomen with intravenous (IV) contrast material or by PET/CT scan. In places where CT is not available, patients with stages IIB, III, and IVA disease who have symptoms in the colon and rectum may benefit from a barium enema. A skeletal survey may be performed to determine whether bone metastases are present. Historically, pedal lymphangiography was used to assess lymph node involvement in the pelvic or para-aortic nodes with mixed results.⁵⁰^,⁵¹ The number of physicians trained to perform lymphangiography has declined in the United States, and instead PET scan is preferred.

Since the 1990s, the use of CT scanning has rapidly increased worldwide. A CT provides diagnostic information about the presence of metastases, enlarged lymph nodes, and the primary tumor. On a CT scan, the cervical tumor may be seen as an enlarged, irregular, hypoechoic cervix or as a mass with ill-defined margins. Parametrial regions appear dense when involved, and uterosacral involvement may be seen. Lymph nodes appear enlarged, with most >1 cm on axial dimension considered pathologic. The overall accuracy of CT scanning in staging cervical cancer ranges from 63% to 88%.⁵⁰^,⁵² In the detection of lymph node abnormalities, the overall accuracy of conventional CT scanning is 77% to 85%, with sensitivity of 44% and specificity of 93%.⁵³

In order to correlate radiographic and surgical findings, Camilien et al.⁵⁴ reported on 61 patients with carcinoma of the cervix who had both preoperative CT scans and exploratory laparotomy; results showed that 75% of the enlarged pelvic lymph nodes on CT contained metastases, and 97% of patients with negative nodes on CT scan had pathologically negative findings (specificity of 97%). However, histologically positive pelvic nodes were often missed on CT scan (sensitivity of 25%). The CT scan is more valuable in evaluation of the para-aortic lymph nodes (specificity of 100% and sensitivity of 67%).

Several studies evaluated the role of CT or PET/CT with regard to para-aortic nodal detection (Table 69.5). Heller et al.⁵⁵ conducted a prospective evaluation of 320 patients with stages IIB to IVA carcinoma of the cervix entered into a Gynecologic Oncology Group (GOG) protocol in which preoperative CT scan, lymphangiography, and ultrasonography of the aortic area were performed. Para-aortic node dissection was done in patients with negative staging studies. Lymphangiography, CT scan, and ultrasonography had false-negative frequencies for pelvic lymph node evaluation of 14.2%, 25%, and 30%, respectively. The sensitivity was 79% for lymphangiography, 34% for CT scan, and 19% for ultrasonography, and the specificity ratings were 73%, 96%, and 99%, respectively. Ultrasonography, therefore, is not reliable in preoperative detection of lymph node metastases, but it has limited value in evaluating extrauterine tumor involvement. Ultrasound has a primary role in assisting with intracavitary brachytherapy applicator insertion and may detect uterine perforation, allowing for proper positioning, which is critical for adequate dosing and affects survival.⁵⁶^,⁵⁷ PET has a higher sensitivity than CT and higher specificity than MR in detecting bone metastases.⁵⁸

Magnetic Resonance Imaging

MRI is frequently used for the initial assessment of the cervical tumor and of extracervical tumor extension,⁵⁹ often in lieu of an examination under anesthesia. MRI is contraindicated in patients with pacemakers, cochlear implants, metallic prostheses, metallic fragments from prior accidents, or large vascular clips. On T2-weighted images, a cervical cancer may be seen as a mass of intermediate to high signal intensity, usually of greater intensity than the fibrocervical stroma. On T1-weighted images, tumors are usually isointense with the normal cervix and may not be seen⁶⁰ but can increase in intensity with the administration of IV contrast. Abnormal, irregular cervical margins, prominent parametrial strands, exocentric parametrial enlargement, and loss of parametrial fat planes on T1-weighted images or high signal in the parametria or cardinal/uterosacral ligaments on T2-weighted images are indicative of more extensive tumors.⁵²^,⁵⁹^,⁶¹ Parametrial tumor may be identified as brighter regions on T2-weighted images when compared to the low signal intensity of the cervix and uterine ligaments.

A comparative evaluation of pretreatment tumor staging and volume as assessed by examination under anesthesia (EUA), transrectal ultrasonography (TRUS), and MRI in 60 patients with invasive carcinoma of the cervix was reported by Hawnaur et al.⁶² TRUS and MRI assigned the same tumor stage in only 30% of patients, and EUA and MRI agreed on tumor stage in an additional 27%. In cases of disagreement, the MRI staging correlated better with outcome than TRUS or EUA. Sixty-two percent of patients with enlarged lymph nodes on pretreatment MRI either died or had tumor recurrence or metastases. MRI was superior to both TRUS and EUA in assessing the full extent of bulky tumors and lymph node enlargement.

Postema et al.⁶³ compared MRI with pelvic examination (including under general anesthesia in selected patients) and surgicopathologic findings in 103 patients with invasive cervical carcinoma. MRI was better at identifying extracervical tumor spread, but it had more false-positive results. The pelvic examination led to correct treatment decisions in 89% of patients. In a study by Hansen et al.,⁶⁴ clinical assessment (done according to International Federation of Gynecology and Obstetrics [FIGO] recommendations) was superior to low-field MRI with contrast enhancement in staging cervical cancer in 95 women who had both within 2 weeks after clinical diagnosis; the clinical staging correctly classified 57 patients (accuracy, 92%) compared with 52 for MRI (accuracy, 84%).

A prospective study by the American College of Radiology Imaging Network compared clinical examination, CT, and MRI.⁵³ MRI was significantly better than clinical examination or CT for detecting uterine-body involvement or measuring tumor size,⁶⁵ but no method was accurate at evaluating the cervical stroma. MRI was significantly better⁶⁶ at detecting the tumor and parametrial involvement. MRI also somewhat increased detection of involved lymph nodes.⁵³

The tumor is less likely to be as visible on MRI for adenocarcinoma cases, compared to squamous cell cancer. Haider et al.⁶⁷ evaluated 56 patients with adenocarcinoma involving the cervix using MRI and noted that 42 (75%) had a visible mass. Kodaira et al.⁶⁸ reviewed records of 84 patients with stage II cancer evaluated by MRI. The 5-year disease-free survival (DFS) rate of patients with maximal tumor size (D_max) of ≥50 mm was significantly lower than that for patients with D_max < 50 mm (46% vs. 88%; p < .0001).

Ebner et al.⁶⁹ reviewed MRI findings in 12 women with recurrent pelvic tumors and 10 with a fibrotic mass (confirmed by laparotomy or biopsy in 21 patients). They were able to differentiate between the two processes accurately in most instances. However, it is highly desirable to confirm abnormal or suspect lymph node radiographic findings with CT-guided fine-needle aspiration biopsies.

Corn et al.⁷⁰ evaluated endorectal coil MRI in 18 patients with stages IB to IIIB cervical carcinoma; in 7 patients, tumors were a higher stage by endorectal coil MRI because of proximal vaginal involvement or the combination of proximal vaginal involvement and parametrial extension. Compared with those who had a dark or intermediate signal, patients with bright signal characteristics tended to present with earlier stages, were less likely to have anemia, and were more likely to have complete response to external-beam radiation.

Radiation-induced changes detected over the course of radiation may predict local recurrence and survival. Mayr et al.⁷¹ studied 34 patients with cervical cancer of various FIGO stages who underwent 1.5-T MRI before and after radiation therapy. Tumor volumetry (3D measurements) based on T2-weighted images quantified the tumor regression rate. Sequential tumor volumetry using MR imaging may be a very effective measure of the responsiveness of cervical cancer to irradiation. MRI dynamic contrast enhancement during the first 2 weeks of radiation therapy may provide early prediction of tumor regression rate. In 7 patients, tumor regression rates ranged from 2% to 15.2% per day and correlated positively with changes in both peak and mean tumor enhancement (p < .01). Hatano et al.⁷² evaluated MRI in 42 patients with advanced cervical cancer treated with external-beam irradiation and high–dose-rate (HDR) brachytherapy. In biopsies performed immediately after radiation therapy (RT), no residual cancer was found in 36 patients (86%). The simultaneous MRI study demonstrated no high-signal intensity on T2-weighted images in 28 patients (75%). A high–signal-intensity area was observed in 14 patients, and this disappeared 3 months after RT in 8 patients with a negative biopsy. The sensitivity, specificity, and accuracy of MRI tumor response studies at 3 months after radiation therapy were 100%. MRI studies performed after 30 Gy of external-beam irradiation and 3 months after all radiation therapy predicted local tumor control. Similar studies were published by Gong et al.⁷³ and van de Bunt et al.⁷⁴ Furthermore, MRI is useful in providing accurate target volume definition in brachytherapy treatment planning (Fig. 69.4).⁷⁵

FIGURE 69.4. A: Magnetic resonance imaging (MRI) at diagnosis showing an enlarged cervical tumor. B: MRI with tandem and ring brachytherapy applicator in place showing dramatic shrinkage of the tumor after concurrent chemotherapy with external beam radiation.

Positron Emission Tomography

PET scanning is increasingly used in the evaluation of patients with malignant neoplasia, including invasive cervical cancer, using 2-[¹⁸F]-fluoro-2-deoxy-D-glucose (FDG). Rose et al.⁷⁶ observed uptake in 91% of the primary tumors in 32 patients with locally advanced carcinoma of the cervix. Squamous cell carcinoma is more often FDG avid than is adenocarcinoma. Compared with surgical staging, PET scanning had a sensitivity of 75% and a specificity of 92% in detecting para-aortic metastasis.⁷⁷ PET-CT provides highly accurate localization of focal radiotracer uptake, which significantly improves the diagnostic accuracy compared with PET or CT alone. Diagnostic PET images may be fused with simulation CT images to ensure accurate radiation dose coverage of the target and any PET-avid lymph nodes (Fig. 69.5). Care must be taken in interpretation because physiologic FDG excretion into the urinary bladder may result in false-positive assessment of the primary tumor, and ureters may be contoured as lymph nodes; therefore, tracing the ureters and complete bladder voiding prior to imaging are recommended.

Grigsby et al.⁷⁷ compared CT and FDG-PET scanning for lymph node staging in 101 patients with carcinoma of the cervix. CT demonstrated abnormally enlarged pelvic lymph nodes in 20 patients and para-aortic lymph nodes in 7, whereas PET demonstrated abnormal FDG uptake in pelvic lymph nodes in 67, in para-aortic lymph nodes in 21, and in supraclavicular lymph nodes in 8. The 2-year progression-free survival rate, based solely on para-aortic lymph-node status, was 64% in CT-negative and PET-negative patients, 18% in CT-negative and PET-positive patients, and 14% in CT-positive and PET-positive patients (p < .0001). The most significant prognostic factor for progression-free survival was the presence of positive para-aortic lymph nodes on PET imaging (p= .025). Among 76 patients with no abnormal FDG uptake, the 2-year survival rate was 86%, with persistent abnormal uptake in 40%; there were no survivors among patients who developed new sites of abnormal uptake.⁷⁸ In a follow-up study of 152 patients, the authors reported a 5-year cause-specific survival rate of 80% in 114 patients without abnormalities on posttherapy FDG-PET versus 32% in 20 patients with persistent uptake, and no survivors among 18 patients with new sites of abnormal uptake.⁷⁹ In another study, Grigsby et al.⁸⁰ noted in 208 patients a close correlation between radiation doses, number and size of positive lymph nodes and outcome (treatment failures and survival; Fig. 69.6). Hope et al.⁸¹ performed FDG-PET scans in 58 patients with cervical carcinoma who had an endometrial biopsy or dilatation and curettage; 36 (64%) had pathologic endometrial invasion (EI). Pelvic lymph node metastasis was more commonly detected in this group than in patients without EI (70% vs. 23%; p < .001), as were para-aortic and supraclavicular nodal metastasis (30% vs. 0%; p = .006). Furthermore, 2-year survival rates were 78% versus 58%, and overall survival rates were 92% versus 65%, respectively (p = .047). Lin et al.,⁸² using FDG-PET in 32 patients with cervical carcinoma, observed a reduction in physiologic tumor volume of 50% occurring within 20 days from the initiation of radiation therapy.

Kidd et al.⁸³^–⁸⁷ demonstrated that maximum standardized uptake value (SUV max) is an independent predictor of death from cervical cancer and is associated with persistent disease. Similarly, the SUV of the pelvic node predicts pelvic disease recurrence. Survival rates are worse with supraclavicular nodal PET positivity; para-aortic lymph node metastases portend a survival rate between those of pelvic node and supraclavicular positivity. The detection of supraclavicular metastases on FDG-PET at diagnosis and its relationship to clinical outcome for 186 cervical cancer patients was reported by Tran et al.⁸⁸ Fourteen patients (8%) had abnormal FDG uptake in left supraclavicular lymph nodes without palpable disease, confirmed on biopsy; 6 were treated with palliative intent, and 7 received definitive irradiation and concurrent chemotherapy. The median overall survival was 7.5 months; all patients developed distant metastases. After external-beam radiation is finished, an FDG-PET scan provides important information about posttreatment uptake and is prognostic with regard to outcome.⁸⁹^–⁹²

FIGURE 69.5. A fusion of a diagnostic positron emission tomography (PET) scan with simulation computed tomography delineates the hypermetabolic lymph nodes, allowing for radiation dose escalation. In this case, the entire para-aortic chain received 45 Gy, followed by a sequential boost to the PET-avid node with a 7-mm margin to approximately 65 Gy.

FIGURE 69.6. Cause-specific survival in patients with carcinoma of the cervix correlated with pelvic lymph node status on posttreatment 2-[¹⁸F]fluoro-2-deoxy-D-glucose/positron emission tomography. (From Grigsby PW, Singh AK, Siegel BA, et al., Lymph node control in cervical cancer. Int J Radiat Oncol Biol Phys 2004;59:637–638; with permission from Elsevier.)

STAGING

The FIGO staging system is based on clinical evaluation (inspection, palpation, colposcopy); roentgenographic examination of the chest, kidneys, and skeleton; and endocervical curettage and biopsies. Lymphangiograms, arteriograms, imaging findings, and laparoscopy or laparotomy findings should not be used for clinical staging. The 2009 FIGO staging system for cervical cancer has one modification from the previous version: Stage IIA has been divided into stage IIA1, with tumors invading into the upper vagina but ≤4 cm in size, and stage IIA2, with tumors >4 cm in size.⁹³

Patients with hydronephrosis or a nonfunctioning kidney ascribed to extension of the tumor are classified as stage IIIB regardless of the pelvic findings. Other prognostic factors, such as endometrial extension of cervical carcinoma, stromal invasion, lymphatic/vascular permeation, and involvement of the lateral parametrium (as opposed to the medial parametrium) in stage IIB, are not included in the staging system. Suspected invasion of the bladder or rectum should be confirmed by biopsy. Bullous edema of the bladder and swelling of the mucosa of the rectum are not accepted as definitive criteria for staging. For a lesion to be classified as stage IIIB based on tumor extension without hydronephrosis, the tumor should extend to the lateral pelvic wall, although fixation is not required.

A parallel TNM staging system is published by the American Joint Committee on Cancer;⁹⁴ however, this system requires nodal staging, which is not feasible in many settings, and radiologic nodal information is not available to most patients with cervical cancer worldwide. The FIGO system remains the standard staging system, given the lack of 3D imaging to determine nodal status in countries with the highest incidence of cervical cancer. All histologic types should be included. When there is a disagreement regarding the staging, the earlier stage should be recorded (Table 69.6 and Fig. 69.7).

FIGURE 69.7. Diagrammatic representation of various anatomic stages of carcinoma of the uterine cervix, according to the International Federation of Gynecology and Obstetrics classification. Stage IIA has been divided into stage IIA1, with tumors invading into the upper vagina but ≤4 cm in size, and stage IIA2, with tumors >4 cm in size.

PATHOLOGIC CLASSIFICATION

More than 90% of tumors are squamous cell carcinoma. Approximately 7% to 10% are classified as adenocarcinoma, and 1% to 2% are the clear-cell mesonephric type. Squamous cell (or epidermoid) carcinoma is composed of cores and nests of epithelial cells arranged randomly; cells show central keratinization with pearls and sometimes necrosis. Nonkeratinizing tumors may be seen. Electron microscopy may show desmosomes and tonofilaments. Squamous cell carcinomas are divided into three types: large-cell keratinizing, nonkeratinizing, and small-cell carcinomas. They are subdivided according to the degree of differentiation into well, moderately, or poorly differentiated.

Verrucous carcinoma is a variant of a very well differentiated squamous cell carcinoma that characteristically has a tendency to recur locally but not to metastasize.⁹⁵ Mitotic activity is very low. It may be difficult to discriminate verrucous carcinoma from a giant condyloma with cytologic atypia or from a well-differentiated invasive squamous carcinoma. Microscopically, verrucous carcinoma is exophytic, with an undulating, hyperkeratotic surface; the deep margin is composed of large, bulbous masses that invade along a wide front in a “pushing” fashion.

Adenocarcinoma arises from the cylindrical mucosa of the endocervix or the mucus-secreting endocervical glands. Mucinous is the most common subtype of adenocarcinoma. This endocervical adenocarcinoma may form mucosal glands lined by high columnar cells and produce tubular folds oriented in many directions. In another subtype, cells resemble those of the intestines; the epithelium tends to be pseudostratified and may contain goblet cells. The third variant is the signet-ring cell adenocarcinoma, which is rare and usually mixed with the endocervical or intestinal patterns.

Endometrioid carcinoma is the most common cell type of endocervical adenocarcinoma; the cells resemble those of the endometrium, and the presence of intracytoplasmic mucin in some cells may be seen in a substantial proportion of tumors. The World Health Organization recommends that endometrioid or endocervical types of adenocarcinoma be graded according to their architecture, based on the degree of gland formation.⁹⁶

Sometimes it is difficult to differentiate a primary endocervical adenocarcinoma from an endometrial tumor. Drescher et al.⁹⁷ described a higher incidence of involvement of the uterine corpus and the regional lymph nodes in 21 patients with adenocarcinoma compared with a similar number of patients with squamous cell carcinoma. Chao et al.⁹⁸ and Contag et al.⁹⁹ described the use of microarray analysis for gene profiling (cDNA/RNA) to understand the molecular features of these tumors, which could aid in their classification. HPV has been identified in some subtypes of adenocarcinoma of the cervix.¹⁰⁰

Adenoma malignum is a rare form of cervical cancer that is difficult to diagnose, and often highly malignant and refractory to treatment.¹⁰¹ Adenoma malignum is associated with Peutz-Jeghers syndrome and has an ominous natural history, with few reported cures.¹⁰² Adenosquamous carcinoma is also relatively rare (2% to 5%) and consists of intermingled epithelial cell cores with squamous features and glandular structures. The squamous component is frequently nonkeratinizing. If the squamous component is benign metaplasia, the tumor is called adenoacanthoma.

Glassy-cell carcinoma (1% to 2%) is considered a poorly differentiated adenosquamous tumor; it is rare and highly malignant. Survival is poor after surgery or irradiation. Ulbright and Gersell,¹⁰³ in five cases of glassy-cell carcinoma evaluated by light and electron microscopy, described both glandular and squamous differentiation. Littman et al.¹⁰⁴ reported only 4 of 13 patients, the majority with stage II disease, surviving 5 years (6 had extrapelvic failures). Piura et al.¹⁰⁵ reported on 5 patients with cervical glassy-cell carcinoma, 3 with stage IB1 disease. All 3 patients were alive without disease 4, 12, and 18 months after diagnosis.

Adenoid cystic carcinoma is a rare variant of adenocarcinoma of the cervix (<1%), with an appearance similar to its counterparts in the salivary gland or the bronchial tree.¹⁰⁶ The tumor is composed of nests and nodules of small carcinoma cells with a few characteristic cribriform patterns. Immunohistochemical findings for type IV collagen and laminin reveal intercellular cylinders composed of basement membrane material in the solid area without a cribriform pattern. They are locally aggressive and prone to metastasize.¹⁰⁷

Clear-cell carcinoma (mesonephric), not related to DES exposure, comprises approximately 2% primary cervical adenocarcinomas and is believed to arise in mesonephric remnants.²⁴ These tumors are submucosal, composed of clear and “hobnail” cells, and may grow in a tubular, glandular, papillary, or solid pattern. They appear at any age, with one-third occurring in women younger than 30 years of age. The clear cell is characterized by a voluminous cytoplasm filled with glycogen and the hobnail cell by single-cell apical projections into the neoplastic lumina. These tumors tend to be deeply positioned, with the bulk of the lesion on the stroma forming tubular structures, diffusely infiltrating the cervical stroma.

Cervical malignant mixed Müllerian tumors, compared with their counterparts in the corpus, are more commonly confined at presentation and may have a better prognosis. Clement et al.¹⁰⁸ described the clinicopathologic features with mixed Müllerian tumors of the cervix in nine patients. Gross examination revealed polypoid or pedunculated masses that invaded the cervical wall in 50% of the hysterectomy specimens. On microscopic examination, five tumors contained basaloid carcinoma or squamous cell carcinoma and four contained adenocarcinoma. In seven tumors, the sarcomatous component was homologous, usually resembling fibrosarcoma or endometrial stromal sarcoma, and two tumors contained heterologous sarcomatous elements.

Small-cell carcinoma of the cervix, according to some authors, arises from endocervical argyrophilic cells or their precursors, multipotential neuroendocrine cells; however, some small-cell tumors do not contain morphologic evidence of neuroendocrine origin. Nuclear molding, absence of nucleoli, cell necrosis, and high mitotic activity are common. One-third to one-half stain positively for neuroendocrine markers such as chromogranin, serotonin, synaptophysin, or somatostatin.⁴⁵ In the majority of patients, the cervical stroma is extensively infiltrated by single small, round cells.¹⁰⁹ Lymphatic and vascular invasion are significantly more common in small-cell carcinomas (noted in 58% of patients with stage IB disease; 40% of these patients had lymph-node metastases at the time of radical surgery).¹¹⁰ HPV 18 has been detected in the majority of these tumors.¹¹¹

Van Nagell et al.,¹¹² in an analysis of 25 patients, noted a 5-year survival rate of 54% for all stages of small-cell carcinoma, compared with 68% for matched large-cell nonkeratinizing squamous cell and 74% for keratinizing squamous cell carcinomas. Viswanathan et al.⁴⁵ studied 21 patients. All were confirmed after central pathology review to stain positively for chromogranin, synaptophysin, or CD56. The median time to first relapse from the initiation of treatment was 8.4 months. No patient had brain metastases as the sole site of first recurrence. However, 2 patients developed brain metastases concurrently with lung metastases. The overall survival rate was 29% at 5 years; none of the patients who had disease more extensive than stage IB1 or clinical evidence of lymph node metastases survived their disease.

Basaloid carcinoma or adenoid-basal carcinoma, an extremely uncommon tumor, is characterized by nests or cords of small basaloid cells, prominent peripheral palisading of cells in the tumor nests, no significant stromal reaction or capillary space invasion, and an infiltrating growth pattern. Some authors have suggested a slow growth pattern with limited local invasiveness and low probability of lymph node metastases.¹¹³ Prognosis is excellent.¹¹⁴

Primary sarcomas of the cervix have been occasionally described (e.g., leiomyosarcoma, rhabdomyosarcoma, stromal sarcoma, carcinosarcoma).¹¹⁵ Malignant lymphomas, primary or secondary in the cervix, have been sporadically reported. They should be treated like other lymphomas.¹¹⁶ Melanoma of the cervix is similarly extremely rare and difficult to cure despite attempts at radical surgery. Metastasis of distant tumors to the uterine cervix is rare (about 4% of all tumors) and should be considered in the differential diagnosis. Metastases to the cervix from the breast, ovary, and kidney have been reported.¹¹⁷^–¹¹⁹

PROGNOSTIC AND PREDICTIVE FACTORS

Patient-Related Factors

Age

According to some reports, age is not a prognostic factor in carcinoma of the cervix.¹²⁰ Other authors noted decreased survival in women younger than 35 or 40 years,¹²¹ who have a greater frequency of poorly differentiated tumors. In contrast, two European studies showed improved outcome for younger patients.¹²² This apparent contradiction may be explained by an analysis by Rutledge et al.,¹²³ who showed an interaction between age and stage in the relative hazard plots for 250 patients younger than 35 years of age and matched control subjects. Mitchell et al.¹²⁴ evaluated 398 patients with stage I to III cervical carcinoma treated with radiation therapy. Patients were divided into nonelderly (35 to 69 years of age; n = 338) and elderly (≥70 years of age; n = 60) groups. Comorbid conditions in the elderly resulted in diminished ability to undergo intracavitary brachytherapy. Although the 5-year actuarial disease-free and cause-specific survival (CSS) rates were comparable in the two groups, tumor recurrence and death from cervical cancer were more common beyond 5 years in the elderly group.

Race/Socioeconomic Status

Several authors noted a correlation between racial or socioeconomic characteristics of patients and outcome of therapy. Mundt et al.¹²⁵ examined factors affecting outcome in 316 African American and 94 white patients undergoing RT for cervical cancer. With a median follow-up of 72.4 months, African Americans had a trend toward poorer 8-year cause-specific survival rates (47.9% vs. 60.6%; p = .10) compared with white patients. Factors correlating with poor outcome, including lower hemoglobin (Hb) levels during RT (p = .001), lower median income (p = .001), and less frequent intracavitary brachytherapy (p = .09), were more likely to be present in the African American group. Multivariate analysis demonstrated that race was not an independent prognostic factor after controlling for differences in patient, tumor, and treatment factors. In a report on 452 white and 124 African American women with stage II or III cancer of the cervix treated with RT alone, Grigsby et al.,¹²⁶ observed 5-year CSS rates for stage II of 66% and 61% (p = .56) for those with stage II and of 38% and 47% (p = 0.34) for those with stage III disease, respectively. Overall survival rates for stage II for the two racial groups were different (60% and 51%, respectively; p = .02) and may be related to non–cancer-related comorbidity factors.

Brooks et al.¹²⁷ evaluated 1,009 patients with invasive carcinoma of the cervix: 606 white, 354 African American, and 5% “other” races. African Americans were more likely to have Medicaid or to be uninsured (44% vs. 23%; p = .001) and were more likely to be admitted for an emergency or for a cancer-related complication (p = .036), to have comorbid illness (p = .001), to be admitted for a transfusion (p = .01), or to be treated with radiation rather than surgery (p = .001). Racial differences existed in patterns of admission, type of therapy, and severity of illness.

Moreover, in an analysis of the 1994 Patterns of Care study of 471 cases of squamous cell carcinoma treated in the United States and a randomly selected 215 additional cases from 17 institutions that admitted >40% minority patients, women who lived in low-income neighborhoods, who had only Medicaid coverage, or who were treated at large academic or minority-rich institutions tended to have a poorer initial performance status, higher-stage or bulky central tumor, and a lower pretreatment hemoglobin level.¹²⁸

General Medical Factors

Anemia and Tumor Hypoxia

Although stage, tumor volume, histologic type of the lesion, and vascular or lymphatic invasion are known to affect the prognosis of patients with cervical carcinoma, hemoglobin levels may also contribute to patient prognosis. Many radiation oncologists routinely administer red blood cell transfusions (RBCTs) to correct anemia before treatment with radiation therapy. This may have a generally favorable effect on the patient’s sense of well-being and energy level, and an impact on tumor radiosensitivity. Typically patients receive transfusion to maintain hemoglobin levels >12 to 12.5 g/dL.

Hirst¹²⁹ emphasized that in animal tumor models the opportunity to affect radiosensitivity by blood transfusion is transient. Blood transfusion is in general beneficial to the anemic patient with cancer, but it must be given as soon as possible before the first radiation dose to maximize its effects. Accounting for both the normal pulmonary and peripheral circulation and parallel flow through tumor tissue, Kavanagh et al.¹³⁰ calculated that decreasing hemoglobin–oxygen affinity should render a quantitatively greater decrease in radiobiologically hypoxic regions than what has been measured after the use of transfusions alone.¹³¹

Investigators have reported worse outcomes for patients whose tumors have either a median partial pressure of oxygen (PO₂) level, measured using polarographic needle electrodes for direct tumor-tissue oxygen measurements, of <10 mm Hg,¹³² or a high percentage of PO₂ measurements <5 mm Hg.¹³³^,¹³⁴ Comparisons of intratumoral oxygen measurements before and after external-beam radiation therapy have usually indicated a trend toward improved oxygenation after radiation therapy,¹³⁵^,¹³⁶ but the significance of posttreatment measurements is unclear.¹³⁷ Hypoxic tumors are more likely to recur locoregionally than well-oxygenated tumors regardless of whether surgery or radiation therapy is the primary local treatment.¹³²

Haensgen et al.¹³⁸ analyzed 70 patients with stage IIB to IVA cervical cancer treated with EBRT and brachytherapy. In vivo oxygenation was measured with an Eppendorf probe, and patient hemoglobin levels were recorded. Patients with a hemoglobin level of <11 g/dL had a 3-year survival rate of 27%, compared with 62% for those with a hemoglobin level of ≥11 g/dL (p = .006). Combining hypoxia and tp53 allowed stratification of subgroups with differing 3-year survival rates: 79% for tp53 (n = 10) and 47% for tp53 without hypoxia (n = 44).

A randomized trial reported by Bush¹³⁹ on 132 patients with stage IIB to III cervical cancer required the control arm to receive transfusions only if the hemoglobin level dropped to <10 g/dL, whereas the experimental arm had to maintain the hemoglobin level ≥12.5 g/dL. The results suggested an improved outcome for patients in the experimental arm who received transfusion; however, there was not a statistically significant difference in outcome between treatment arms when compared using an intent-to-treat analysis.¹⁴⁰ Second, the randomization was not stratified according to the potentially confounding influence of tumor size. Finally, the thresholds for transfusion were based on anemia during therapy, not the initial hemoglobin. Thomas¹⁴¹ reviewed the Canadian experience and found that in 605 eligible patients with cervical cancer, 25% received blood transfusions, most frequently when Hb was <100 g/L. On multivariate analysis, baseline Hb was not a significant prognostic factor, but average weekly nadir during radiation therapy was significant, with those with values >120 g/L having lower incidences of local relapse and distant metastasis and a better 5-year survival rate.

Dunst et al.¹⁴² showed that pretreatment anemia had a significant impact on 3-year relapse rates (6% in 20 patients with Hb of >13 g/dL, 15% in 47 with Hb between 11 and 13 g/dL, and 67% in 20 with Hb of <11 g/dL). The 3-year survival rate was 38% in patients with poorly oxygenated tumors, compared to 68% in patients with higher Po₂ (p = .02). Munstedt et al.,¹⁴³ in a study of 183 patients who received adjuvant RT after radical surgery, noted that those with Hb of <11 g/dL had lower recurrence-free and overall survival rates, primarily in a subgroup of women who had inadequate surgery.

In a retrospective review of >600 patients treated at seven different cancer centers in Canada, Grogan et al.¹⁴⁴ observed that the patients who maintained an average weekly hemoglobin level of >12 g/dL with or without transfusions had a significantly higher 5-year survival rate than patients with lower average weekly hemoglobin levels, regardless of the hemoglobin at presentation.

Kapp et al.¹⁴⁵ reported on 204 patients who received RBCT during RT when Hb level was <11 g/dL. Patients whose Hb was corrected (18.5%) had outcomes similar to those of nontransfused patients. However, nonresponders to RBCT had decreased tumor control and survival rates. Vaupel et al.,¹⁴⁶ in a review of published data, concluded that maximum oxygenation of tumors is expected with Hb in the range of 12 to 14 g/dL for women and that higher Hb levels may not be better.

Recombinant human erythropoietin is not routinely recommended as an alternative means of sustaining or raising hemoglobin levels during radiation therapy. Thrombotic complications¹⁴⁷ and the lack of any survival benefit¹⁴⁸mitigate the utility of this as a therapeutic intervention.

Other Medical Factors

Jenkin and Stryker¹⁴⁹ observed a higher incidence of pelvic recurrences and complications in patients with arterial hypertension (diastolic pressure of >110 mm Hg). Kapp and Lawrence¹⁵⁰ reported on 398 patients; patients with temperatures of >101°F had a higher incidence of distant metastases and a lower survival rate. In patients with cervical cancer screened for HIV and treated with RT, Campbell et al.¹⁵¹ observed a 4.2% positive HIV rate. These patients had more-advanced tumors. The duration of remission was shorter than in the HIV-negative group. RT had no effect on the HIV titers. Women who are HIV positive or have acquired immunodeficiency syndrome associated with in situ or invasive carcinoma of the cervix are at a higher risk for tumor recurrence after treatment and death as a consequence of the malignant process.¹⁵²^,¹⁵³

Evidence continues to mount that increasing levels of plasma micronutrients are associated with a decreasing risk of cervical cancer. Increasing serum lycopene and α- and γ-tocopheral levels and higher intake of dark green and deep yellow vegetables and fruit were significantly inversely associated with cancer.¹⁵⁴^–¹⁵⁶ Women should be counseled to eat a well-balanced diet, particularly those at high risk for developing cervical cancer.

Tumor Factors

HPV Subtype

HPV 16 and 18 are the most frequent HPV subtypes worldwide. Studies have reported a higher risk of lymph node and other distant metastases with HPV 18 compared to HPV 16.¹⁵⁷^,¹⁵⁸ Wang et al.¹⁵⁹ studied 1,010 patients with cervical cancer after radiotherapy between 1993 and 2000. The HPV genotypes were determined by a gene chip that can detect 38 types of HPV. A total of 25 genotypes of HPV were detected in 992 specimens, of which 8 types that predominated were HPV16, 58, 18, 33, 52, 39, 31, and 45. Two high-risk HPV species were identified: α-7 (HPV18, 39, 45) and α-9 (HPV16, 31, 33, 52, 58). Risk groups determined included the high-risk group, which consisted of patients without HPV infection or those infected with the α-7 species only. The medium-risk group included patients coinfected with the α-7 and α-9 species.

Tumor Volume

There is a close correlation between depth of stromal invasion, tumor size, and incidence of parametrial and pelvic node metastases and survival in patients with cervical cancer.¹⁶⁰^,¹⁶¹ In a study of women treated with radical hysterectomy, the 5-year disease-free survival rate was 90% in 181 patients with stage IB1 (≤4 cm) and 72.8% in 48 patients with stage IB2 disease (p = .02).¹⁶²

Toita et al.,¹⁶³ in a review of 70 patients with stage IIB and IIIB carcinoma of the uterine cervix treated with RT alone, reported no significant correlation of 5-year DFS with size of the cervical tumor <60 mm (70% to 85%); however, in patients with tumor ≥60 mm, the 5-year DFS was 28.6%. Piver and Chung¹⁶⁴ showed a greater incidence of lymphatic and distant metastasis and lower survival rates in patients with bulky and barrel-shaped stage IB and IIA tumors treated by radical hysterectomy. In addition, a higher incidence of pelvic recurrences and distant metastases and a decreased survival rate were reported by Fletcher,¹⁶⁵ Eifel et al.,¹⁶⁶ and Perez et al.¹⁶⁷ in patients with larger tumors treated with irradiation. In stages IB and IIA, higher radiation doses improved local tumor control.¹⁶⁸^,¹⁶⁹

Furthermore, Leveque et al.,¹⁷⁰ in patients with stage I to II adenocarcinoma of the cervix treated with RT alone or combined with radical surgery, noted that FIGO stage and pelvic node involvement were the most important parameters influencing overall survival. Silver et al.,¹⁷¹ in 93 patients with stage I adenocarcinoma of the cervix, described patient age and tumor grade as significant prognostic variables for survival (p < .01 and .01, respectively); tumor size was significant (p < .01) for survival and progression-free survival.

In contrast, Grigsby et al.,¹⁷² in patients with stage IB and IIA carcinoma of the cervix treated with preoperative irradiation and radical or conservative hysterectomy, observed no correlation of tumor volume with outcome. The 5-year pelvic failure rates for stage IB were 16% for tumors <3 cm and 9% for larger tumors (p = .90) and for stage IIA were 22% for tumors <3 or >3 cm (p = .75).

Several retrospective studies demonstrated decreased survival and a greater incidence of distant metastases in patients with endometrial extension of a primary cervical carcinoma (endometrial stromal invasion or replacement of the endometrium by tumor only).³⁶ Grimard et al.,¹⁷³ on the other hand, confirmed these findings only in patients with stage IB tumors but not in more advanced stages. Similar findings were noted by Noguchi et al.¹⁷⁴ Patients without uterine body invasion had a 5-year survival rate of 92.4%, compared with 53.8% in patients with invasion.

Perez et al.,¹⁶⁹ in an update of a previous report,¹⁶⁷ reviewed 1,499 patients (stages IA to IVA) treated with definitive irradiation (combination of external-beam irradiation plus two intracavitary insertions to deliver doses of 70 to 90 Gy to point A). There was a close correlation between tumor size and extent and pelvic tumor control, incidence of distant metastasis, and disease-free survival in all stages.

Margin Status After Radical Hysterectomy

In addition to the known high risk factors of positive margins, positive parametrial spread, and/or positive lymph nodes and the intermediate risk factors of depth of stromal invasion, lymphovascular invasion, and tumor size, small series have indicated the significance of close margin status.¹⁷⁵^,¹⁷⁶ Viswanathan et al.¹⁷⁷ studied 284 patients after radical hysterectomy (RH). The crude rates for any recurrence were 11%, 20%, and 38% for patients with negative (≥1 cm), close (>0 and <1 cm), and positive margins, respectively. Postoperative RT decreased the rate of local recurrence (LR) from 10% to 0% for negative, 17% to 0% for close, and 50% to 25% for positive margins. The significant predictors of decreased relapse-free survival on univariate analysis were the depth of tumor invasion (hazard ratio [HR] = 2.14/cm increase, p = .007), positive margins (HR = 3.92, p = .02), tumor size (HR = 1.3/cm increase, p = .02), lymphovascular invasion (HR = 2.19, p = .03), and margin status (HR = 0.002/increasing millimeter from cancer for those with close margins, p = .03).

Histologic Grade

Most reports have shown no significant correlation of survival or tumor behavior with the degree of differentiation of squamous cell carcinoma or adenocarcinoma of the cervix.¹⁷⁸^–¹⁸⁰ Alfsen et al.¹⁷⁸ analyzed 417 adenocarcinomas and 88 other non–squamous cell carcinomas of the cervix; on multivariate analysis, small-cell histology, corpus infiltration, vascular invasion, and positive lymph nodes were significant prognostic variables. Although Reagan and Fu¹⁸¹ demonstrated prognostic value of histologic differentiation in patients treated with irradiation, Crissman et al.¹⁸² failed to observe a correlation between histologic parameters and patient survival. In the era of chemoradiation, Monk et al.¹⁸³ showed no significant impact of histology or grade on survival in postoperative cervical cancer patients with other high-risk features.

Treatment Duration

In patients treated with radiation therapy, overall treatment time should be as short as possible, and any planned or unplanned interruptions or delays should be avoided. Timely integration of external-beam and intracavitary irradiation in patients with carcinoma of the uterine cervix is an important factor in improving pelvic tumor control (Fig. 69.8).¹⁸⁴ Several studies described lower pelvic tumor control and survival rates in invasive carcinoma of the uterine cervix when the overall time in a course of irradiation is prolonged.¹²⁰^,¹⁸⁵^–¹⁸⁷ Chatani et al.,¹⁸⁸ in 216 patients with stage IIB to III cervical carcinoma treated with a combination of external-beam and HDR brachytherapy, noted that overall treatment time was the most highly significant factor for local tumor control in multivariate analysis (p = .0005). For relapse-free survival, stage classification (p = .0001), overall treatment time (p = .0035), and hemoglobin level (p = .0174) were the three most important prognostic factors; there was no relationship between treatment time and late complications.

Fyles et al.¹⁸⁵ reported approximately 1% loss of tumor control per day of prolongation of treatment time beyond 30 days in 830 patients with cervical carcinoma treated with irradiation alone. Lanciano et al.,¹⁸⁷ in an analysis of 837 patients with squamous cell carcinoma of the cervix from the Patterns of Care Study who were treated with irradiation and received doses of 66 Gy or greater, described a 4-year actuarial in-field recurrence increase from 6% to 20% when total treatment time increased from 6 weeks or fewer to 10 weeks (p = .0001); this translated into significantly decreased survival. Girinsky et al.,¹⁸⁶ in 386 patients with stage IIB or III carcinoma of the cervix, also observed that the 10-year local recurrence–free survival rate decreased when overall treatment time exceeded 52 days. A 1.1% loss of pelvic tumor control per day was also observed in their regression analysis.

Perez et al.,¹⁸⁹ in 1,330 patients treated with definitive irradiation, noted a major impact of prolongation of treatment time on pelvic tumor control in stages IB, IIA, and IIB. In stage III, although the rate of pelvic failure was higher with prolongation of treatment time, the difference was not statistically significant. There was also a strong correlation between overall treatment time and survival. Regression analysis confirmed previous reports that prolongation of overall treatment time resulted in an increased failure rate of 0.59% per day in stage IB and IIA and 0.86% per day in stage IIB disease. Performance of all intracavitary insertions within 4.5 weeks from initiation of irradiation yielded lower pelvic failure rates (8.8% vs. 18% in stage IIB tumors; p ≤ .01).

FIGURE 69.8. Pelvic failure rate correlated with length of treatment in stages IB (A) and IIA (B) carcinoma of the uterine cervix. (From Perez CA, Grigsby PW, Castro-Vita H, et al. Carcinoma of the uterine cervix: I. Impact of prolongation of treatment time and timing of brachytherapy on outcome of radiation therapy. Int J Radiat Oncol Biol Phys1995;32:1275–1288; with permission from Elsevier.)

Biomarkers

Several studies assessed various biologic markers to determine whether they are prognostic; however, the majority suffered from not having multivariate analyses to determine whether these may be valid independent factors. Noordhuis et al.,¹⁹⁰ in a systematic review of 42 studies with 82 cell-biologic markers, reported that on univariate analysis, 34 biologic markers showed a relation with survival, 27 of which were independently associated with survival.

Angiogenesis and Hypoxia

Angiogenesis—the formation of new blood vessels—relies on the presence of proangiogenic growth factors, such as vascular endothelial growth factor (VEGF). As new blood vessels form, they deliver nutrients and oxygen to the cancerous cells. As tumors expand, the newly formed blood vessels may no longer reach the central portions of the tumor, and a hypoxic core develops. Hypoxia-inducible factor (HIF-1α) and HIF-2α regulate the response to hypoxic stress; HIF-1α but not HIF-2α has been associated with poor disease-free survival.¹⁹¹^–¹⁹⁴ The HIF-2α/CD68 ratio was correlated with poor disease-free survival.¹⁹⁴ One study found that VEGF decreased overall survival.¹⁹⁵^,¹⁹⁶Loncaster et al.,¹⁹⁵ in a retrospective study of 100 patients, found that VEGF expression in tumor biopsies in advanced carcinoma of the cervix was associated with a poor prognosis. Level of thymidine phosphorylase,¹⁹⁶ which increases hypoxic conditions, similarly was associated with poor outcomes. Nitric oxide synthase¹⁹⁷ and carbonic anhydrase (CA) may be prognostic for a poor outcome. In particular, CA9 is related to poor disease-free survival.¹⁹⁸^,¹⁹⁹ CA12, in contrast, was related to metastasis-free survival.²⁰⁰

Microvessel count is higher in patients with cervical neoplasia than in control patients and higher in patients who experience posttreatment recurrences. Obermair et al.,²⁰¹ in 166 patients with stage IB cervical cancer, observed a 5-year survival rate of 89.7% in 102 patients whose tumors had a microvessel density of 20 per field or less and 63% in 64 patients whose tumors had a microvessel density of >20 per field (log rank p < .0001). In a multivariate Cox model, microvessel density, lymph node involvement, tumor size, and the application of radiation therapy were independent prognostic factors for survival. Similar findings were reported by Cooper et al.²⁰²

Flow Cytometry Studies on DNA and Growth Fraction

Some authors noted no significant difference in recurrence rates between patients with diploid or aneuploid tumors. Kristensen et al.,²⁰³ in a study 465 patients with invasive carcinoma of the uterine cervix on whom DNA index and S-phase fraction studies were performed, observed that neither ploidy level nor S-phase fraction had prognostic significance. Others²⁰⁴ noted more relapses in tumors with an S-phase rate of 20% or greater.

Apoptosis

Whether apoptotic markers might be of importance in cervical cancer is unclear, given heterogeneity in the data. Morphologic studies have been negative, but some studies evaluating apoptotic protein expression such as that of Bcl-2 and p63 show association with poor disease-free survival.²⁰⁵^,²⁰⁶

Ohno et al.²⁰⁷ studied 20 patients before and after administration of 9 Gy and found an increase in apoptotic cell index and Bax protein. Wootipoom et al.,²⁰⁵ in 174 patients with cervical cancer, noted Bax, Bcl-2, and p53 expression in 68.4%, 25.9%, and 77.6% of the cases, respectively. Bax expression was associated with better survival, whereas Bcl-2 expression was associated with poor survival. Jain et al.²⁰⁸ also found that neither Bcl-2 nor p53 expression was an independent predictor of outcome in locally advanced cervical cancer.

The p53 gene controls entry into the S phase of the cell cycle. Mukherjee et al.²⁰⁹ analyzed radioresistant cervical cancer cases and found that 15% had positivity for Bcl-2 and p21 proteins and 34% showed mutant p53 protein. None of the radiosensitive tumors were positive for these proteins. Seventy-five percent of the radiosensitive tumors were positive for the Bax antibody, whereas 81% of the radioresistant tumors were negative for Bax (p < .01). Kainz et al.,²¹⁰ in a study of 109 surgically treated patients, and Ebara et al.,²¹¹ in 46 patients with stage IIIB squamous cell carcinoma of the cervix treated with RT alone, noted no significant difference in outcome when correlated with p53 protein expression.

Cell Cycle and Cellular Oncogenes

Cerciello et al.,²¹² in 40 patients with stage IIA to IIIB cervix cancer treated with RT without chemotherapy, obtained biopsies before and after five fractions of RT. They observed significant changes in the cell cycle of cervical cancer, indicating intact G2/M checkpoint function, leading to the expectation that targeting compounds interfering with G2/M transition may enhance the effect of irradiation on cervix cancer.

In patients with carcinoma of the uterine cervix treated with irradiation, Tsang et al.,²¹³ observed that the most significant factors for disease-free survival were large tumor size (p = .01), low hemoglobin (p = .01), labeling index (LI) flow cytometry (disease-free survival, 67% for LI < 7%; 33% for LI ≥ 7%; p = .03), and potential doubling time (T_pot; 66% for T_pot > 5 days, 35% for T_pot ≤ 5 days; p = .04). For small tumors (<6 cm in diameter), either a high LI (>7%) or a high apoptotic index (>1%) was associated with poorer disease-free survival. West et al.²¹⁴ evaluated the intrinsic radiosensitivity of 145 tumor biopsies from patients with cervical carcinoma (in vitro survival fraction at 2 Gy using a clonogenic assay). Diploid tumors tended to be more radioresistant than aneuploid tumors (p = .07).

The p27/Kip1 gene inhibits a variety of cyclin-dependent kinase complexes and regulates cell growth. Oka et al.²¹⁵ studied 202 biopsy specimens obtained from 77 patients with squamous cell carcinoma of the cervix before and during RT for expression of p27 and p53 proteins. A high p27 LI before radiation therapy was associated significantly with good disease-free and metastasis-free survival rates. A high p53 LI before irradiation was associated with poor overall survival.

Both specific point mutations and amplification of ras genes have been noted. Overexpression of the ras gene p21 product is associated with a poor prognosis and increased frequency of lymph node involvement.²¹⁶ Although loss of heterozygosity of the c-Ha-ras gene in squamous cell carcinomas was not associated with advanced-stage disease, mutations were associated with a poor prognosis. In contrast, mutations of the Ki-ras gene have been detected in a small percentage of cervical adenocarcinomas but have not been significantly associated with stage, grade, or survival.²¹⁷^,²¹⁸

The c-myc oncogene is amplified from 3 to 30 times in approximately 20% of squamous cell carcinomas and is more frequent in high-stage compared with low-stage tumors. Overexpression of c-myc has been associated with a worse clinical outcome.²¹⁹^,²²⁰

Gadd45 belongs to the class II family of DNA damage-inducible genes, and its role in DNA repair has been proven in many experimental models. Santucci et al.,²²¹ in 14 patients with cervical cancer, found a correlation between the lack of gadd45 induction and a clinical response to irradiation (both local tumor control and disease-free survival) when a dose ranging from 18 to 25 Gy was delivered to the pelvis.

CD 34 is an antigen present in hemopoietic progenitor cells and is a sensitive marker for endothelial cells. In 62 patients with cervical cancer evaluated by Vieira et al.,²²² CD 34 reactivity and higher microvessel density were associated with squamous cell carcinoma. CD 109 is a cell surface protein that was found to be expressed in cervical cancer more than in endometrial adenocarcinoma.²²³

Cytokeratin Markers and the Epidermal Growth Factor Receptor Pathway

Altered expression of c-ercB-2 (HER2) protein was shown to have prognostic significance in adenocarcinoma but not in squamous cell carcinoma of the cervix.²²⁴ HER1, as well as coexpression of epidermal growth factor receptor and HER2, has been associated with poor disease-free survival.²²⁵ PTEN mutations have also been associated with poor prognosis.²²⁶

In 80 patients with carcinoma of the cervix, expression of cytokeratin 10 and 13 and involucrin was found in 24%, 64%, and 53%, respectively.²²⁷ There was no difference in the expression of cytokeratin or involucrin between patients with positive or negative lymph nodes, although in the lymph node–positive group, survival was higher in patients lacking cytokeratin 13 expression (p = .02).

Squamous Cell Carcinoma Antigen and Carcinoembryonic Antigen

Tsai et al.,²²⁸ in 117 patients with adenocarcinoma of the cervix, 28 of whom had preoperative carcinoembryonic antigen (CEA) levels of >5 ng/mL, noted a correlation with larger tumor size, deeper cervical invasion, and lymphovascular invasion (p < .001). A Spanish study of 96 patients with invasive carcinoma of the cervix and 7 with intraepithelial neoplasia showed elevated CEA levels in 33%, CA 19.9 in 32%, and CA 125 in 21.5% of patients.²²⁹ Specificity for each tumor marker was 98%. Increased CEA and CA 19.9 levels were found with more advanced stages of the disease and in patients with adenocarcinoma compared with squamous cell carcinoma. At follow-up, all cases of progressive tumor or recurrence were detected by elevation of one of the three antigens. Specificity during follow-up was 92% for CEA and CA 125 and 92.6% for CA 19.9.

In a study of 272 patients with invasive carcinoma of the cervix with 1,053 samples, Bolli et al.²³⁰ noted an elevation of squamous cell carcinoma antigen (SCC-Ag) before treatment in 53% of 103 patients, increasing with advancing tumor stage at diagnosis. In 70 patients with recurrent tumor, 81% had elevated SCC-Ag. Ngan et al.²³¹ also identified elevation of serum SCC-Ag in 62% of 308 women with carcinoma of the cervix. Posttreatment SCC-Ag levels were raised in 69 patients (22.4%), and this was associated with a <5% 5-year survival rate, in contrast to 87% in women with normal SCC-Ag levels.

Hong et al.,²³² in 401 patients with stage I to IV squamous cell carcinoma of the cervix treated with RT, noted that the preirradiation SCC-Ag level strongly correlated with disease stage. A persistently elevated SCC-Ag level 3 months after RT was a stronger predictor for treatment failure than residual induration by pelvic examination, and it was associated with a higher incidence of distant metastasis.

Similarly, Micke et al.,²³³ in 141 patients with cervical cancer treated with RT, noted that the pretherapy serum level of SCC-Ag was elevated in 72% (>2 ng/mL). Patients with a SCC-Ag of <7.2 U/mL had better tumor response than those with higher levels. After RT, 98% of patients in complete remission and 87% of those in partial remission had a serum level below the cutoff. In recurrent tumors, 82% of patients had a significant increase in serum levels before clinical manifestation of relapse (≤0.001). Hong et al.,²³⁴ in 1,031 patients with squamous cell cervical cancer treated with RT with or without chemotherapy, noted that independent risk factors for local relapse were advanced stage and age <45 years; 5-year local relapse-free survival was higher (90%) if squamous cell carcinoma antigen was <2. This antigen may be a useful marker in the prognosis of patients with carcinoma of the uterine cervix. Huang et al.²³⁵^,²³⁶ noted that SCC-Ag and CEA were predictive of para-aortic node failure.

Epstein-Barr Virus, Transforming Growth Factor,

β-Integrin, and Other Markers

Activity of Epstein-Barr virus antigen–specific killer T cells and shedding of Epstein-Barr virus were evaluated in 55 patients with carcinoma of the cervix.²³⁷ Activity was decreased in patients with cervical carcinoma compared with control patients; it became increasingly lower as the clinical stage of the disease advanced, and activity after treatment was clearly related to patient survival. These data may indicate an imbalance in local immunity against viral infection and impairment of T-cell immunity in patients with advanced cervical carcinoma.

In 79 patients undergoing radiation therapy for carcinoma of the cervix, pretreatment transforming growth factor-β₁ (TGF-β₁) levels were a significant prognostic factor for survival and local tumor control. There were weak significant correlations of TGF-β₁levels with disease stage and the levels of circulating tumor markers (CA 125).²³⁸ Hazelbag et al.²³⁹ also assessed TGF-β₁ and plasminogen activator inhibitor (PAI-1) expression in 108 specimens of cervical carcinoma and noted that TGF was not associated with worse prognosis, whereas PAI-1 was.

Gruber et al.,²⁴⁰ in biopsies of 82 patients with cervical cancer, found that β₃-integrin was expressed in 50 (61%) and correlated it with higher incidence of locoregional recurrences and decreased survival.

Cyclooxygenase-2

Gaffney et al.,²⁴¹ in 24 patients with carcinoma of the cervix treated with RT, observed that 5-year overall survival rates for tumors with low versus high COX-2 values were 75% and 35%, respectively (p = .021). COX-2 staining intensity was found to correlate positively with tumor size (p = .022).

Kim et al.²⁴² screened 84 patients with stage IIB squamous cell and 21 with adenocarcinoma cervical cancer and found COX-2 expression more frequently in the adenocarcinoma group (57% vs. 24%; p = .007). The 5-year survival rate was 83% for COX-2–negative and 57% for COX-2–positive patients, regardless of histologic subtype (p = .001). Pyo et al.²⁴³ also showed that expression of COX-2 and coexpression of COX-2 and thymidine phosphorylase were correlated with high locoregional recurrence and lower survival. Moreover, Kang et al.,²⁴⁴ in 84 patients with cervix adenocarcinoma, observed a higher incidence of lymph node metastasis and decreased survival with elevated expression of COX-2.

Hormonal Receptors

Suzuki et al.²⁴⁵ investigated the expression of estrogen receptors and progesterone receptors (PgRs) in biopsy specimens from cervical tumors before RT in 44 patients with cervical adenocarcinoma and 22 with adenosquamous cell carcinomas. Staining for estrogen receptors or PgR was positive in 12 patients (19%). The estrogen receptor status did not correlate with the local tumor control, or disease-free, or cause-specific survival. The disease-free survival rate of PgR-positive patients was significantly higher than that of PgR-negative patients (p = .044), but PgR status was not statistically significant in relation to 5-year cause-specific survival or local tumor control.

FIGURE 69.9. Risk of developing acute ovarian failure, defined as ovarian failure within 5 years, stratified by age and radiation dose to the ovary. (From Wo JY, Viswanathan AN. Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys2009;73:1304–1312; with permission from Elsevier.)

TECHNIQUES USED FOR TREATMENT

Preinvasive Disease

Patients with CIN may be candidates for observation or treatment. CIN1-2 has a spontaneous regression rate in 1 to 3 years of >50%,²⁴⁶ and therefore observation may be an appropriate course. For patients with persistent dysplasia, cryotherapy has a very low complication rate and is highly successful but may be less effective than laser ablation for high-grade dysplasia.²⁴⁷ Cold knife conization (CKC) may be used for diagnostic and therapeutic intent, with side effects of bleeding, cellulitis, cervical stenosis, or loss of cervical competence. Loop electrosurgical excision procedure (LEEP) has become popular, although bleeding and stenosis may occur; pregnancy outcomes may be better with LEEP than with CKC.²⁴⁸^–²⁵⁰

Invasive Disease

Surgical Techniques

Simple Conization

In patients with minimal invasion, no parametrial involvement, and small tumor size, simple conization with lymphadenectomy has been reported. Although only 36 patients were studied, after a median follow-up of 66 months, only 1 pelvic nodal relapse was observed.²⁵¹

Radical Trachelectomy

Described in the 1960s,²⁵² trachelectomy entails removal of the cervix entirely. Radical trachelectomy also removes the parametrial tissue. As a means of fertility preservation in early-stage cervical-cancer patients,²⁵³ trachelectomy should be combined with preoperative PET imaging to confirm no nodal involvement and with MRI to confirm no endocervical canal extension of tumor into the uterus.²⁵⁴ A lapraroscopic lymphadenectomy should accompany the trachelectomy to confirm no nodal involvement. A nonabsorbable cerclage is placed around the uterine isthmus. Radical abdominal trachelectomy also may result in successful fertility preservation.²⁵⁵ Selection criteria for a trachelectomy include those patients requesting fertility sparing surgery, age <40 years, stage IA1, IA2, or IB1 with no nodal involvement detected on MRI or PET scan, squamous cell or adenocarcinoma with a lesion <2 cm, no lymphovascular invasion on initial biopsy, and no upper endocervical involvement. The main site for recurrence is central pelvis (average 5% risk), at the cervico-uterine junction, or in the adjacent parametrial tissue.

Types of Hysterectomy

Several types of hysterectomy are used in the management of carcinoma of the uterine cervix (Table 69.7).²⁵⁶

Total (extrafascial) abdominal hysterectomy (class I) consists of removal of the cervix and adjacent tissues, as well as a small cuff of the upper vagina in a plane outside the pubocervical fascia. There is minimal disturbance of the ureters and the trigone of the bladder. This may be the surgical treatment of choice for stage IA1 cervical cancer.

The use of a radical hysterectomy for cervical cancer was first described by Wertheim in 1912.²⁵⁷ In a modified radical extended hysterectomy (class II), the cervix and upper vagina are removed, including paracervical tissues, and the ureters are dissected in the paracervical tunnel to their point of entry into the bladder. Because the ureters are unsheathed and retracted laterally, parametrial and paracervical tissue can be safely removed medial to the ureter. This operation is performed with a lymphadenectomy. This is the most common surgical approach selected for stage IA2 cervical cancer.

Radical abdominal hysterectomy (class III) with bilateral pelvic lymphadenectomy consists of a wider resection of the parametrial tissues to the pelvic wall, with dissection of the ureters and mobilization of the bladder, as well as of the rectum to allow for more extensive removal of tissues. This approach was described by Meigs in 1944.²⁵⁸ In addition, a vaginal cuff of at least 2 to 3 cm is always included in the procedure, as well as the uterosacral ligaments.²⁵⁶ A bilateral pelvic lymphadenectomy is usually carried out. This operation is often referred to as the Wertheim or Meigs procedure. The extended radical hysterectomy (class IV) includes complete dissection of the ureter from the vesicouterine ligament, sacrifice of the superior vesicle artery, and removal of the upper three-fourths of the vagina. Due to the high rate of fistula and significant morbidity, it is rarely used.²⁵⁶ In 2007, after a consensus conference in Japan, a new classification system was released based only on the lateral extent of the resection.²⁵⁹ Four levels of hysterectomy are described (A to D) and four levels of lymphadenectomy (1 to 4). The levels of lymph node dissection include the internal and external iliac (level 1), common iliac and presacral (level 2), aortic inframesenteric (level 3), and aortic infrarenal (level 4). The levels of primary tumor resection include the following:

Type A: Extrafascial hysterectomy, with minimum resection of the paracervix medial to the ureter and minimal vaginal resection <1 cm, without removal of the paracolpos.

Type B: Modified radical hysterectomy with partial resection of the vesicouterine and uterosacral ligaments, unroofing of the ureter, transection of the parametrial tissue at the ureter, and removal of at least 1 cm of the vagina. This type is divided into B1, without removal of paracervical lymph nodes, and B2, with removal of lateral paracervical nodes.

Type C: Classic radical hysterectomy, variant in which the entire uterosacral and vesicouterine ligaments are removed, 1.5 to 2 cm of vagina with paracolpos is excised, and neuronal preservation is critical.

Type D: Includes the complete radical hysterectomy and resects tissues to the pelvis sidewall, including the hypogastric (internal iliac) vessels, and exposes the sciatic nerve (type D1). Type D2 also removes the fascial and lateral muscles, called the laterally extended endopelvic resection.

Pelvic Exenteration

Pelvic exenteration has been used for en masse removal of the pelvic viscera for recurrent carcinoma of the cervix. Modern radiation therapy with concurrent chemotherapy results in high complete response rates and has made residual extensive disease a rare indication for exenteration. Patients with adjacent organ invasion are given a course of radical concurrent chemoradiation, followed by interstitial brachytherapy, with exenteration reserved for salvage.²⁶⁰^–²⁶² This operation, which is not done as a palliative procedure, consists of a radical hysterectomy, pelvic lymph-node dissection, and removal of the bladder (anterior exenteration), removal of the rectosigmoid colon (posterior exenteration), or both (total exenteration). The ileum or sigmoid has been the usual means of achieving urinary diversion. Because some patients have a pelvic recurrence after radiation therapy, the bowel is used for the urinary conduit. Proof that there is no fixation to the pelvic wall and no extension of disease beyond the pelvis is mandatory. Metastases outside the pelvis, including those in para-aortic lymph nodes or any viscera, are absolute contraindications to the procedure. Bilateral ureteral obstruction secondary to tumor is also a relative contraindication.²⁶³ Patients with sacroiliac or hip pain or leg edema rarely benefit from this procedure and should be excluded on a clinical basis.

TABLE 69.6 FIGO STAGING OF CARCINOMA OF THE UTERINE CERVIX

TABLE 69.7 TYPES OF ABDOMINAL HYSTERECTOMY

TABLE 69.8 CARCINOMA OF THE UTERINE CERVIX: SURVIVAL AFTER STAGING LAPAROTOMY

Pretreatment Surgical Nodal Assessment

Exploratory laparotomy and nodal staging to evaluate the presence of metastases to the pelvic or para-aortic nodes may provide diagnostic information but has not had a demonstrated impact on survival (Table 69.8). In a prospective evaluation of 290 patients with carcinoma of the cervix,²⁶⁴ para-aortic node metastases were found in 19 of 58 patients (32.8%) with clinical stage IIB and 19 of 61 (31.1%) with stage IIIB disease. A number of studies compared the significance of para-aortic nodal metastases with other clinical and surgical findings with regard to progression-free survival and overall survival.²⁶⁵ In 626 patients treated on GOG randomized studies, the relative risk associated with positive para-aortic nodes was 11.0 for time to recurrence and 6.2 for survival time. In addition to the significant increase in risk of regional relapses, patients with para-aortic nodal metastasis are more likely to have extrapelvic failure.²⁶⁶

Cosin et al.²⁶⁷ reviewed 266 patients with locally advanced cervical carcinoma who underwent extraperitoneal pelvic and para-aortic lymphadenectomy before RT. Patients were divided into four groups: group A had negative lymph nodes; B, resected, microscopic lymph node metastases; C, macroscopically positive lymph nodes that were resectable at the time of surgery; and D, unresectable lymph nodes. Lymph node metastases were detected in 50% of patients. All patients received pelvic external-beam radiotherapy (EBRT; pre–intensity-modulated radiation [IMRT] era) and brachytherapy; patients with lymph-node metastases received extended-field irradiation. Five- and 10-year disease-free survival rates were similar for all patients in groups B and C. All patients in group D recurred. There was a 10.5% incidence of severe radiation-related morbidity and a 1.1% incidence of treatment-related deaths.

The potential benefit of surgical nodal debulking followed by irradiation has been studied.²⁶⁸ Potish et al.²⁶⁹ noted that more than half of the patients with advanced cervical cancer with grossly positive pelvic nodes that were debulked survived, compared with none with unresectable lymph nodes, findings closely paralleling those of Inoue and Morita²⁷⁰; however, these studies pre-dated the ability to implement dose escalation with IMRT to the involved nodes. Nonetheless, surgical debulking of nodes decreases the dose of radiation required to these regions. The use of high-energy photon beams and limitation of the tumor dose to extended volumes in the para-aortic region for those with completely resected but positive nodes to 45 to 50 Gy decrease the probability of complications. IMRT also enhances the sparing of adjacent abdominal normal tissues.²⁷¹^,²⁷² However, if node dissection is not feasible or would result in a treatment delay, patients may successfully be managed with IMRT with dose escalation to approximately 60 to 65 Gy to the grossly enlarged lymph nodes.⁸⁰^,²⁷³^,²⁷⁴^,²⁷⁵

Complication risk may be high (Table 69.9), particularly when patients are treated with postresection RT. One study showed an 11.5% incidence of major primarily small-bowel complications with transperitoneal compared with 3.9% in the extraperitoneal lymphadenectomy group (p = .03).²⁷⁶ Transperitoneal lymphadenectomy should be avoided.²⁷⁷^,²⁷⁸

Due to a high rate of complications, preirradiation laparotomy was discontinued at the MD Anderson Cancer Center. The status of the lymph nodes is investigated with lymphangiography and verified when possible with percutaneous transabdominal needle biopsy. Wharton et al.²⁷⁹ reported on 120 patients who had preirradiation celiotomy; 16 had fatal complications, and 32 had major intestinal complications. Most patients with positive lymph nodes died with distant metastasis. More recently, PET/CT followed by biopsy may be a useful approach. In one series of 60 patients without evidence of para-aortic lymph node involvement on preoperative CT or MRI, patients underwent a preoperative PET/CT followed by surgery. Twenty-six patients had a negative PET/CT, of whom 3 (12%) had positive nodes pathologically. Of the 27 with positive pelvic but negative para-aortic nodes on PET/CT, 6 (22%) had pathologically positive para-aortic nodes, indicating a sensitivity of 36% and a specificity of 96%. In another study, 125 patients had a PET/CT followed by para-aortic lymphadenectomy.²⁸⁰ Seventeen percent had positive para-aortic metastases, 66% of whom had a negative PET/CT. The sensitivity and specificity of PET/CT were 33% and 94%, respectively. Morbidity of the surgery was 7%, and there was no delay in initiating chemoradiotherapy. A Cochrane overview of pretreatment surgical para-aortic lymph-node assessment in stage IB2-IVA cervical cancer identified one randomized trial of 61 women that favored CT or MRI over surgical staging.²⁸¹^,²⁸² Alternatively, para-aortic node sampling may be performed through a laparoscopic approach; the procedure is well tolerated, recovery is prompt, and yield is adequate.²⁸³^,²⁸⁴

Aside from para-aortic nodes, supraclavicular metastases may rarely be involved. Perez-Mesa and Spratt²⁸⁵ found no supraclavicular node metastasis in 73 consecutive patients with various stages of cervical carcinoma. Manetta et al.²⁸⁶ also did not detect scalene node metastasis in 24 patients with recurrent carcinoma of the cervix evaluated for exploration and possible pelvic exenteration. There is no indication for removal of the supraclavicular nodes.

TABLE 69.9 COMPLICATION RATE FOR PRETHERAPY SURGICAL STAGING

Sentinel Lymph Node Biopsy

Sentinel lymph node (SLN) studies show mixed results, with a 20% false-negative rate and a 50% incidence of other pelvic metastases.²⁸⁷ However, the method allows for aborting surgery and pursuing RT instead. Sentinel node biopsy in patients with cervical cancer is used in several institutions; a seven-center prospective study analyzed 139 patients and detected 454 sentinel lymph nodes. Intraoperative examination did not detect micrometastasis or isolated tumor cells. Other techniques, such as molecular assays, may improve SLN assessment in the future.²⁸⁸^,²⁸⁹ The SENTICOL study²⁹⁰ injected 145 stage IA1 to IB1 cervical-cancer patients with combined technetium-99 and Patent Blue. The sensitivity (92%) and lack of false-negative results were favorable, but SLN biopsy was reliable only when SLNs were detected bilaterally.

Ovarian Transposition

In premenopausal women, surgery and radiation may directly impact gonadal function. For women with early-stage cervical cancer who undergo a radical hysterectomy, ovarian function may be preserved. In patients who require postoperative radiation, transposition of ovarian tissue outside of the radiation field may help to preserve ovarian function, although even low doses to the ovaries may cause acute ovarian failure (Fig. 69.9). In women who require radical radiation to the uterus and ovarian tissue, counseling before treatment begins with a fertility expert in reproductive endocrinology may be of benefit if an intervention such as egg retrieval is desired. Care must be taken to ensure that any potential intervention does not delay the initiation of curative treatment. In addition, women with early-stage cervical cancer have an approximately 1% risk of ovarian metastasis with squamous cell carcinoma and 5% risk with adenocarcinoma. Therefore, women should be counseled on the potential risks of recurrence with ovarian preservation.²⁹¹

In a survey of 124 patients who had undergone radical hysterectomy and lymphadenectomy with ovarian transposition, 68 responders were premenopausal at the time of surgery. Six of 30 women (20%) with ovarian preservation experienced early hormonal failure (5 had one ovary, and 1 patient had both preserved).²⁹² Combined-modality therapy affects ovarian function more than operation alone.²⁹³ Anderson et al.²⁹⁴ noted that only 4 of 24 patients (17%) with ovarian transposition who received postoperative pelvic irradiation had continued ovarian function. Feeney et al.²⁹⁵ reported on 132 patients on whom lateral ovarian transposition was performed at the time of radical hysterectomy; 28 patients received postoperative pelvic irradiation. Fourteen of 28 patients (50%) who received pelvic irradiation had evidence of ovarian failure, in contrast to 3 of 104 patients (2.9%) on whom ovarian transposition was performed, without postoperative irradiation. Buekers et al.²⁹⁶ also evaluated ovarian function in 102 patients with cervical cancer, 83 of whom underwent radical hysterectomy and 19 of whom had a staging laparotomy, all with ovarian preservation (80 included ovarian transposition); 26 patients received postoperative radiation therapy. After ovarian transposition without RT, 98% of patients retained ovarian function for a mean of 126 months, with menopause at a mean age of 45.8 years. When ovarian transposition and RT were added, 41% retained ovarian function for a mean of 43 months and experienced menopause at a mean age of 36.6 years.

Morice et al.²⁹⁷ reported on 107 patients treated for cervical cancer with radical hysterectomy and lymphadenectomy, 104 of whom (98%) had ovarian transposition to the paracolic gutters performed. Preservation of ovarian function was achieved in 100% for patients treated exclusively by surgery, 90% for those treated by postoperative vaginal brachytherapy, and 60% for patients treated by postoperative EBRT and vaginal brachytherapy.

Ovarian transposition or oophoropexy has been performed using laparoscopy, achieving continued hormonal function in 68% (8 of 11) and 50% (3 of 6) of the patients.²⁹⁸ Mean follow-up was 8.5 years, and mean radiation absorbed dose to the displaced ovaries was 26 Gy. Stockle et al.²⁹⁹ performed laparoscopic lateral ovarian transposition during staging lymphadenectomy in 11 patients with carcinoma of the cervix treated with brachytherapy (11 cases), EBRT (9 cases), and chemotherapy (2 cases). Ovarian preservation was achieved in 30% of the cases. Age was the most predictive factor for ovarian function preservation. Pahisa et al.³⁰⁰ performed laparoscopic ovarian transposition on 29 FIGO stage IB1 cervical-cancer patients. After a mean follow-up of 44 months, ovarian function was preserved in 93% of the nonirradiated and 64% of the irradiated patients.

Radiation Therapy Techniques

Since the early 1900s, radiation has been used in the curative management of cervical cancer, with a combination of external-beam and brachytherapy resulting in the highest survival rates. Over the ensuing 100 years, treatment-planning techniques have evolved, as has the equipment used for treatment. Several methods have been developed to aid with conformality and normal-tissue sparing. External irradiation is used to treat the whole pelvis. Structures treated include the uterus and cervix or, in the postoperative cases, the tumor bed, the vagina, the parametrial tissue, and the pelvic lymph nodes, including the internal, external, and common iliac nodes. In selected cases the para-aortic lymph nodes may be treated. In patients with locally advanced disease, in addition to external-beam radiation, treatment of central disease (cervix, vagina, and medial parametria) relies heavily on dose given with intracavitary sources through brachytherapy. The techniques described apply, with some individualization, to most patients with locally advanced cervical carcinoma.

External-Beam Irradiation

External-beam treatments may be routinely administered to cervical cancer patients with stages IB2 to IVA in a curative fashion. Patients with stages IA to IB1 may be considered for external-beam treatment if they are deemed inoperable or prefer to avoid surgery. Patients with stage IVB disease may receive palliative radiation to the pelvis for selected indications such as to stop vaginal bleeding, relieve pain, or alleviate urethral obstruction from extrinsic compression. External-beam radiation covers the primary cervical tumor, treats any adjacent parametrial or uterosacral, uterine, or vaginal extension, and, most important, addresses microscopic disease present in pelvic lymph nodes. In treatment of invasive carcinoma of the uterine cervix, it is important to deliver adequate doses of irradiation not only to the primary tumor, but also to the pelvic lymph nodes to maximize tumor control.

The initiation of external-beam radiation typically precedes brachytherapy. Although brachytherapy may be interdigitated with external-beam treatment, based on the desire to minimize the duration of treatment, the brachytherapy dose to the normal tissues may be better optimized after maximal tumor shrinkage; therefore, many institutions prefer to wait until the completion of 45-Gy treatment before initiating brachytherapy for patients with large tumors.

Patient Positioning

Patients may be positioned in either the supine position for stability or the prone position on a belly board. The prone position aids in shifting small bowel out of the pelvis. In patients who have had a hysterectomy, small bowel may drop into the pelvic area. For those patients treated for cervical cancer with an intact cervix, the small bowel often lies superior to the uterus and above the pelvic brim, creating less need to shift the bowel out of the pelvis. For patients receiving IMRT, due to stability of the pelvis, the supine position is typically preferred with immobilization devices surrounding the pelvis to ensure minimal motion during treatment. IV contrast may be helpful to localize the pelvic vessels for contouring but is not routinely used in most centers. Oral contrast delineates the small bowel. Rectal contrast and placement of a Foley catheter for bladder contrast are not considered necessary in the majority of cases that use CT simulation because the outer wall of these normal-tissue structures can be contoured without contrast on CT.

Plain X-Ray Simulation

If CT is not available, simple plain film simulation may be performed. The standard plain radiographic simulation to the pelvis with x-rays, typically using opposed anterior–posterior:posterior–anterior (AP-PA) fields, results in comprehensive coverage of all pelvic regions. Due to the lack of visible soft-tissue detail, contrast may be placed using barium in the rectum, a vaginal tube in the vagina, and/or a wire marker over surgical scars. The superior border is set at the L4-5 interspace in order to cover the common iliac lymph nodes and the lateral borders 1.5 to 2 cm from the pelvic brim, and the inferior border covers at least the obturator foramen (Fig. 69.10). More commonly in patients with large tumors, the inferior border extends to the ischial tuberosities. When there is vaginal involvement, the entire length of this organ should be treated down to the introitus. It is very important to identify the distal extension of the tumor at the time of simulation by placing a radiopaque clip or bead on the vaginal wall or inserting a small fiducial marker in the vagina. When the tumor involves the distal half of the vagina, the portals should be modified to cover the inguinal lymph nodes because of the increased probability of metastases (see Fig. 69.2).

For the lateral field borders, in both postoperative and intact cervix settings, the posterior border must be set in such a way that the entire sacrum is covered because the uterosacral ligaments are at high risk for harboring microscopic extension. The uterosacral ligaments insert onto the sacrum, and therefore the posterior block should ensure coverage of the entire sacrum. The anterior border on the lateral field should be set at a vertical line anterior to the pubic symphysis, since the external iliac lymph nodes must be covered.

For patients with para-aortic nodal involvement, simple plain film simulation followed by AP-PA treatments to the para-aortic nodal chain may overdose the kidneys, spinal cord, and small bowel. Dose escalation to para-aortic nodes to approximately >45 Gy is not feasible with AP-PA fields, given potential bowel complications. The use of four fields, including AP-PA and two lateral fields, is implemented as an alternative to AP-PA alone as a way to reduce some of the dose to the anterior small bowel. Patients receive oral barium approximately 30 minutes before the simulation to ensure blockage of as much small bowel as feasible superiorly. The superior border covers the renal hilum, often at the T12-L1 interspace, and the inferior borders cover the obturator foramen, unless there is distal vaginal or inguinal node involvement. For the para-aortic portion of the field, the anterior border rests 2 cm in front of the vertebral body or enlarged nodes as contoured, and posteriorly the border bisects the mid-vertebral body. The pelvic portion mimics that described for the four-field pelvic setup. The use of lateral fields allows a decrease in dose to the small bowel, but care must be taken to include all structures of interest.³⁰¹^–³⁰³

Three-Dimensional Conformal Treatment Planning

CT simulation allows direct assessment of the pelvic vessels and by adjacent location the para-aortic and pelvic nodes. Oral contrast is beneficial to identify the small bowel. Cerrobend customized blocks or multileaf collimator blocking is used on each field to block the radiation to selected areas, including the skin, muscle, soft tissue, anterior small bowel, and portions of the anus and lower rectum (Fig. 69.11).

The superior border is set based on the CT-visualized bifurcation of the common iliac nodes into the external and internal iliac nodes, which may lie as high as the L3-4 interspace. If patients have positive pelvic nodes based on PET imaging, the superior border may be shifted to either the superior border of the common iliac nodes or the superior aspect of the renal hilum to treat the para-aortic nodes. In postoperative cases in which the patient has had an extensive surgical staging, the superior border may be reduced to the L5-S1 interspace. Similar to plain x-ray simulation, in patients with vaginal involvement, the inferior border is extended to cover 2 cm below the lowest extent of disease, which may lie in the vulvar tissue, and in such cases the inguinal lymph nodes are treated, resulting in a wider AP field.

On the lateral fields, the anterior border covers the front of the pubic symphysis. Bonin et al.,³⁰⁴ in a review of 22 patients on whom detailed anatomic mapping of the anatomy of the pelvic lymph nodes was carried out by lymphangiography, concluded that if the criteria for adequacy of standard pelvic fields as defined in prior clinical trials were applied (anteroposterior: 1.5-cm margin on the pelvic rim; lateral field anterior edge is a vertical line anterior to the pubic symphysis and posterior border), 10 patients (45%) would have had inadequate nodal coverage in the irradiation fields. The incompletely irradiated lymph nodes were in the lowest lateral external iliac group. However, CT simulation with contouring may prevent omission of these nodes.

For the lateral borders in postoperative and intact cervix cases, posterior coverage of the entire sacral hollow is imperative. Zunino et al.³⁰⁵ reviewed the appropriateness of radiation therapy box technique for cancer of the cervix in 35 sagittal MRIs and 10 lymphangiograms. If the posterior border were to be placed at the S2-3 interspace, for 50% of the patients with FIGO IB and in 67% with stage IIA disease, the posterior border of the lateral field would not adequately encompass the planning target volume (PTV). In stage IIB, the posterior border was inadequate in eight patients (42%). In patients with stage IIB and IVA disease, the PTV was not encompassed. Furthermore, Knocke et al.³⁰⁶ used standard simulator planning guided by bony landmarks for pelvic irradiation in 20 patients with primary cervical carcinoma, stages I to III, using a four-field box technique. After defining the PTV with a 3D planning system, they compared the field configuration of the simulator planning with a second one based on the defined PTV. They evaluated the ability of the PTV to encompass the treatment volume (International Commission on Radiation Units and Measurements [ICRU]). Planning by simulation resulted in 1 geographic miss, and in 10 more cases the coverage of the PTV by the treatment volume was inadequate.

Finlay et al.³⁰⁷ contoured pelvic blood vessels on CT scans as surrogates for lymph nodes in 43 patients and found this to be more accurate than bony landmarks for field delineation. In total, 95% of patients planned with conventional fields had inadequate coverage of some portion of lymph node coverage, whereas in 56% additional normal tissue was treated that did not require radiation. Therefore, most centers implement 3D simulation when feasible. Taylor et al.³⁰⁸ used MRI to outline the pelvic lymph nodes in 20 patients and noted that with margins of 10 mm, nodal coverage was 94% and with 15 mm, 99%; with a modified 7-mm margin they ensured 99% nodal coverage with less volume of small bowel at risk.

FIGURE 69.10. A: Anteroposterior simulation film of the pelvis illustrating portals used for external irradiation. The 15 by 15 cm portals at source-to-skin distance are used for stage IB (broken line), and 18 by 15 cm portals are used for more advanced disease (solid line). This allows better coverage of the common iliac lymph nodes. The distal margin is usually placed at the bottom of the obturator foramina. B: Diagram of pelvic portals used in external irradiation of carcinoma of uterine cervix. Standard portal for stage IB tumors is outlined (solid line indicated as A). When the common iliac nodes are to be covered, the upper margin is extended to the L4–5 space (indicated in section B). If there is vaginal tumor extension, the lower margin of the field is drawn at the introitus (indicated in section C).

FIGURE 69.11. Anterior–posterior and lateral digitally reconstructed radiograph simulation film of the pelvis, illustrating portals used for external irradiation with the patient in the prone position on a belly board to minimize small-bowel dose. Pelvic lymph nodes are indicated in their approximate position. The uterus, cervix, and vagina are contoured to ensure adequate coverage.

In the postoperative setting, van den Berg et al.,³⁰⁹ using 47 lymphangiograms and 15 CT scans, asked radiation oncologists (n = 17) to define the clinical target volume (CTV) and PTV and to delineate on simulation films the RT treatment portals to be used after a radical hysterectomy with lymph node dissection for stage IB or IIA cervical carcinoma with positive iliac lymph nodes. Large variations were observed in the portals used and in treatment techniques. From the digitized films, it appeared that in 50% of the cases the defined PTV was not covered adequately. Furthermore, 71% of the treatment plans would not cover the lateral borders of the reference PTV sufficiently. Thus, there is a need for careful adherence to standardized guidelines.

Treatment techniques may have an effect on outcome. Yamazaki et al.³¹⁰ compared 34 patients with cervical cancer treated with irregularly shaped four-field whole-pelvis radiation therapy using CT simulation and 40 patients receiving whole-pelvis EBRT with parallel-opposed fields in a nonrandomized study of postoperative radiation therapy consisting of 50 Gy in 25 fractions in 6 weeks. With a mean follow-up of 60 months, the actuarial 5-year pelvic tumor control was 94% with the two-field technique and 100% for the irregularly shaped four-field technique. The incidence of grade 2 or 3 bowel complications in the irregularly shaped–technique group (2.9%, 1 of 34) was significantly lower than that in the two-field–technique group (17.5%, 7 of 40; p < .05).

Burnett et al.³¹¹ described a prosthetic silicone plastic device that is filled with saline and Renografin for x-ray visualization (capacity between 750 and 1,500 mL) to conform to the pelvis and exclude the small bowel from the irradiated volume. The device remains in place throughout the radiation therapy course and is removed through a small incision after draining the contents of the prosthesis. Seven devices had been placed to date of the report. In the postoperative period, there was one pulmonary embolism. All seven patients completed planned radiation therapy. The devices have been removed with no adhesions to the prosthesis.

Intensity-Modulated Radiation

IMRT was developed using the techniques required for inverse planning. That is, one starts with the necessary dose around the target then works backward to develop the requisite beam intensities. IMRT spatially modulates the intensity of the beam using the motion of multileaf collimators. Because of the increasing use of intensity-modulated or image-guided radiation therapy (IMRT/IGRT) in the treatment of patients with gynecologic malignancy, there is growing emphasis on imaging the pelvic anatomic structures, including lymph nodes, for treatment planning.³¹² IMRT may reduce the amount of small bowel and bone marrow that receives the full dose of radiation.

The use of IMRT has been standardized in the postoperative setting but remains a topic of debate for intact cervix cases. What constitutes adequate margins in the intact cervix setting continues to be a matter of concern, given significant organ motion during treatment. Uncertainties in the definition of target volumes arise using 3D techniques. Bladder-filling and rectal-filling changes require accurate definition of margins for the PTV.³¹³ Beadle et al.³¹⁴found that mean maximum changes in the center of the cervix were 2.1, 1.6, and 0.82 cm in the superior–inferior, anterior–posterior, and right–left lateral dimensions, respectively. Mean maximum changes in the perimeter of the cervix were 2.3 and 1.3 cm in the superior and inferior, 1.7 and 1.8 cm in the anterior and posterior, and 0.76 and 0.94 cm in the right and left lateral directions, respectively. Haripotepornkul et al.³¹⁵ found in 10 women with locally advanced cervical cancer that within and between radiation treatments, cervical motion averages approximately 3 mm but may be up to 18 mm in any given direction. The mean intrafractional movements in cervical seed positions in the lateral, vertical, and AP directions were 1.6 mm (standard deviation [SD] ± 2.0), 2.6 mm (SD ± 2.4), and 2.9 mm (SD ± 2.7), respectively, with a range from 0 to 15 mm for each direction. The mean interfractional movements in the lateral, vertical, and AP directions were 1.9 mm (SD ± 1.9), 4.1 mm (SD ± 3.2), and 4.2 mm (SD ± 3.5), respectively, with a range from 0 to 18 mm for each direction. Tyagi et al.³¹⁶ show that a uniform CTV planning treatment volume margin of 15 mm would not encompass the cervical CTV in 32% of fractions. With IMRT, there is a need for continual replanning (at least every other week), given rapid tumor regression and internal-organ motion.³¹⁷^–³¹⁹

FIGURE 69.12. Intensity-modulated radiation therapy treatment plan for external irradiation of pelvic lymph nodes while sparing organs at risk.

After a CT scan for simulation, the images are brought into a treatment-planning workstation. Contouring the gross tumor volume (GTV) may include the uterus, cervix, and/or vagina. Lim et al.³²⁰ had 19 experts in gynecologic radiation oncology contour a case of locally advanced cervical cancer on axial magnetic resonance images of the pelvis. Substantial Simultaneous Truth and Performance Level Estimation (STAPLE) agreement sensitivity and specificity values were seen for GTV delineation (0.84 and 0.96, respectively) with a kappa statistic of 0.68 (p < .0001). Agreement for delineation of cervix, uterus, vagina, and parametria was moderate. The greatest variability in physician contouring was in the parametrial tissue.³²⁰

The CTV for the pelvic lymph nodes was based on the Radiation Therapy Oncology Group (RTOG) atlas for the female postoperative pelvis.³²¹ An example of dose distribution achieved with supine IMRT pelvic irradiation is illustrated in Figure 69.12. Fiducial markers may be placed in the apex of the vagina for identification on CT scan and show up to 3.5 cm of vaginal cuff motion during treatment.³²² Therefore, for postoperative patients, the vagina is contoured using a full-bladder CT scan fused to an empty-bladder CT scan to account for vaginal mobility due to differences in bladder filling.³²³ This vaginal target volume has been referred to as an integrated target volume (ITV). The expansion of the CTV and/or ITV to the PTV is necessary, although given the movement of the uterus, the exact amount of margin is a matter of debate. Generous margins of approximately 2 to 3 cm are considered, particularly in the regions of the uterus and cervix or in the postoperative case around the ITV vagina. Dose constraints required for an optimal IMRT plan have not been standardized. In the RTOG postoperative clinical trial 0921 using IMRT,³²⁴a PTV of 7 mm around the nodal contours is recommended, and the dose is prescribed to cover 97% of the vaginal PTV and nodal PTV. A volume of 0.03 cc within any PTV should not receive >110% of the prescribed dose. No more than 0.03 cc of any PTV will receive <93% of its prescribed dose. Any contiguous volume of 0.03 cc or larger of the tissue outside the vaginal/nodal PTVs must not receive >110% of the dose prescribed to the vaginal/nodal PTV; for normal tissues the small/large bowel (30% of the entire bowel volume must not receive >40 Gy), rectum/sigmoid (60% of the rectosigmoid volume must receive ≤40 Gy), bladder (35% of the bladder volume must receive ≤45 Gy), and femoral head (15% of the femoral head volume must receive <35 Gy) constraints are being tested in RTOG 0921. Careful attention must be paid to all normal-tissue organ motion because the bladder and rectum may have 3- to 5-cm shifts due to filling changes in a short time frame.

For patients that have had a diagnostic PET or MRI before the simulation, these images may be registered to create a fused data set for contouring, particularly when a nodal boost is required. This allows the physician to visualize areas of PET enhancement or tumor volume, as seen on the MRI, onto the simulation films. Grigsby and colleagues³²⁵ use a PET-defined target volume contoured with a metabolically active tumor specified at the 40% threshold. Normal-tissue structures, including the rectum, sigmoid, bladder, and small bowel, are routinely contoured for patients treated with IMRT who will be undergoing a nodal boost in order to limit the dose received primarily to the small bowel. Based on an overview of published data, the absolute volume of small bowel receiving ≥15 Gy should be held to <120 cc when possible to minimize severe acute toxicity if delineating the contours of bowel loops themselves. Alternatively, if the entire volume of peritoneal space in which the small bowel can move is delineated, the volume receiving >45 Gy should be <195 cc when possible.³²⁶ For the rectum, dose–volume constraints selected as a conservative starting point that have not yet been validated for 3D treatment planning include V₅₀ < 50%, V₆₀ < 35%, V₆₅ < 25%, V₇₀ < 20%, and V₇₅ < 15%.³²⁷ No dose constraint for external beam planning for the bladder could be identified, although the limits for prostate cancer may be adopted for gynecologic IMRT, including a dose constraint of no more than 15% of the volume to receive a dose >80 Gy, no more than 25% of the volume to receive a dose >75 Gy, no more than 35% of the volume to receive a dose >70 Gy, or no more than 50% of the volume to receive a dose >65 Gy.³²⁸

Imaging may guide more accurate definition of lymph nodes.³⁰⁸ Portelance et al.²⁷² carried out IMRT as well as conventional planning with two- and four-field techniques in 10 patients. Prescription was 45 Gy in 25 fractions to the uterus and the pelvic and para-aortic lymph nodes. All IMRT plans were normalized to obtain a full coverage of the cervix with the 95% isodose curve (Fig. 69.13A). The volumes of small bowel receiving the prescribed dose (45 Gy) with IMRT para-aortic–only technique were, with four fields, 11%; with seven fields, 15%; and with nine fields, 13.5% (Fig. 69.13B). These dose distributions were all significantly better than with two-field or four-field conventional techniques (p < .05.) Ahmed et al.³²⁹ arrived at similar conclusions in five patients with para-aortic node metastasis, and they demonstrated the feasibility of escalating the dose to 60 Gy while sparing the kidneys, spinal cord, small bowel, and bone marrow. Heron et al.,³³⁰ in a study of 10 patients, showed that with IMRT there was a reduction of 52% in the small-bowel volume receiving >30 Gy and a decrease of 66% for the rectum and 36% for the bladder compared with 3D radiation therapy. D’Souza et al.,³³¹ in 10 patients, also noted a reduction of small-bowel volume (33%) with IMRT compared with four-field pelvic RT; however, small volumes of bowel received 55 to 60 Gy with the IMRT plans. Positioning the patient prone on a belly board was shown to reduce the volume of small-bowel irradiated. However, patients on a belly board may have large daily anatomic shifts that make prone IMRT unreproducible.³³²

Brixey et al.³³³ and Lujan et al.³³⁴ also used IMRT planning to spare the bone marrow of patients with gynecologic tumors. Brixey et al.,³³³ in 36 patients, noted no significant difference in hematologic toxicity with IMRT or conventional RT alone; however, in patients receiving chemotherapy, less grade 2 white blood cell toxicity was observed with IMRT (31.2% vs. 60%, respectively).

Hasselle et al.³³⁵ report on 111 patients treated with multiple different approaches, including 22 treated with postoperative IMRT, 8 with IMRT followed by intracavitary brachytherapy and adjuvant hysterectomy, and 81 with IMRT followed by planned intracavitary brachytherapy. Median follow-up time was 27 months. Acute and late grade 3 toxicity or higher was 2% (95% confidence interval [CI], 0% to 7%) and 7% (95% CI, 2% to 13%), respectively. Guerrero et al.³³⁶ proposed using an IMRT simultaneous integrated boost (SIB) as an alternative to conventional whole-pelvis irradiation and used the linear quadratic equation to calculate equivalent uniform dose in multiple plans. However, a report by Kavanagh et al.³³⁷ found that accelerated fractionation caused an unacceptably high rate of complications.

Although IMRT has dosimetric advantages over conventional RT, IMRT exposes a greater amount of normal tissues to lower irradiation levels, which has the potential to increase the incidence of radiation-induced second cancers,³³⁸ a phenomenon already described with conventional RT techniques.³³⁹

FIGURE 69.13. A: Axial views of intensity-modulated radiation therapy dose distribution. B: The functional volume of small bowel, rectum, and bladder receiving ≥45 Gy with intensity-modulated radiation therapy or conventional techniques when 100% of the target volume (uterus) receives ≥95% of the prescription dose (45 Gy). (From Portelance L, Chao KSCC, Grigsby PW, et al. Intensity-modulated radiation therapy [(IMRT)] reduces small bowel and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation. Int J Radiat Oncol Biol Phys 2001;51:261–266; with permission from Elsevier.)

Image-Guided Radiation Therapy

Although not always available, some institutions on protocol have attempted daily cone-beam CT imaging for in-room image-guided RT (IGRT).³⁴⁰ Particularly in cases with a large, mobile uterus, such as is seen in young women, if an extended field is used and there is concern that the uterus may be out of the field, this may be instituted. In clinics where IMRT is used for locally advanced cervical cancer, the priority should be to treat with wide margins, so that the field mimics that of a 3D conformal (four-field) plan.³¹⁶

Stereotactic body radiotherapy (SBRT) uses highly conformal treatments with large fraction sizes and in selected cases has been considered for a nodal boost of an isolated para-aortic node, although care must be taken to treat the entire para-aortic chain to 45 Gy with IMRT or 4 Field (4F) prior to considering an SBRT boost in order to ensure eradication of adjacent micrometastatic disease.³⁴¹ SBRT should not be used instead of brachytherapy, given the significant increase in normal-tissue doses with SBRT compared to brachytherapy.³⁴²

Midline Shielding in AP-PA Portals and Use of a Parametrial Boost

Depending on the institution and brachytherapy dose administered, midline shielding with rectangular or specially designed blocks has been traditionally used for a portion of the external beam dose delivered with the AP-PA ports.³⁰² Midline blocks may be individualized, based on the point A isodose line or a rectangular block of approximately 4-cm width. In one series, overall survival and incidence of chronic complications were not related to the type of shielding.³⁴³ However, in the era of three-dimensional brachytherapy planning, the use of a midline block has been questioned because it may result in tumor underdosing while still contributing significant dose to the bladder, sigmoid, and rectum.³⁴⁴

Several institutions reported placing a midline block after a full course of external-beam treatment to the pelvis in order to boost the parametria or nodes for patients with persistent disease after approximately 45 to 50 Gy. When parametrial tumor persists, 50 to 60 Gy may be delivered to the parametria, with reduced anteroposterior–posteroanterior portals (8 by 12 cm for unilateral and 12 by 12 cm for bilateral parametrial coverage). However, careful estimation of dose to the small bowel, sigmoid, and rectum is needed. In the modern era, the use of highly conformal boosts with 3D planning allows an increase in normal-tissue sparing. Contours on CT of the parametrial and nodal region allow more precise tailoring of dose. For patients with enlarged nodes, when available, IMRT techniques may be best at providing conformal dose escalation to 54 to 65 Gy.

Similarly, with 3D brachytherapy and computerized optimization as available with high HDR or pulse–dose-rate (PDR) brachytherapy, the physician may cover the adjacent parametria using large enough fraction sizes that an additional external-beam boost is not needed. When one prescribes HDR brachytherapy, the per-fraction nodal dose is approximately 25% of prescription. In one study the per-fraction dose to the pelvic lymph nodes by HDR brachytherapy, when the high-risk clinical target volume (HR-CTV) received 5.5 Gy per fraction, was 1.4 Gy per fraction. Therefore, HDR brachytherapy may obviate the need for a parametrial boost, given the high per-fraction dose to the parametria and pelvic sidewall.³⁴⁴

In a comparison of three different approaches, Fenkell et al.³⁴⁵ reported on parametrial boost with midline shielding in six patients with locally advanced cervical cancer (IIB to IIIB) treated with definitive chemoradiotherapy and MRI-guided brachytherapy. A three-phase plan was modeled: 45-Gy (1.8 Gy per fraction) four-field box, 9-Gy (1.8 Gy per fraction) midline-shielded anteroposterior/posteroanterior fields (MBB), and intracavitary MRI-guided brachytherapy boost of 28 Gy (7 Gy per fraction). Midline shields 3, 4, and 5 cm wide were simulated for each patient. Brachytherapy and MBB plans were volumetrically summed. After a 4-cm MBB, HR-CTV D₉₀ remained <85 Gy in all cases (mean, 74 Gy; range, 64 to 82 Gy). Bladder, rectum, or sigmoid D_2ccincreased by > 50% of the boost dose in four of six patients. The authors concluded that a midline block may not be beneficial in patients receiving 3D image-planned brachytherapy with adequate optimization of dose to the tumor and away from the normal tissues.

FIGURE 69.14. Extended-field intensity-modulated radiation therapy for external irradiation of uterine cervix and pelvic and para-aortic lymph nodes. Dose–volume histogram values for the spinal cord, kidneys, para-aortic nodes, and pelvic node boost are shown for a patient who had an unresectable 4-cm pelvic lymph node.

FIGURE 69.15. A, B: Example of treatment plan with intensity-modulated radiation therapy for irradiation of para-aortic lymph nodes. C: Dose–volume histogram illustrating sparing of left kidney and small intestine (Plan 7A, solid line; Plan 7B, dashed line). CTV, clinical target volume. (From Mutic S, Malyapa RS, Grigsby PW, et al. PET-guided IMRT for cervical carcinoma with positive para-aortic lymph nodes—a dose-escalation treatment planning study. Int J Radiat Oncol Biol Phys 2003;55:28–35; with permission from Elsevier.)

Para-Aortic Lymph Node Irradiation

If para-aortic node metastases are enlarged or suspected to harbor disease, patients are treated with 45 to 50 Gy to the para-aortic area plus a sequential 5- to 10-Gy boost to enlarged lymph nodes through reduced lateral or rotational portals.²⁷⁵ If feasible, 3D planning with IMRT treatment is preferred to spare normal tissues, superiorly covering above the level of the renal hilum or the highest extent of disease and inferiorly covering 2 cm below the lowest extent of disease (Fig. 69.14).

The use of IMRT has allowed dose escalation to para-aortic nodes, particularly unresectable nodes. Clinical reports show excellent control of disease with dose escalation, with one report demonstrating an 85% 2-year nodal control rate after IMRT with a median dose of 63 Gy.³⁴⁶ Esthappan et al.²⁷¹ described a technique using CT and FDG-PET to treat the para-aortic lymph nodes (50.4 and 59.4 Gy) with IMRT (Fig. 69.15). Acceptable dose distribution of the target volumes and sparing of the stomach, liver, and colon were achieved. Sparing of the spinal cord was dependent on the number and arrangements of the beams, as it was for the small bowel, sparing of which was limited because of overlap with the target volume. Adjusting the number of beams and prescription parameters minimally improved kidney sparing.

When only conventional techniques are available, the para-aortic lymph nodes are irradiated either with an extended field, often using a four-field approach, that includes both the para-aortic nodes and the pelvis or through a separate portal (Fig. 69.16).³⁰²^,³⁴⁷ This may be done as one long field, or, in cases requiring extended distance, one may instead choose to separate the pelvic and para-aortic fields. This requires a “gap calculation” between the pelvic and para-aortic portals to avoid overlap and excessive dose to the small intestines. The upper margin of the field is at the T12-L1 interspace and the lower margin at L5-S1. The width of the para-aortic portals (in general, 8 to 10 cm) can be determined by CT scans, MRI, lymphangiography, FDG-PET scans, or IV pyelography outlining the ureters. The spinal cord dose (T12 to L2–3) should be kept to <45 Gy by interposing a 2-cm-wide 5–half-value-layer shield on the posterior portal (usually after 40-Gy tumor dose) or using lateral ports and limiting the kidney dose to <18 Gy. A technique using four isocentric fields weighted 2:1 anteroposterior–posteroanterior over lateral portals and 1.8-Gy fractions was described by Russell et al.³⁴⁸ to deliver high-dose therapy (56 to 61 Gy). Kodaira et al.³⁴⁹ evaluated a four-field para-aortic irradiation technique with 10-MV photons (mean, 50.4 Gy) in 97 patients with cervical cancer. The 5-year cause-specific survival rate was 32.2%. Grade 1 or 2 stomach and duodenum sequelae developed in 26.8%, grade 2 sequelae of small bowel in 3.1%, and grade 2 sequelae of bone in 3.1%. Rates of toxicity with IMRT may be lower.²⁷⁵

FIGURE 69.16. Extended field simulated with conventional plain films for external irradiation of pelvic and para-aortic lymph nodes.

FIGURE 69.17. Example of isodose curves of 4F box irradiation of the pelvis with high-energy photons and high-dose-rate brachytherapy optimized to cover the tumor and minimize dose to the bladder and rectum.

Beam Energies

For IMRT, 6-MV energy is used to provide the most homogeneous dose. However, in conventional irradiation, because of the thickness of the pelvis, high-energy photon beams (10 MV or higher) are especially suited for this treatment. They decrease the dose of radiation delivered to the peripheral normal tissues (particularly bladder and rectum) and provide a more homogeneous dose distribution in the central pelvis. With lower-energy photons (⁶⁰Co or 4- to 6-MV x-rays), higher maximum doses must be given, and more complicated field arrangements should be used to achieve the same midplane tumor dose (three-field or four-field pelvic box or rotational techniques) while minimizing the dose to the bladder and rectum and to avoid subcutaneous fibrosis (Fig. 69.17).³⁵⁰ Biggs and Russell³⁵¹ noted that the presence of a metallic prosthesis when using lateral fields or a box pelvic irradiation technique may result in a dose decrease of approximately 2% for 25-MV x-rays and average increases of 2% for 10-MV x-rays and 5% for ⁶⁰Co. Allt³⁵² and Johns,³⁵³ in an update of a randomized study, reported better pelvic tumor control and survival and fewer complications in 65 patients with stages IIB and III cervical carcinoma treated with 23-MV photons compared with 61 treated with external irradiation with ⁶⁰Co in addition to brachytherapy in both groups. In contrast, Holcomb et al.³⁵⁰ compared outcome of 195 patients with stages IIB and IVA cervical carcinoma treated with ⁶⁰Co radiation therapy (group 1) and 53 treated with linear accelerators (group 2). There was no significant difference in overall survival, although there was a trend toward increasing pelvic recurrence in the ⁶⁰Co group (50.8%) compared with group 2 (35.8%; p = .08). Mixed-beam external radiation with neutrons and photons resulted in unacceptably high toxicity rates and is not recommended.³⁵⁴ Similarly, carbon-ion therapy was reported but resulted in major intestinal complications.³⁵⁵

Hyperfractionated or Accelerated Hyperfractionated Radiation Therapy

MacLeod et al.³⁵⁶ reported on a phase II trial of 61 patients with locally advanced cervical cancer treated with accelerated hyperfractionated radiation therapy (1.25 Gy administered twice daily at least 6 hours apart to a total pelvic dose of 57.5 Gy). A boost dose was administered with either low–dose-rate (LDR) brachytherapy or EBRT to a smaller volume. Thirty patients had acute toxicity that required regular medication. One patient died of acute treatment-related toxicity. The overall 5-year survival was 27%, relapse-free survival was 36%, and actuarial local tumor control was 66%. There were eight severe late complications observed in seven patients, who required surgical intervention (actuarial rate of 27%). Five patients also required total hip replacement.

Another study reported on 30 patients with stage II or III cervical cancer randomized to receive either hyperfractionation (15 patients) or conventional fractionation (15 patients).³⁵⁷ At 5 years, 2 patients in the hyperfractionation group and 8 patients in the conventional treatment group had recurrent tumor (p = .04). Delayed bowel complications (grade 2 and 3) occurred in 9 women in the hyperfractionation group and 2 patients in the conventional group (p = 0.0006).

RTOG 88-05 conducted a phase II trial of hyperfractionation (1.2 Gy to the whole pelvis twice daily at 4- to 6-hour intervals, 5 days per week) with brachytherapy in 81 patients with locally advanced carcinoma of the cervix. Total dose to the whole pelvis was 24 to 48 Gy, followed by one or two LDR intracavitary applications to deliver 85 Gy at point A and 65 Gy to the lateral pelvic nodes. Grigsby et al.³⁵⁸ updated the results and noted that external irradiation was completed in 71 cases (88%). The 5-year cumulative rate of grade 3 and 4 late effects for patients with stage IB2 or IIB tumors was 7% and at 8 years was 10%, and with stage III or IVA disease, it was 12% at 5 years. The absolute survival was 48% at 8 years, and disease-free survival was 33%. Comparison with historical control patients treated on other RTOG studies showed equivalent rates of pelvic tumor control, survival, and grade 3 and 4 toxicities at 3, 5, and 8 years, respectively.

Calkins et al.³⁵⁹ assessed the toxicities of multiple–daily-fractionated (twice-daily, 1.2-Gy fractions) whole-pelvis radiation plus concurrent chemotherapy for locally advanced carcinoma of the cervix. In the first study (GOG 8801), for 38 patients, hydroxyurea was given orally (80 mg/kg to a maximum of 6 g) at least 2 hours before irradiation, twice every week. In the second study (GOG 8901), for 30 patients, cisplatin and fluorouracil (5-FU) were used concomitantly with RT. Acute toxicity was primarily enteric and appeared to be dose related. The maximum tolerated dose of whole-pelvis radiation that could be delivered in a hyperfractionated setting with concomitant chemotherapy was 57.6 Gy in 48 fractions, followed by brachytherapy.

Thomas et al.³⁶⁰ conducted a four-arm study in which 234 women with bulky stage IB to IVA cervical cancer were randomized to receive either standard RT (EBRT and brachytherapy to deliver 90 Gy to point A) with or without a 4-day infusion of 5-FU (1 g/m²) on days 1 to 5 and 22 to 25, or partially hyperfractionated RT with or without the same chemotherapy regimen. The partially hyperfractionated regimen delivered two fractions, 6 hours apart, on the first 4 days of treatment, coinciding with the infusion of 5-FU. The addition of 5-FU did not improve pelvic tumor control (37% to 75% at 5 years) or overall survival. However, this study closed without reaching target patient accrual. A concomitant boost technique was reported by Kavanagh et al.³³⁷ but had an unacceptably high rate (8 of 20 patients) of late complications.

GENERAL MANAGEMENT

Carcinoma in Situ

Patients with persistent high-grade carcinoma in situ are usually treated with a total abdominal hysterectomy with or without a small portion of the upper vagina removed. The decision to remove the ovaries depends on the age of the patient and status of the ovaries. Occasionally, when the patient wishes to have more children, carcinoma in situ may be treated conservatively with a therapeutic conization,³⁶¹ laser therapy, or cryotherapy.³⁶² This approach should be judiciously selected when the extent of tumor allows it and the patient is reliable for continued follow-up.³² Conization microscopic margins are critical in decision making regarding a conservative approach or proceeding with a hysterectomy. A therapeutic hysterectomy can be performed 6 weeks after the conization.

Irradiation may be useful for the treatment of carcinoma in situ, particularly in patients with strong medical contraindications to surgery or when there is extension of the lesion to the vaginal wall or multifocal carcinoma in situ in both the cervix and the vagina.³⁰²^,³⁶³ In a group of 26 patients with carcinoma in situ treated at Washington University with intracavitary brachytherapy alone (approximately 5,000 milligram-hours [mgh], 45 Gy to point A with LDR) with tandem and ovoids, no recurrences were recorded.³⁶⁴ Ogino et al.³⁶⁵ used HDR brachytherapy in 14 patients with grade 3 cervical and 6 with grade 3 vaginal intraepithelial neoplasia (3 with microinvasion) and 6 with recurrent cervical intraepithelial neoplasia after hysterectomy. Seventeen patients were treated with HDR brachytherapy alone and 3 in combination with EBRT without surgery. The mean dose of HDR brachytherapy was 26.1 Gy (range, 20 to 30 Gy) prescribed at point A for intact uterus, or at 1 cm superior to the vaginal apex or 1 cm beyond vaginal mucosa for lesions of the vaginal stump. At mean follow up of 90 months, 14 patients were alive and 6 had died from intercurrent disease; none had recurrent disease. Rectal bleeding occurred in 3 patients and subsided spontaneously. Moderate and severe vaginal reactions were noted in 2 patients in whom the treatment included the entire vagina.

Invasive Disease

Based on available resources globally and the stage of disease, a debate continues among those who advocate radical surgery,³⁰²^,³⁶⁶^,³⁶⁷ those who favor radiation, and those who favor chemoRT for the treatment of carcinoma of the uterine cervix. Patients should be treated with close collaboration between the gynecologic oncologist and the radiation oncologist, and an integrated team approach should be vigorously pursued. In countries with access to RT facilities and financial resources to supply chemotherapy, the use of concurrent chemoRT represents the accepted standard for patients with stage IB2 to IVA cervical cancer. For earlier-stage patients, the use of either surgery or chemoRT is recommended. The most recent survey of patterns of radiotherapy practice again documented a rise in the use of cisplatin-based concurrent chemoRT in patients with advanced stages, from 63% in 1999 to 74% in 2007.¹⁵⁴^,³⁶⁸^,³⁶⁹ Moreover, Barbera et al.³⁷⁰ also reported a significant increase in the use of chemoRT in Canada after the U.S. National Cancer Institute Bulletin on the subject.³⁷¹

Carcinoma of the Cervix Inadvertently Treated with a Simple Hysterectomy

Occasionally, a simple or total abdominal hysterectomy is performed and invasive carcinoma of the cervix is incidentally found in the surgical specimen. In general, extrafascial abdominal hysterectomy is not curative because the paravaginal or paracervical soft tissues and vaginal cuff are not removed. Furthermore, it may be technically difficult to perform an adequate radical operation after previous simple hysterectomy. If only microinvasive carcinoma is found when a total or extrafascial hysterectomy with a wide cuff is performed, no additional therapy is necessary. For lesions with deeper stromal invasion, at most one or two vaginal intracavitary insertion(s) to deliver a 65-Gy LDR mucosal dose (or 7 Gy é six fractions prescribed at the vaginal surface, or 5 Gy at 0.5 cm é six fractions with HDR brachytherapy) to the vault are sufficient. If a less comprehensive resection was carried out, it is critical that these patients receive radiation therapy immediately with or without concurrent chemotherapy, depending on the risk factors present pathologically when their postoperative status allows it because the prognosis is worse if postoperative irradiation is not administered.

In patients with fully invasive tumor, therapy consists of approximately 40 to 45 Gy to the whole pelvis with cylinder brachytherapy to the vaginal vault for an approximately 60-Gy mucosal dose. If there is gross tumor present in the vaginal vault or parametrium, the dose to the whole pelvis should be 45 Gy with concurrent weekly cisplatin chemotherapy, followed by an additional parametrial dose of 10 to 20 Gy. An intracavitary insertion should be performed. If there is gross residual tumor, an interstitial implant should be carried out to selectively increase the dose to this volume.

Several studies have reported results of postoperative external-beam irradiation after conservative surgery (Table 69.10). Andras et al.³⁷² reported on 148 patients, 90 of whom were available for 10-year evaluation, who were divided into five groups, depending on tumor extent when therapy was instituted. The majority of patients were treated with 50-Gy total-pelvis irradiation (with 10-Gy parametrial boost through reduced fields), at times combined with vaginal vault intracavitary irradiation. Eight major complications were noted in 148 patients.

Ampil et al.³⁷³ described results in 44 patients receiving postoperative irradiation after hysterectomy for stage IB and IIA carcinoma of the uterine cervix (15 patients treated with radical hysterectomy). Their 5-year results were 80% local tumor control and 63% overall survival. In 3 patients treated with intracavitary vaginal cuff irradiation only, 2 had tumor control.

Green and Morse³⁷⁴ reported 9 of 30 patients (30%) surviving 5 years after definitive radiation therapy for treatment of invasive cervical carcinoma after simple hysterectomy. The same authors noted that 14 of 32 patients retreated with another surgical procedure, usually a Wertheim hysterectomy, died within 5 years. They pointed out that the 5-year cure rate was 30% in patients treated within 1 year after the hysterectomy but was only 16% in those treated after 1 year. Thus, the time at which the patient is treated and the volume of tumor are important prognostic factors.

Crane and Schneider³⁷⁵ described results in 18 patients treated with RT (with or without brachytherapy) for invasive carcinoma of the cervix discovered after simple hysterectomy. The 10-year actuarial local tumor control was 88%, and the overall survival rate was 93%. Huerta Bahena et al.,³⁷⁶ in 59 patients with carcinoma of the cervix incidentally found in simple hysterectomy specimens (27 with gross residual tumor) who were treated with postoperative RT, reported a 3-year survival of 59%; factors affecting prognosis included gross residual tumor, time between hysterectomy and irradiation >6 months, RT doses < 50 Gy, and histologic tumor type.

Munstedt et al.³⁷⁷ reported on 119 patients who received postoperative RT after radical hysterectomy and 80 who received it after simple hysterectomy. There was a trend toward better survival in the radical hysterectomy group, but the authors concluded that postoperative RT is a good treatment in patients with invasive cervical cancer who undergo a simple hysterectomy. In another report of 105 patients with invasive cervical carcinoma found in inadequate surgery specimens treated with postoperative RT, 5-year pelvic tumor control was 72% and the survival rate was 55%. Late rectal toxicity was 19%, bladder toxicity was 4.8%, and small-bowel toxicity was 14.3%.³⁷⁸

In a series of 147 patients treated at Asan Medical Center in Korea, 48 patients with stage IA1 lesions did not receive further treatment. Another 99 patients had stage IA2 to IIA lesions incidentally identified. Of these, 26 received no further therapy, 44 had either radiation or chemoradiation, and 29 had a radical parametrectomy. For patients with stage IA1 disease who were observed, 0% relapsed, whereas 35% of patients with stage IA2 to IIA disease who were observed suffered from a recurrence.³⁷⁹ Either radical parametrectomy or radiation is required for patients with stage IA2 or higher cancer after a simple hysterectomy. However, these treatments increase the risk of side effects,³⁸⁰ including for those patients receiving robotic parametrectomy.³⁸¹

TABLE 69.10 RESULTS OF POSTOPERATIVE EXTERNAL-BEAM IRRADIATION AFTER CONSERVATIVE HYSTERECTOMY IN EARLY-STAGE CARCINOMA OF THE CERVIX^A

Stage IA

The definition of microinvasive (stage IA) carcinoma of the cervix includes invasive carcinoma diagnosed only by microscopy. Conization is mandatory for a more accurate diagnosis. According to Kolstad,³⁸² lesions <1 mm in depth can be treated with conization, provided all margins are tumor free and continued careful follow-up is instituted. Raspagliesi et al.³⁸³ used margins of 8 to 10 mm as guidelines for clearance in conization. Smaller margins or lymphovascular invasion in addition to depth of invasion were prognostic factors for recurrence.

Tumor volume in the stroma may be a more reliable criterion than depth of invasion to arrive at a definition of stage IA. Vascular space involvement does not impact stage. Depth of invasion and tumor confluence have been identified as prognostic factors that should be taken into consideration in the planning of therapy.³⁸⁴

Early invasive carcinoma of the cervix (stage IA2) is usually treated with a total abdominal or modified radical hysterectomy or in some cases with simple conization²⁵¹ or radical trachelectomy.³⁸⁵ Inoperable patients may be treated with intracavitary radioactive sources alone with 6,500 to 8,000 mgh, 60 to 75 Gy to point A, in two LDR insertions, respectively, or with the equivalent dose using HDR brachytherapy, approximately 10 fractions of 5 Gy per fraction. In 47 patients with microinvasive carcinoma treated at Washington University—20 with intracavitary therapy only and 27 patients with combined external irradiation and intracavitary brachytherapy—only 1 patient had a pelvic recurrence and distant metastases 10 years later; the 5-year disease-free survival rate was 96%.³⁶⁶

When the depth of penetration of the stroma by tumor is <3 mm, the incidence of lymph node metastasis is 1% or less, and a lymph node dissection or pelvic external irradiation is not warranted.³⁰²^,³⁶⁶ With more extensive lesions, a Wertheim radical hysterectomy with pelvic lymphadenectomy is the preferred treatment. Tumor control with all treatment methods is >95%, with patients eventually dying of intercurrent disease. Gadducci et al.³⁸⁶ treated 30 patients with conization and 82 with total and 54 with radical hysterectomy; the recurrence rates were 10%, 4.9%, and 9.3%, respectively. None of 67 patients subjected to lymphadenectomy had positive pelvic nodes. In 98 patients with adenocarcinoma of the cervix, none of 48 with depth of invasion (DOI) of ≤5 mm had involved parametria or positive nodes, in contrast to 6 of 36 (16%) with DOI of >5 mm.³⁸⁷

Vaginal trachelectomy (removal of the cervix) and laparoscopic lymphadenectomy have been used to treat young patients with microinvasive carcinoma to preserve fertility. The overall incidence of central recurrence is approximately 5%.³⁶⁴ Webb et al.³⁸⁸ analyzed lymph node status and survival rates of women with microinvasive cervical adenocarcinoma (FIGO stages IA1 and IA2) from the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 1997. Among reported cases, 131 had stage IA1 and 170 had stage IA2 disease. Simple hysterectomy was done in 54 women with IA1 and in 64 women with IA2 disease and radical hysterectomy in 50 and 83 women, respectively. Only 1 of 140 women who had lymphadenectomy had a single positive lymph node. There were 4 tumor-related deaths (1 with IA1 and 3 with IA2 disease). The survival rate was 98.7%.

Stages IB to IIA

The choice of definitive irradiation or radical surgery for stage IB and IIA carcinoma of the cervix remains controversial, and the preference for one procedure over another depends primarily on the impact on the patient’s fertility and on the institution, the gynecologic oncologist or radiation oncologist involved, the general condition of the patient, and characteristics of the lesion. An operation has been preferred by some in young women to preserve the ovaries, attempting to prevent premature menopause. However, in some reports²⁹⁴ ovarian function preservation has been observed in only 50% to 60% of surgically treated patients not receiving irradiation. Postmenopausal patients may have a survival benefit with chemoradiation and avoid the operative risks. When therapeutic results in invasive carcinoma of the cervix are evaluated, a direct comparison of surgically treated or irradiated patients is fraught with many uncertainties, including patient selection, reporting of surgical cases using staging determined by laparotomy findings, and different treatment techniques.³⁸⁹ In particular, in the modern era when concurrent chemoradiation is known to be superior to radiation alone, a direct comparison of chemoradiation versus surgery in early-stage cervical cancer is needed.

Surgery provides an opportunity for a thorough pelvic and abdominal evaluation. However, surgical staging has not been shown to improve overall patient survival.²⁷⁹^,³⁹⁰ Kupets et al.³⁹¹ assessed the value of debulking large nodes and concluded that the incremental overall benefit by stage was small. Delgado et al.¹⁶¹ described a GOG study in which 1,125 patients were registered before surgery; 80 were ineligible after strict pathology review, and an additional 129 patients were explored, but the hysterectomy was abandoned because of intraoperative complications in 49 patients or extent of disease beyond the uterus in 80 patients. In the era of MRI, surgeons may rely on imaging findings to screen for operability. The impact of patient selection in results of surgical series was illustrated by Whitney and Stehman,³⁹² who evaluated the frequency with which intended radical hysterectomy for cervical cancer is abandoned and the outcomes for those selected patients. In 1,127 patients with stage IB carcinoma of the cervix entered on GOG Protocol 49, 98 women (8.7%) were found at surgery to have extrauterine disease, and the proposed radical operation was abandoned. Subgroups of patients with extrapelvic disease³¹ and pelvic extension,³⁸⁷ including grossly positive pelvic nodes,¹⁶⁰ other pelvic implants,³⁹³ and gross serosal extension,¹⁰⁹ were identified. Sixty-three (93%) patients subsequently underwent pelvic radiation therapy and brachytherapy. Para-aortic fields were added for 8 patients who were found to have positive para-aortic nodes. The disease-free survival was shorter for patients whose radical procedure was abandoned than for those patients who underwent radical hysterectomy.

The important contribution of external-beam irradiation to improve pelvic tumor control in larger lesions has been documented. Hamberger et al.,³⁹⁴ in 151 patients with stage IA or IB lesions <1 cm in diameter treated with intracavitary therapy alone to high doses (8,640, 9,340, and 13,680 mgh), noted no failures in 41 patients with stage IA disease, and only 4 of 93 patients (4%) with stage IB, small-volume disease. However, 3 of 17 patients (18%) with more extensive stage IB lesions, treated with intracavitary therapy only, had regional failures. Only 3 of 151 patients (0.2%) had grade 3 complications.

Volterrani and Lombardi³⁹⁵ reported 5-year survival of 82.6% in 23 patients with occult stage IB carcinoma of the cervix treated with intracavitary ²²⁶Ra only (7,500 mgh), in contrast to only 64.8% with larger stage IB tumors and 50% with stage II. Unfortunately, the authors did not report the exact location of the failures. It is obvious that intracavitary therapy alone is grossly inadequate to irradiate larger primary tumors, including stage IB1.

With EBRT and brachytherapy without chemotherapy, the usual 5-year survival rate for stage IB is 86% to 92% and for stage IIA is approximately 75%.³⁹⁶ Late toxicity was observed in 1% to 2% of patients. Concurrent chemotherapy significantly improves survival, including in stage IB to IIA disease. In RTOG 90-01, for the subset of 272 stage IB to IIA patients, the 8-year overall survival was 55% with RT alone versus 78% with concurrent chemoradiation (p < .001).³⁹⁷

Randomized Studies: Surgery Versus Radiation

Few randomized trials have compared the results of radical hysterectomy with definitive RT, and none have compared surgery to chemoradiation. Outcome between radiation alone versus surgery is comparable. Newton³⁹⁸ and Roddick and Greenlaw³⁹⁹ reported, in prospectively randomized studies, equivalent survival and pelvic recurrence rates in patients with stage IB and IIA carcinoma of the uterine cervix treated with a radical hysterectomy or irradiation alone. Landoni et al.³⁵ published results of a prospective, randomized trial of radiation therapy versus surgery; 469 women with stage IB and IIA cervical carcinoma were referred for treatment and 343 were randomized (172 to surgery and 171 to radiation therapy). Postoperative irradiation was delivered after surgery for women with surgical stage pT2b or greater, <3 mm of cervical stromal invasion and cut-through margins or positive pelvic nodes. Scheduled treatment was delivered to 169 and 158 women, respectively; 62 of 114 women with cervical diameters of <4 cm and 46 of 55 women with >4 cm received radiation therapy. After a median follow-up of 87 months (range, 57 to 120 months), 5-year overall and disease-free survival rates were nearly identical in the surgery and radiation therapy groups (83% and 74%, respectively); recurrent disease developed in 86 women: 42 (25%) in the surgery group and 44 (26%) in the radiation therapy group (Fig. 69.18). Forty-eight patients (28%) in the surgery group had severe morbidity, compared with 19 (12%) in the radiation therapy group (p = .0004; Table 69.11). The combination of surgery and radiation therapy had the worst morbidity, especially urologic complications.

Of note, no randomized study has compared chemoRT to radical hysterectomy, although chemoRT has a significant survival advantage over RT alone for patients with stage IB to IIA cervical cancer.⁴⁰⁰ In a meta-analysis looking at the value of adjuvant cisplatin-based chemotherapy after radical hysterectomy, radiation therapy, or both for patients with stage IA2, IB1, or IIA cervical cancer, three randomized clinical trials were evaluated.⁴⁰⁰ Two of the three trials showed a significant benefit compared to adjuvant chemotherapy concurrent with radiation, with a reduced risk of death (HR = 0.56, 95% CI = 0.36 to 0.87). No benefit was seen when chemotherapy was given prior to radiotherapy.

Neoadjuvant chemotherapy plus surgery does not improve survival over surgery alone.⁴⁰¹ In a meta-analysis of six trials, although there was an improvement in progression-free survival with neoadjuvant chemotherapy (HR = 0.76, 95% CI = 0.62 to 0.94, p = .01), this did not translate into an overall survival benefit. Another meta-analysis reviewed 18 trials with locally advanced cervical-cancer patients treated with neoadjuvant chemotherapy before radiation or surgery or both and excluded concurrent chemoradiation trials; it showed significant heterogeneity and no conclusive results.⁴⁰²

FIGURE 69.18. Overall actuarial survival of patients with carcinoma of the cervix randomized to treatment with radical surgery or radiation therapy according to treatment group and cervical diameter. (From Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage IB-IIA cervical cancer. Lancet1997;350:535–540; reprinted with permission from Elsevier.)

TABLE 69.11 RANDOMIZED TRIAL OF RADICAL SURGERY OR IRRADIATION IN STAGES I TO II CERVICAL CANCER: RELAPSES AND MORBIDITY

Nonrandomized Studies Comparing Surgery to Radiation

Keilbinska et al.,⁴⁰³ in a long-term study of 792 women treated with irradiation and 789 women treated with hysterectomy and/or irradiation for stage I cervical carcinoma, found no difference in survival, general health, incidence of recurrent carcinoma, or appearance of second primary malignancies. Piver et al.⁴⁰⁴ treated 103 women with stage IB cervical carcinoma with either radical hysterectomy and pelvic lymphadenectomy (if tumor was <3 cm in greatest diameter) or irradiation (tumor of >3 cm or medically inoperable). The 5-year disease-free survival rate was 92.3% for the surgical group and 91.1% for the radiation therapy group. Equivalent overall 5-year survival rates were noted. Einhorn et al.,⁴⁰⁵ in a nonrandomized study, observed a 100% 5-year survival rate in 49 patients with stage IB disease receiving combined therapy in comparison with 81% in 64 patients treated with irradiation alone. No difference was observed in 25 patients with stage IIA tumor treated with combined therapy and 40 patients treated with irradiation alone (5-year survival rate, 75%).

Perez et al.⁴⁰⁶ reported on a prospectively randomized study of 118 patients with stage IB or IIA carcinoma of the uterine cervix in which patients were treated with RT alone or irradiation and surgery (20 Gy to the whole pelvis, one intracavitary insertion for 5,000 to 6,000 mgh, followed by a radical hysterectomy with pelvic lymphadenectomy 2 to 6 weeks later). In stage IB, the 5-year tumor-free survival was 80% and 82% (p = .23), respectively, and in stage IIA it was 56% and 79%, respectively (p = .13). The incidence of grade 2 or 3 complications for radiation alone was 13.8% and with preoperative irradiation and surgery was 11%. Subsequently, Perez et al.⁴⁰⁷ described results in 415 patients with stage IB or limited stage IIB treated with preoperative or postoperative irradiation and surgery. The 10-year cause-specific survival rate for patients with stage IB nonbulky tumors treated with irradiation alone or irradiation combined with surgery was 84% with either modality. With bulky tumors (>5 cm), the 10-year rates were 61% and 68%, respectively (p = .5). For patients with stage IIA nonbulky tumors, the 10-year cause-specific survival rates were 66% and 71%, respectively, and with bulky tumors, 69% and 44%, respectively (p = .05). In patients with stage IIB nonbulky tumors treated with irradiation alone or combined with surgery, the 10-year cause-specific survival rates were 72% and 65%, respectively. In stage IB and IIA disease after a hysterectomy and lymphadenectomy (even combined with irradiation), patients with metastatic lymph nodes have survival rates that are approximately 50% of those of patients with negative nodes.⁴⁰⁸

Randomized Trials of Postoperative Radiation Therapy or Chemoradiation After Radical Hysterectomy

Patients who have undergone radical hysterectomy with no preoperative radiation therapy are considered for postoperative chemoradiation therapy if they have high-risk prognostic factors, which include positive pelvic lymph nodes, as are patients with negative nodes who have microscopic positive margins of resection or parametrial involvement.⁴⁰⁹

Patients with any two of deep stromal invasion, vascular/lymphatic permeation, and large tumor size are candidates for postoperative radiation.⁴¹⁰ These patients have an intermediate risk of failure.¹⁶¹ Whether to add concurrent chemotherapy to postoperative radiation in the intermediate risk group is being tested in an accruing randomized trial; many institutions routinely implement chemoRT for intermediate-risk patients. Song et al.⁴¹¹ reported a 20-year experience in stage IB to IIA cervical-cancer patients with intermediate-risk factors (two or more of deep stromal invasion, lymphovascular invasion, and large tumor size) received postoperative RT or chemoradiation. Chemoradiation significantly decreased pelvic recurrence and distant metastases; there was no difference in acute or chronic grade 3 and 4 gastrointestinal side effects.

One randomized study showed improved recurrence-free survival with postoperative pelvic irradiation (46 to 50.4 Gy in 23 to 28 fractions) after radical surgery in the presence of positive pelvic nodes or node-negative high-risk factors in women with stage IB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy. There were 277 eligible patients with at least two of the following risk factors: greater than one-third stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter; 137 patients were randomized to pelvic radiation therapy and 140 to no further treatment. The results were updated by Rotman et al.;⁴¹² 24 (17%) patients in the irradiation group and 43 (30.7%) in the no-further-treatment group had cancer recurrences. In the radiation therapy group 27 patients died of cancer, and in the no-further-treatment group 40 died from cancer. There was a statistically significant reduction in risk of recurrence in the irradiation group, with recurrence-free rates at 2 years of 88% versus 79% for the irradiation and no-further-treatment groups, respectively. Overall survival difference did not reach statistical difference (p = .074; Fig. 69.19). Severe or life-threatening (GOG grade 3 or 4) adverse effects occurred in 9 patients (6.6%) in the radiation therapy group and 3 (2.1%) in the observation group. A meta-analysis of trials including stage IB1 to IIA cervical cancer found that women who received postoperative radiation had a significantly lower risk of disease progression at 5 years (RR = 0.6, 95% CI = 0.4 to 0.9). The risk of serious adverse events was not significantly higher if women received radiotherapy rather than no further treatment, possibly because the rate of adverse events was low.⁴¹³

Sundfør et al.⁴¹⁴ conducted a randomized study in which 122 patients with stage IIA and 20 patients with stage IIB cervix cancer were treated with intracavitary radium followed by either radical pelvic surgery including lymphadenectomy (group A, 72 patients) or EBRT (40 Gy) to the pelvis (group B, 70 patients). Postoperative RT (40 to 50 Gy) was given to patients in group A found to have node metastasis at operation. Fourteen patients in group A and 23 in group B died of recurrent cancer. The 10-year survival was 84% and 69%, respectively.

FIGURE 69.19. Recurrence-free survival (A) and overall survival (B) of patients with stage IB carcinoma of the cervix, correlated with treatment method. (From Rotman M, Sedlis A, Piedmonte MR. A phase III randomized trial of postoperative pelvic irradiation in patients with stage IB cervical carcinoma with poor prognostic features: follow up of a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 2006;65:169–176; with permission from Elsevier.)

Nonrandomized Trials of Postoperative Radiation Therapy or Chemoradiation After Radical Hysterectomy

Snijders-Keilholz et al.⁴¹⁵ described results in 233 women who underwent radical hysterectomy for stage I or IIA cervical carcinoma; 156 were treated with surgery alone, and 77 received adjuvant radiation therapy for tumor-related high-risk prognostic factors. The most important prognostic factor for survival and disease-free survival was pelvic lymph node positivity; additional factors were depth of invasion and positive surgical margins. Twelve patients recurred after surgery alone, all in the pelvis (100%). Of the 23 recurrences after surgery and adjuvant radiation therapy, 13 were in the pelvis (56%; p = .003). Ten patients with poor prognostic factors and negative nodes received adjuvant radiation therapy, and none of these patients recurred. The incidence of severe gastrointestinal radiation-related side effects was 2%. The incidence of lymphedema of the leg was 11%, which was similar to that in the surgery-alone group.

Garipagaoglu et al.⁴¹⁶ investigated prognostic factors in 100 patients with stage IB or IIA cervical carcinoma treated with radical hysterectomy and postoperative irradiation. The 5-year overall survival, disease-free survival, and pelvic tumor control rates were 83.6%, 82.8%, and 91.8%, respectively. Pelvic lymph node metastasis (p = .008), interval between surgery and irradiation (p = .001), overall radiation therapy time (p = .007), and tumor size (p = .028) were significant factors for pelvic tumor control, as well as for overall survival.

Lahousen et al.⁴¹⁷ reported on a GOG prospectively randomized, multicenter trial in which patients with stage IB or IIB cervical cancer treated with radical hysterectomy who had pelvic lymph node metastases or vascular invasion randomly received adjuvant chemotherapy (400 mg/m² carboplatin and 30 mg bleomycin), external pelvic radiation therapy, or no further treatment. After a median follow-up of 4.1 years (range, 2 to 7 years), there were no statistically significant differences (p = .9539) in disease-free survival rates among the three treatment arms, suggesting that adjuvant chemotherapy or radiation does not improve survival or recurrence rates in high-risk patients with cervical cancer after radical hysterectomy.

González González et al.⁴¹⁸ reported that in 89 patients with stage IB or IIA cervical cancer with positive lymph nodes receiving postoperative irradiation, the 5- and 10-year survival rates were 60% and 51%, respectively. By comparison, 43 patients with negative lymph nodes had a survival rate of 85%. In the surviving patients, there were 4 gastrointestinal and 7 genitourinary severe complications requiring surgical correction. In 4 patients, asymptomatic stenosis of the ureters was detected by IV pyelography performed routinely every year.

Bianchi et al.,⁴¹⁹ in 60 patients receiving external irradiation for pelvic node metastasis after radical hysterectomy, observed a 65% 5-year survival rate. In contrast, in 15 patients who refused postoperative irradiation, only 3 (20%) survived 5 years.

Chatani et al.⁴²⁰ reported on 128 patients with stage IB to IIB carcinoma of the cervix who underwent radical hysterectomy with bilateral pelvic lymphadenectomy and postoperative EBRT. The 5-year local and distant failure rates were, respectively, 2% and 12% for negative nodes, 23% and 25% for one positive node, and 32% and 57%, for two or more positive nodes (p = .0029 and .0051, respectively). The 5-year cause-specific survival rates were 90%, 59%, and 42%, respectively (p = .0001). The most common complication was lymphedema of the lower extremity, experienced by half of the patients (42% at 5 years and 49% at 10 years).

Uno et al.⁴²¹ evaluated results of postradical hysterectomy irradiation in 98 patients with stage IB to IIB cervical cancer; all of the patients had at least one pathologic risk factor for pelvic recurrence. The 5-year overall survival was 82%. There were pelvic recurrences in 5 cases and distant metastases in 15 cases. The 5-year overall survival rates for patients with or without pelvic lymph node metastasis were 76% and 89%, respectively (p = .018).

Kinney et al.⁴²² compared results of therapy in 82 patients with stage IB or IIA carcinoma of the cervix found to have pelvic lymph node metastases at Wertheim hysterectomy and bilateral lymphadenectomy without additional adjuvant therapy with 103 similar patients who received 50 Gy to the pelvis after surgery. The 5-year survival rate was 72% for the surgery-only patients and 64% for the group receiving adjuvant irradiation. The incidences of pelvic recurrence were 67% and 27%, respectively. The lack of impact on overall survival in the irradiated patients is most likely related to a higher incidence of distant metastases, which may be a reflection of shorter survival time and more high-risk patients. In 117 patients treated with radical hysterectomy and pelvic lymphadenectomy, histologically proven nodal metastatic disease was detected in 51 patients (44%; squamous cell in 35 and nonsquamous in 16). Nodal involvement was bilateral in 24 patients (47%).⁴²³ Para-aortic lymph node dissection was performed in 14 patients, and 5 had tumor involvement. Postoperative pelvic irradiation was administered to 29 of 51 patients (51.2 Gy, two fractions). Extended fields to the para-aortic area were used in 6 patients. The 5-year survival rates were 33% for the group receiving irradiation and 50% for the nonirradiated group. Only 1 patient treated with postoperative irradiation had a pelvic failure, in contrast to 7 patients not irradiated.

Inoue and Morita²⁷⁰ described results in 72 patients treated with extended-field irradiation after radical surgery for nodal metastases with stages IB (37 patients), IIA (6 patients), and IIB (29 patients) cervical cancer. The median dose to para-aortic lymph nodes was 43.5 Gy and to the pelvis was 45 Gy. The 5-year disease-free survival rates were 72% in 61 patients with squamous cell carcinoma and 27% in 11 patients with non–squamous cell carcinoma. The 10-year disease-free survival rates were 88% for 22 patients with one positive node, 67% for 15 patients with two or three positive nodes, 64% for 16 patients with four to 17 positive nodes, and 20% for 10 patients with unresectable lymph nodes. Nineteen severe complications occurred in 17 patients; 5 were attributed to surgery, 5 to irradiation, and 9 to both modalities. Four patients (5%) died of severe complications. Another 6 patients (8%) underwent major abdominal surgery for rectovaginal and ureterovaginal fistulas.

Mitsuhashi et al.⁴²⁴ described an analysis of 108 patients with carcinoma of the cervix treated with postoperative EBRT to the pelvis followed by intravaginal cone boost with electron beam to the vaginal cuff. The 5-year cause-specific survival rates were 89% for 89 patients undergoing elective radiation therapy and 56% for 19 patients undergoing salvage irradiation (p < .001). Recurrent tumors at the vaginal cuff were observed in only 2 patients in the elective irradiation group. Vesicovaginal fistula developed in 4 patients; only 1 patient had grade 2 rectal complications.

A Japanese group treated 189 stage IIB cervical cancer patients; 95 had a radical hysterectomy followed by adjuvant RT, and the other 94 patients had RT alone.⁴²⁵ There was a significant increase in grade 3 to 4 late toxicities in the surgery group, 24% versus 10%, p = .048. Therefore, RT is preferable, and in the modern era, chemoRT provides a superior outcome and should be administered to all stage IIB patients. The same group reported on 55 stage IA2 to IIB patients with multiple pelvic lymph nodes positive treated either with pelvic RT and concurrent chemotherapy or extended-field RT. Overall survival significantly improved with concurrent chemotherapy (p = .03).⁴²⁶

Lee et al.⁴²⁷ retrospectively compared 201 stage IB1 to IIB cervical cancer patients who had a radical hysterectomy with pelvic lymph node dissection followed by adjuvant concurrent weekly cisplatin to triweekly combination chemotherapy. With a median follow-up of 52 months, the weekly cisplatin group had the same therapeutic effect with less toxicity. The 5-year disease-free and overall survival were 82% and 81%, respectively, for patients treated with weekly cisplatin chemotherapy versus 74% and 79% for those treated with triweekly combination chemotherapy (p = NS). Leukopenia, neutropenia, thrombocytopenia, anemia, and hepatopathy were significantly more common in the triweekly combination chemotherapy group.

Postoperative External-Beam Radiation Dose

When metastatic pelvic lymph nodes are present, treatment has consisted of 45 Gy to the whole pelvis delivered with a four-field technique with concurrent weekly cisplatin. If gross residual disease is present, dose escalation to 54 to 65 Gy, depending on small-bowel dose limits (for example, D_5cc < 55 Gy), may be considered with a sequential IMRT nodal boost.⁸⁰ Patients with positive common iliac or para-aortic node metastases should receive 45 Gy to the entire para-aortic region with the superior border covering the renal hilum, with consideration of a boost to the tumor bed. If gross residual nodal disease is left, a nodal boost up to 65 Gy with IMRT is particularly suited to treat these patients.^271,275

In patients for whom postoperative irradiation is indicated for deep stromal invasion in the cervix or close or positive surgical margins, an alternative is to deliver 45-Gy pelvic external irradiation in combination with an intracavitary insertion (LDR, PDR, or HDR) and LDR equivalent dose of 65 Gy to the vaginal mucosa, using colpostats or a cylinder.⁴²⁸ At some institutions, external irradiation alone (50 Gy to the midplane of the pelvis) with a four-field box technique has been used. Hong et al.¹⁷⁶ recommended, for node-negative patients with high-risk factors, to irradiate only the low pelvis (median dose, 50 Gy), which resulted in a reduction of grade 3 small bowel morbidity (3 of 149 = 2%) in comparison with patients treated to the whole pelvis (6 of 79 = 8%). Five-year disease-specific survival was 84% and 86%, respectively.

Postoperative Intracavitary High–Dose-Rate Brachytherapy

Depending on the extent of surgical resection of the vagina, the vaginal cuff may be at risk for recurrence. There is no clear agreement on the indications for vaginal brachytherapy after radical hysterectomy, although adjuvant vaginal brachytherapy for cervical cancer is most commonly used as a boost after EBRT. Based on the American Brachytherapy Society guidelines, vaginal cuff boost should be considered in patients with a less-than-radical hysterectomy, close or positive margins, large or deeply invasive tumors, parametrial or vaginal involvement, or extensive lymphovascular invasion.⁴²⁸ Consideration of postoperative vaginal intracavitary brachytherapy after external-beam therapy is recommended for patients with carcinoma at the vaginal margin of resection.³⁰² If parametrial margins were close or positive, defined by either surgical clips or in the region of the surgical tumor bed, an external-beam dose of at least 54 Gy for close margins and higher for positive margins is recommended.

In patients receiving postoperative irradiation, extreme care should be exercised in designing treatment techniques, including intracavitary insertions; because of the surgical extirpation of the uterus, the bladder and rectosigmoid may be closer to the radioactive sources than in the patient with an intact uterus. Furthermore, vascular supply may be affected by the surgical procedure, and adhesions can prevent mobilization of the small-bowel loops that may be fixed in the pelvis. HDR brachytherapy after surgery is particularly suited for patients with cervical cancer because it prevents the prolonged immobilization required for LDR brachytherapy. In some patients at higher risk for parametrial tumor or lymph node metastases, HDR brachytherapy is combined with external-beam pelvic irradiation.

Hart et al.⁴²⁹ described results in 83 patients who received postoperative RT for early-stage cervical cancer with positive surgical margins, positive pelvic or para-aortic lymph nodes, lymphovascular space invasion, or deep stromal invasion or for disease discovered incidentally at simple hysterectomy. Twenty-eight patients were treated with LDR brachytherapy with or without EBRT and 55 with EBRT to the pelvis and HDR intracavitary. Of these 83 patients, 66 were evaluable (20 LDR and 46 HDR patients). Mean follow-up time was 101 months for the LDR group and 42 for the HDR group. The 5-year disease-free survival rates were 89% and 72%, and local tumor control rates were 90% (18 of 20) and 89% (41 of 46), respectively. Three of 20 patients (15%) receiving LDR and 4 of 46 (9%) receiving HDR experienced grade 2 or 3 late treatment-related complications. No patient in either group had grade 4 or 5 complications.

Busch et al.⁴³⁰ studied the outcome of 68 patients with cervical carcinoma; 48 were treated with radical hysterectomy and, because of risk factors, with postoperative RT (group 1), and 20 patients (group 2) were pretreated with standard hysterectomy and then admitted to the hospital for postoperative radiation therapy of the whole pelvis. Postoperative pelvic RT consisted of 39.6 Gy (box technique) and 6-Gy external-beam therapy to the pelvic lymph nodes, sparing the midline, plus two HDR applications (7.5 Gy each). Survival, locoregional tumor control, and metastatic disease rates were nearly identical in both groups. Patients with positive lymph nodes had a worse prognosis (75% 3-year survival rate).

Atkovar et al.⁴³¹ described results in 126 patients treated with postoperative irradiation (median of 50 Gy in 5 weeks); 37 received vaginal cuff HDR brachytherapy (three fractions of 8 to 10 Gy at 5 mm, weekly). Overall and disease-free survival and locoregional tumor control rates were 71%, 69.9%, and 78.1%, respectively. Grade 2 and 3 complications developed in 5.5% of patients. Survival was the same in 67 patients treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy and in 59 patients treated with radical hysterectomy and pelvic lymphadenectomy.

Stages IB2 to IVA: Chemoradiation

Patients with stages IB2 to IVA tumors are treated with irradiation including external beam and brachytherapy combined with concurrent chemotherapy. Numerous reports have been published on the concomitant use of irradiation and cytotoxic agents (hydroxyurea, cisplatin, and 5-FU, in some trials combined with mitomycin C) administered to obtain a radiosensitizing effect.⁴³²^–⁴³⁴ Cisplatin is one of the most active cytotoxic agents in squamous cell carcinoma of the uterine cervix.⁴³⁵ When cisplatin and irradiation are used concomitantly, substantial enhancement of cell killing is observed. Coughlin and Richmond⁴³³ and Douple⁴³⁶ suggested two mechanisms for radiation enhancement by cisplatin: (a) in hypoxic or oxygenated cells, free radicals with altered binding of cisplatin to DNA are formed at the time of irradiation, and (b) interaction inhibits repair of sublethal damage.

It is important, however, that patients complete the full course of 45 Gy with, ideally, five to six weekly doses of cisplatin or two doses of cisplatin and 5-FU every 3 weeks. In a study of 41 patients who had weekly biopsies while receiving RT and chemotherapy for cervix cancer, increased tumor cell proliferation and accelerated repopulation was observed within 2 weeks from the initiation of therapy. Patients with a sustained yield and high S-phase fraction for 2 or more weeks were at increased risk for tumor progression.⁴³⁷

Green et al.,⁴³⁸ in a search of medical databases for randomized trials of cervical cancer that compared RT with or without concurrent chemotherapy, identified 19 trials comprising 4,580 randomized patients, and they were the subjects of the meta-analysis. Concomitant chemotherapy and radiation improved tumor control and overall survival (RR = 0.71; p < .0001) and progression-free survival (RR = 0.61; p < .0001). The benefit was maximal in early-stage (I and II) disease. The absolute survival benefit was 12%. Patients receiving chemoirradiation had a higher incidence of grade 3 or 4 hematologic and gastrointestinal toxicities.

Patients with stage IVA disease (bladder and/or rectal invasion) can be treated either with higher doses of external radiation to the whole pelvis with concurrent chemotherapy followed by intracavitary or interstitial insertions (total dose to point A with LDR brachytherapy about 90 Gy) and additional parametrial irradiation, or with pelvic exenteration.⁴³⁹ Niibe et al.,⁴⁴⁰ in an analysis of 179 patients with stage IIIB adenocarcinoma, suggested that an optimal dose for large tumors was a total biological effective dose of >100 Gy.

A prospective single-arm trial, RTOG 0116, treated patients with positive para-aortic or high common iliac lymph nodes with extended-field radiation combined with cisplatin chemotherapy followed by brachytherapy.⁴⁴¹ IMRT was not allowed. The trial showed that this regimen is feasible, but the late grade 3 and 4 toxicity rate was 40%. There was no reduction in acute toxicity with the addition of amifostine.⁴⁴² The use of extended-field IMRT has been shown to reduce the risk of gastrointestinal toxicity in two retrospective series reports^443,275 and may be of benefit to patients with positive common or para-aortic lymph nodes requiring extended-field radiation with concurrent chemotherapy.

In countries or circumstances where a wait time exists and patients cannot immediately start on concurrent chemoradiation, induction chemotherapy may be considered. An alternative to cisplatin in this situation may be concurrent nedaplatin, which did not cause any nephrotoxicity in an analysis of 104 patients.⁴⁴⁴

Randomized Trials of Chemoradiation

Results from several cooperative oncology groups demonstrated that cisplatin-based chemotherapy, when given concurrently with RT, prolongs survival in women with locally advanced cervical cancers (Table 69.12), as well as in women with stage I to IIA disease who have metastatic disease in the pelvic lymph nodes, positive parametrial disease, or positive surgical margins at the time of primary surgery.⁴⁴⁵

The GOG conducted randomized Protocol 85, in which patients with carcinoma of the cervix, a clinical stage of IIB to IVA, and negative para-aortic nodes were treated with external pelvic irradiation (51 Gy) combined with 30 Gy to point A with LDR brachytherapy.⁴⁴⁶ One hundred twenty- seven patients received 5-FU (IV infusion, 1 g/m² for 4 days) and cisplatin (50 mg/m² IV) on days 1, 29, and 30 to 33, and 191 patients received hydroxyurea (80 mg/kg orally twice weekly). With a median follow-up for survivors of 8.7 years, the 5-year survival rate in the cisplatin/5-FU arm was 60%, compared with 47% for women in the hydroxyurea arm.

TABLE 69.12 DETAILS OF THE TREATMENT PROTOCOLS OF THE FIVE RANDOMIZED TRIALS THAT FORMED THE BASIS OF THE NATIONAL CANCER INSTITUTE ANNOUNCEMENT

After completion of GOG 85, the group opened GOG 120⁴⁴⁷^,⁴⁴⁸ for the same patient population, which was a three-arm randomized trial comparing irradiation plus hydroxyurea versus irradiation plus weekly cisplatin versus irradiation plus hydroxyurea, cisplatin, and 5-FU. In 526 evaluable patients with a median follow-up for survivors of 106 months, the 5- and 10-year survival rates for women in both the weekly cisplatin and irradiation arm and the irradiation, 5-FU, and cisplatin arm were 60% and 53%, respectively, compared with 40% and 34% in the hydroxyurea and irradiation arm (p ≤ .01). Overall survival was also significantly better in the two patient groups receiving cisplatin. Hematologic toxicity was greater in the group treated with the three drugs compared with cisplatin or hydroxyurea alone.

The RTOG conducted a randomized study of 389 patients with stage IB to IIA of >5 cm, proven positive pelvic lymph nodes, or stage IIB to IVA carcinoma of the cervix in which patients were treated with either pelvic and para-aortic irradiation (best arm of RTOG Protocol 79-20) or pelvic irradiation and three cycles of concomitant chemotherapy with cisplatin (75 mg/m²) and 4-day infusion of 5-FU (1,000 mg/m² per day).⁴⁴⁹ Results were updated by Eifel et al.³⁹⁷ With a median follow-up of 6.6 years for 228 survivors, the 8-year overall survival rate for women on the irradiation and cisplatin/5-FU arm was 67% versus 41% in the irradiation-only arm (p < .0001). Disease-free survival rates were 66% and 36%, respectively. There were no significant differences in late complications in the treatment groups.

Southwest Oncology Group 8797 was a study for women with FIGO stage IA2, IB, or IIA carcinoma of the cervix with metastatic disease in the pelvic lymph nodes, positive parametrial involvement, or positive surgical margins at the time of primary radical hysterectomy with total pelvic lymphadenectomy. Patients had confirmed negative para-aortic lymph nodes; if the para-aortic lymph nodes were not sampled, the patients had confirmed negative common iliac lymph nodes. One hundred twenty-seven patients were randomized to treatment with pelvic EBRT with 5-FU infusion and cisplatin, and 116 were treated with irradiation alone. The 3-year survival for women on the adjuvant cisplatin/5-FU and RT arm was 87%, compared with 77% for women on the pelvic irradiation arm.⁴⁰⁹ The difference was statistically significant. An updated analysis with 5.2-year median follow-up reported 5-year overall survival of 80% versus 66%, favoring postoperative chemoradiation in high-risk patients.¹⁸³

In GOG 123, 369 women were enrolled. One hundred eighty-three women with bulky (≥4 cm) stage IB carcinoma of the cervix with negative pelvic and para-aortic nodes radiographically or surgically determined were randomized to be treated with pelvic EBRT and brachytherapy, followed by extrafascial hysterectomy, and 186 received EBRT and brachytherapy with weekly cisplatin (40 mg/m²; total dose not to exceed 70 mg/week) followed by extrafascial hysterectomy.⁴⁵⁰ In an updated analysis with median follow-up of 101 months⁴⁵¹ the 6-year progression-free survival rate for women treated with irradiation and cisplatin was 71%, compared with 60% for those treated with RT alone, after adjusting for age and tumor size (p < .004). The unadjusted 6-year overall survival rates were 78% and 64%, respectively (p < .015).

The results of randomized trials using concurrent chemoradiation are summarized in Table 69.13.⁴⁵² Curtin et al.⁴⁵³ completed a small phase III trial in which 89 patients with high-risk stage IB or IIA undergoing radical hysterectomy and pelvic node dissection were randomized to be treated with postoperative cisplatin/bleomycin alone (44 patients) or combined with pelvic RT (45 patients). There were 9 and 10 recurrences, respectively, and survival was equivalent.

On the other hand, Pearcey et al.⁴⁵⁴ reported on a Canadian randomized study in which 127 patients with stage IB to IIA of >5 cm or IIB carcinoma of the cervix were randomized to be treated with cisplatin (40 mg/m² weekly) and RT, and 126 patients were treated with RT alone (50.4 Gy to the pelvis combined with brachytherapy). With a median follow-up of 65 months, the 5-year survival rates were 59% and 56%, respectively (p = .43). There was a somewhat greater incidence of significant late morbidity in the RT-alone group (12% vs. 6%; p = .08). Possible explanations for the discrepancy in results between the five U.S. trials³⁷¹ and the Canadian study were analyzed by Lehman and Thomas.⁴⁴⁵ Some theories include that a higher percentage of early-stage patients were accrued, who therefore had less of a difference in survival, given that the baseline survival rate for both arms was quite high; and that treatment time was short for both arms, again minimizing the difference in improving survival in the chemotherapy arm. This was the smallest of the randomized chemoradiation trials, and although the hazard ratio was reduced, given the factors equalizing the two arms, a larger number of patients would have possibly shown a significant difference.

A 2005 update of a meta-analysis of concomitant chemotherapy and radiation therapy found 24 trials and concluded that chemoradiation improves overall survival and progression-free survival, whether or not cisplatin was used, with absolute benefits of 10% and 13% respectively.⁴⁵⁵ Similarly, a 2008 meta-analysis of the 13 trials that compared chemoradiotherapy to radiation found there was a 6% improvement in 5-year survival with concurrent chemoradiation (hazard ratio 0.81, p < .001). The effect was attributed to a reduction in both local and distant recurrence. Chemoradiation increased acute hematologic and gastrointestinal toxicity, but no confirmation was made about a difference in late toxicity.⁴⁵⁶

TABLE 69.13 RANDOMIZED STUDIES OF CONCURRENT CHEMOIRRADIATION IN CERVICAL CARCINOMA

In the United States, weekly cisplatin has become the preferred approach, with less toxicity than an every 3-week regimen and the increased likelihood of completing the treatment on schedule. The number of completed cycles of weekly treatment was shown by Nugent et al.⁴⁵⁷ to be predictive of survival. One hundred eighteen patients with locally advanced cervical cancer (stages IB2 to IVA) were treated with combination weekly cisplatin (40 mg/m²) and radiation between 2003 and 2007. Thirty percent of patients completed fewer than six cycles of chemotherapy. In multivariate analyses, the number of chemotherapy cycles was independently predictive of progression-free survival (PFS) and overall survival (OS). Patients who received fewer than six cycles of cisplatin had a worse PFS (HR = 2.65; 95% CI = 1.35 to 5.17; p = .0045) and OS (HR = 4.47; 95% CI = 1.83 to 10.9; p = .001). Advanced stage, longer time to RT completion, and absence of brachytherapy were also associated with decreased OS and PFS (p < .05). Similar results were found when analysis was conducted using a breakpoint of at least but not less than five chemotherapy cycles. The authors concluded that aggressive supportive care to minimize missed chemotherapy treatments may improve survival after chemoradiation. A retrospective review⁴⁵⁸ questioned whether cervical cancer patients should receive cisplatin 20 mg/m² é 5 days every 21 days concomitant with RT, or weekly 40 mg/m² weekly concomitant with RT, given that an advantage with regard to both acute toxicity and progression-free survival was seen in the 5-day regimen.

High-risk patients may benefit from adjuvant chemotherapy after chemoRT. A randomized trial of 515 cases of stages IIB to IVA cervical carcinoma treated with concurrent gemcitabine plus cisplatin followed by adjuvant gemcitabine and cisplatin compared to standard concurrent cisplatin with radiation showed a significant 3-year progression-free survival benefit 74% versus 65% (p = .03), as well as one in overall survival (HR = 0.68, 95% CI = 0.49 to 0.65).⁴⁵⁹ Grades 3 and 4 toxicity was higher in the extended-chemotherapy arm, including 2 deaths. Ongoing trials comparing “outback” chemotherapy continue to accrue patients.

Alternatives to Concurrent Cisplatin-Based Chemoradiation

In GOG Protocol 165, patients with stages IIB to IVA cervical cancer received either radiation therapy and concurrent weekly cisplatin (40 mg/m²) or radiation therapy and a protracted venous infusion (PVI) of 5-FU. Lanciano et al.⁴⁶⁰ reported that the study was prematurely closed after an interim analysis showed a failure rate 35% higher and would not result in improved DFS with PVI 5-FU/RT compared with weekly cisplatin.

Lorvidhaya et al.⁴⁶¹ reported on 673 patients with predominantly stages IIB and IIIB disease randomized to receive either irradiation alone or combined with chemotherapy administered in an adjuvant, concurrent, or adjuvant and concurrent schedule. Concomitant chemotherapy consisted of mitomycin C (10 mg/m²) given on days 1 and 30 and oral 5-FU (300 mg/m² per day) given on days 1 to 14 and 42 to 56. Adjuvant chemotherapy consisted of three cycles of oral 5-FU (200 mg/day) given for 4 weeks, with a 2-week rest every 6 weeks. With a median follow-up of 25 months, there was a statistically significant improvement in disease-free survival for all patients who received chemotherapy/RT, regardless of the timing of administration of the chemotherapy. However, the authors did not state the radiation dose delivered with brachytherapy, the total dose prescribed to point A, or the overall treatment time. In the absence of this information, the adequacy of the radiation therapy cannot be evaluated, and we cannot assume that the results of this study apply to all patients treated with irradiation.

In a randomized trial comparing monthly fluorouracil and cisplatin versus weekly cisplatin concurrent with pelvic radiation, Kim et al.⁴⁶² enrolled 158 stages IIB and IVA patients. With a median follow-up of 39 months, the acute grades 3 and 4 hematologic toxicity were significantly worse in the fluorouracil/cisplatin arm, 43% versus 26% (p = .04). The trial was not powered to detect a survival difference, and no difference in the overall or progression-free survival was noted.

Tseng et al.⁴⁶³ published results of a study in which patients with advanced carcinoma of the cervix were randomly assigned to either RT alone or concurrent chemotherapy (cisplatin, vincristine, and bleomycin every 3 weeks for a total of four courses) and RT. After a median follow-up of 46.8 months, the disease-free survival and actuarial survival rates were 51.7% and 61.7% in the concurrent group and 53.2% and 64.5% in the RT group, respectively (p = .27). Treatment-related toxicity was higher with the combination therapy compared with irradiation alone (36.7% vs. 17.7%; p = .02).

Several small phase II studies have been performed showing no advantage to weekly paclitaxel over weekly cisplatin⁴⁶⁴ and too high toxicity with concomitant cisplatin–paclitaxel.⁴⁶² Concurrent weekly carboplatin alone has been shown in many studies to be feasible,⁴⁶⁶ including in the elderly; it is also an alternative in patients that have an elevated creatinine. Docetaxel and carboplatin concurrent with radiation was also found to be a feasible regimen.⁴⁶⁷

The GOG carried out a trial of irradiation with either concomitant hydroxyurea (HOU) or a placebo in patients with stage IIIB or IVA cervix cancer.⁴⁶⁸ The study was criticized because patients were not surgically staged, half of the 190 patients were not evaluable, and radiation doses were low.³⁰² Piver et al.⁴⁶⁹ published an update of a study of 130 patients (13 with para-aortic lymph node metastasis), 75 of whom were surgically staged. Of 66 patients who underwent surgical staging, 33 received hydroxyurea and 33 a placebo in combination with irradiation. Of the patients who did not have surgical staging, 27 received hydroxyurea and 37 received placebo. The 2-year survival was higher in the HOU group. Symonds et al.,⁴⁷⁰ in a review of seven randomized trials, found no evidence to support the use of hydrea with RT in cervix cancer.

In larger randomized trial by the GOG reported by Stehman et al.,⁴⁷¹ 296 surgically staged patients with stage IIB to IVA disease and negative para-aortic nodes were randomized to irradiation plus either hydroxyurea (139 patients) or misonidazole (157 patients). Survival was not statistically different between the regimens, with 33.8% deaths in the hydroxyurea group and 38.9% deaths in the misonidazole group (p = .25). Failure limited to the pelvis occurred in 18% of patients in the hydroxyurea group and 23.6% in the misonidazole group. Of note, in a randomized RTOG trial of patients with stage III disease, Leibel et al.⁴⁷² and Overgaard et al.⁴⁷³ reported lower survival in patients receiving misonidazole than in the patients treated with irradiation alone.

Grigsby et al.⁴⁷⁴ published results of an RTOG study in which 120 patients with carcinoma of the cervix were randomized to receive irradiation alone or combined with misonidazole. The 5-year progression-free survival was 22% and 29%, respectively. These findings are similar to those reported by Overgaard et al.,⁴⁷³ who, in a randomized study of 331 patients with carcinoma of the cervix treated with either misonidazole or a placebo and irradiation, found no significant difference in local tumor control (50% vs. 54%), disease-free survival (47% vs. 46%), or crude survival (39% vs. 45%).

Nonrandomized Studies of Chemotherapy and Irradiation

Numerous preliminary reports have been published on results of neoadjuvant/concomitant use of cisplatin and 5-FU, with or without mitomycin C, combined with irradiation to treat patients with locally advanced or recurrent carcinoma of the cervix.⁴⁷⁵

Trials with Cisplatin, 5-Fluorouracil, or Both

Perez and Grigsby⁴⁷⁶ reported on 58 patients with locally advanced carcinoma of the cervix treated with concurrent 5-FU/cisplatin and irradiation and compared the results with 257 patients with similar stages treated with irradiation alone during the same period. Pelvic tumor control and disease-free and cause-specific survival were comparable. The incidence of rectal and bladder fistula was 7% in the chemoirradiation group and 4% with irradiation alone (p = .61).

Park et al.⁴³⁴ described results in 113 patients with high-risk invasive cervical carcinoma treated with cisplatin and 5-FU. For adenocarcinoma, doxorubicin (45 mg/m² IV) was added. The patients subsequently received radiation therapy (not described in the publication). For patients with stage I or II tumors >4 cm, the 5-year survival rate was 78.3% with chemoirradiation and was 48% for 77 patients treated with RT alone (p < .01). For stages III and IV the rates were 69.1% and 57.4%, respectively. Toxicity with combined chemoirradiation was not significantly enhanced compared with irradiation alone.

Sardi et al.⁴⁷⁷ reported results of three courses of cisplatin, vincristine, and bleomycin (days 1 to 3) at 10-day intervals combined with RT in 205 unselected patients with stage IB cervix cancer (tumors >2 cm) who were divided at random into two groups treated with surgery and RT or neoadjuvant chemotherapy, surgery, and irradiation. After 67 months, no difference in survival was seen in patients with tumors 2 to 4 cm in both groups (77% for control patients vs. 82% with neoadjuvant chemotherapy), but statistically significant differences were seen in bulky tumors (>4 cm): 61% versus 80% in favor of neoadjuvant chemotherapy.

Souhami et al.⁴⁷⁸ treated 50 patients with bulky, locally advanced carcinoma of the cervix with a combination of weekly cisplatin (30 mg/m²) concurrent with RT. At 44 months, the actuarial survival rate was 65%, the total pelvic failure rate was 26%, and the distant metastasis rate was 24%. The incidence of late gastrointestinal toxicity was high, with 10 rectal ulcers (4 colostomies required for severe bleeding), 2 rectovaginal fistulas, and 2 small-bowel obstructions.

Park et al.⁴⁷⁹ treated patients with stages I and II carcinoma of the cervix >4 cm with RT alone or concurrent or sequential chemoradiation with cisplatin and 5-FU. The 30-month survival rates were 100% with concurrent chemoirradiation, 89.5% with sequential treatment, and 79.5% with irradiation alone (p < .05).

Lee et al.⁴⁸⁰ treated 40 women with cervix cancer using 50-Gy EBRT and brachytherapy; in 25 cases, three concurrent cycles of cisplatin/5-FU were given, and in 15 cases, six cycles of consolidation chemotherapy were given. There was no difference in 2-year survival between the two groups (98% to 100%). Grade 2 or greater hematologic toxicity was more frequent in the consolidation patients.

Grigsby et al.,⁴⁸¹ in a prospective study of 65 patients with cervical cancer and node negative on FDG-PET treated with RT alone (15 patients) or combined with concurrent weekly cisplatin (50 patients), noted a 5-year cause-specific survival of 78% and 74%, respectively. Severe complications included 1 rectovaginal fistula and 1 rectal stricture in the concurrent chemotherapy/RT group and 1 chemotherapy-related death.

Trials with Carboplatin

Katanyoo et al.⁴⁶⁶ reported 148 patients with stages IIB to IVA cervical cancer treated with concurrent weekly carboplatin (100 mg/m² or area under the curve 2) for a median of six cycles and radiation. Among the 142 responders, 36 experienced recurrences: pelvic recurrences in 7 (4.7%), distant failure in 25 (16.9%), and both pelvic and distant in 4 (2.7%). The 2- and 5-year progression-free survival rates were 75.1% and 63.0%, respectively, with the corresponding 2- and 5-year overall survival rates of 81.9% and 63.5%. No grade 3 or 4 hematologic and nonhematologic toxicities were observed during treatment in any patients. Late grade 3 to 4 gastrointestinal or genitourinary toxicities were 10.1% and 0.7%, respectively.

Cetina et al.⁴⁸² looked at the use of weekly carboplatin in 59 elderly, diabetic, and/or hypertensive stage IB2 to IIIB cervical cancer patients. All patients completed radiation and 80% received five of six planned cycles, with 83% reaching a complete response. With a median follow-up of 20 months, 33% relapsed, and the 3-year overall survival rate was 63%. Although the regimen is safe and tolerable, it may have reduced efficacy compared to weekly cisplatin.

Trials with Mitomycin C or Tirapazamine

Mitomycin C acts as an alkylating agent and inhibits DNA and RNA synthesis. Activation of mitomycin C is increased in hypoxic conditions, and thus it acts as a hypoxic radiosensitizer. Interstitial pneumonitis and pulmonary fibrosis are usually related to the dose of drug. Use of IV dexamethasone before administration of the drug may prevent pulmonary toxicity.

Christie et al.⁴³² described results in three groups of patients with stages IIB and III carcinoma of the cervix treated with pelvic irradiation and an intracavitary insertion combined with chemotherapy. Group A (64 patients) received 5-FU infusion during the first and last weeks of irradiation combined with mitomycin C (10 mg/m² IV). Group B (29 patients) received 5-FU without mitomycin C, and group C (84 patients) received irradiation alone. With median follow-up of 7.2 years, the 5-year survival rates were 56%, 32%, and 36%, and the local tumor control was 73%, 53%, and 50%, respectively. Toxicity was greater in group A (36% grade 3 and 4) compared with the 5-FU and irradiation group (14%) and the irradiation-alone group (20%).

Roberts et al.⁴⁸³ reported on a trial in which 160 patients with locally advanced cervical cancer were randomized to receive RT alone (82 patients) or RT with concomitant mitomycin C (78 patients). The 4-year actuarial survival was 72% and 56%, respectively (p = .13), and the local recurrence-free survival rate was 78% and 63%, respectively (p = .11). There were no treatment-related deaths. No excess in nonhematologic toxicity has been observed with combined mitomycin C and irradiation.

Tirapazamine, a radiation sensitizer with selective cytotoxic effect on hypoxic cells, was combined with cisplatin in 56 patients with recurrent or metastatic cancer. After six cycles given every 21 days, 4 complete and 13 partial responses were noted. Overall 6-month survival was 56%. Better response was seen in patients who had not received radiosensitizing chemotherapy previously.⁴⁸⁴

Besides the usual hematologic and pelvic toxicity described in many of these studies with chemoradiation, Wun et al.,⁴⁸⁵ in a retrospective analysis of 75 patients with gynecologic cancer who received erythropoietin and chemotherapy/RT, noted that 17 had upper- or lower-extremity thrombosis, in contrast to 2 of 72 who did not receive erythropoietin. Of note, Anders et al.,⁴⁸⁶ in a review of the literature, reported that 6 of 128 patients (4.7%) treated with chemotherapy/RT without erythropoietin developed grade 4 or 5 thrombosis toxicity.

Trial with Bevacizumab Concurrent with RT

RTOG 0417 treated patients with once-weekly cisplatin (40 mg/m²) chemotherapy and standard pelvic radiotherapy and brachytherapy. Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for three cycles. A total of 49 patients were evaluable. The median follow-up was 12.4 months (range, 4.6 to 31.4 months). There were no treatment-related serious adverse events. There were 15 (31%) protocol-specified, treatment-related adverse events within 90 days of treatment start; the most common were hematologic (12 of 15; 80%). Eighteen (37%) occurred during treatment or follow-up at any time.⁴⁸⁷

Trial with Epidermal Growth Factor Receptor Inhibition Concurrent with RT

Nogueira-Rodrigues et al.⁴⁸⁸ reported a phase I study administering escalating doses of erlotinib (50/100/150 mg) combined with cisplatin (40 mg/m², weekly, five cycles) and radiotherapy (external beam, 4,500 cGy in 25 fractions, followed by four fractions/600 cGy weekly of brachytherapy) in squamous cell cervical carcinoma patients, stages IIB to IIIB. Fifteen patients were enrolled, 3 at dose level (DL) 50 mg, 4 at DL 100 mg, and 8 at DL 150 mg. Three patients did not complete the planned schedule. One patient at DL 100 mg withdrew informed consent due to grade 2 rash; at DL 150 mg, 1 patient presented with Raynaud’s syndrome and had cisplatin interrupted, and another patient presented with grade 4 hepatotoxicity. The latter was interpreted as dose-limiting toxicity, and a new cohort of 150 mg was started. No further grade 4 toxicity occurred. Grade 3 toxicity occurred in 6 cases: diarrhea in 3 patients, rash in 2 patients, and leukopenia in 1 patient. Treatment did not lead to limiting in-field toxicity.

Intra-Arterial Chemotherapy

Intra-arterial infusion of chemotherapeutic agents in cervical carcinoma was used for some years based on the distinct arterial supply to the tumor-bearing area. Unfortunately, the responses have been uncommon and short, and the toxicity and complication rates have been significant.⁴⁸⁹

Onishi et al.⁴⁹⁰ evaluated intra-arterial cisplatin through catheters inserted into both internal iliac arteries in cervix carcinoma. Patients were randomized into a concurrent intra-arterial infusion of cisplatin with RT (18 patients) or RT alone (15 patients). Five-year overall survival rates were 44.4% and 50%, respectively. In the group receiving intra-arterial infusion, grade 3 or 4 late bowel complications were seen in 44% and grade 3 or 4 myelosuppression in 33%, significantly more than in the RT group.

Neoadjuvant Chemotherapy

Thomas⁴⁹¹ summarized the rationale and potential limitations of neoadjuvant chemotherapy in carcinoma of the cervix. Although response rates to the chemotherapy are between 30% and 85%, none of the studies showed an advantage for pelvic tumor control or survival.⁴⁹²^–⁴⁹⁹ Colombo et al.,⁵⁰⁰ in a review of the literature, concluded that the role of neoadjuvant chemotherapy followed by radiation and by concomitant chemotherapy or by surgery is controversial because no significant advantages in survival or local control have been shown, and receiving upfront chemotherapy may compromise immune status and the patient’s ability to receive definitive treatment with radiation or surgery.

Souhami et al.⁵⁰¹ randomized 107 patients with stage IIIB carcinoma of the cervix to treatment with irradiation alone or combined with bleomycin, vincristine, mitomycin, and cisplatin. The overall 5-year survival rate for the neoadjuvant-treated patients was 23%, in contrast to 39% for those treated with irradiation alone (p = .02). Locoregional and distant failure rates were similar in both groups.

Kumar et al.⁵⁰² reported a randomized trial in which 94 patients with carcinoma of the cervix were treated with chemotherapy (two cycles of bleomycin, ifosfamide-mesna, and cisplatin) followed by RT, and 90 patients were treated with irradiation alone. In the chemotherapy/RT group, 32-month survival was 63% for stage IIB and 50% for stage III, and in the RT group, the rate was 59% for stage IIB and 27% for stage IIIB tumors (differences not statistically significant). There was no difference in radiation-induced toxicity between the two groups.

In a Swedish study,⁴⁹⁸ 47 patients with carcinoma of the cervix were randomized to be treated with irradiation alone (64.8 Gy, 1.8-Gy fractions) and 47 with a combination of three cycles of cisplatin and 5 days of 5-FU administered every third week, followed by the same pelvic irradiation. The 5-year disease-free survival rates were 70% with chemoirradiation and 57% with irradiation alone (p = .07). The incidences of pelvic recurrence were 60% and 47%, respectively, and for distant metastasis they were 19% and 35%, respectively. Two patients in the chemoirradiation and 1 in the irradiation-alone group died as a consequence of therapy.

Response to Chemotherapy Alone for Patients with Metastatic or Recurrent Disease

Cisplatin has been combined with other cytotoxic agents. Long et al.⁵⁰³ conducted a randomized study comparing methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), cisplatin/topotecan, or cisplatin alone in patients with advanced cervical cancer. The MVAC arm was closed after 4 deaths in 63 patients. In 294 patients assigned to the other arms, response rate was 27% for cisplatin/topotecan and 13% for cisplatin alone, with median survival of 9.4 and 6.5 months, respectively.

Paclitaxel, a natural product found initially in the bark of the western yew tree, produces depolymerization and irreversible bundling of tubulin in the cell. It has been shown to have a radiosensitizing effect and may also be considered for patients with metastatic disease. Rose et al.⁵⁰⁴ reported on a phase II study of 44 patients in which the starting dose was paclitaxel (135 mg/m², maximum 170 mg/m²) infused over 24 hours, followed by cisplatin (75 mg/m²) every 21 days. Forty patients (90.9%) had received prior radiation therapy. A median of six courses of chemotherapy was given. Of the 41 assessable patients, 5 (12.2%) had a complete response and 14 (34.1%) had a partial response. Vinorelbine is a semisynthetic derivative of vinblastine. In a phase II trial in patients with prior irradiation, a 28% response rate was observed.⁵⁰⁵ Other trials used the drug as neoadjuvant chemotherapy; in 42 patients, 2 complete and 17 partial responses (45%) were observed.⁵⁰⁶^,⁵⁰⁷

Irinotecan and topotecan are camptothecin derivatives whose cytotoxic mechanism is believed to target topoisomerase I.⁵⁰⁸ An international phase II trial reported a similar 21% response rate in patients predominantly with prior irradiation (1 complete and 8 partial responses among 42 patients).⁵⁰⁹

Gemcitabine, a nucleoside analogue, showed a 4.5% partial response and 36% stable disease in 22 patients.⁵¹⁰ In combination with cisplatin, it was evaluated in 32 women with previously treated cervix cancer (initial dose 800 mg/m² on days 1 and 8, then every 28 days); there were 7 (22%) partial responses and 12 stable disease responses.⁵¹¹

A phase II trial of docetaxel and gemcitabine showed an overall response rate of 21%. With a median survival of 7 months, 39% were alive at 1 year. Doxetaxel combined with carboplatin has been shown to have a 25% response rate.⁴⁶⁷

A four-arm comparison of cisplatin/paclitaxel versus cisplatin/vinorelbine, cisplatin/gemcitabine, or cisplatin/topotecan found that the standard arm of cisplatin/paclitaxel remained the best option for patients with stage IVB, recurrent or persistent cervical carcinoma.⁵¹²

In a phase II GOG study of cetuximab 400 mg/m² initial dose followed by 250 mg/m² weekly until disease progression or prohibitive toxicity, 38 patients (15%) had no progression for at least 6 months. The median OS was 7 months. When cetuximab was combined with cisplatin, no additional benefit beyond cisplatin was identified.⁵¹³

Ifosfamide, paclitaxel, and carboplatin as a triple regimen showed a 33% objective complete or partial response, with an overall median survival of 10 months.⁵¹⁴ Antiangiogenic tyrosine kinase inhibitors pazopanib and lapatinib were tested in 230 patients with stage IVB persistent/recurrent cervical carcinoma. An improvement in progression-free and overall survival was seen with pazopanib.⁵¹⁵

Studies with Radiation Alone

For patients unable to tolerate concurrent chemotherapy or in countries where chemotherapy is not readily available, radiation alone may be used as an alternative to chemoradiation. Mendenhall et al.⁵¹⁶ analyzed 1211 patients treated with radiation alone with a minimum follow up of 3 years. In patients with Stage IB and IIA disease there was no significant correlation between doses to these points and pelvic tumor control. In Stage IIB doses of less than 6000 cGy to point A correlated with a high pelvic failure rate (8 of 12, 66.7%) in contrast to doses of 6000 to 9000 cGy (61 of 261, 23.4%) or higher than 9000 cGy (10 of 74, 13.5%) (P 0.01). In Stage III the pelvic failure rate with doses below 6000 cGy to point A was 72% (18 of 25) compared to 39% (71 of 180) for 6000 to 9000 cGy or 35% (27 of 77) with doses above 9000 cGy (p ≤ 0.01).

Thoms et al.⁵¹⁷ reported on 363 patients with bulky endocervical carcinoma treated with curative intent (246 with irradiation alone and 117 with irradiation and surgery); 10-year survival was 45% and 64%, respectively. In a subset of 48 patients with similar tumors treated with irradiation alone and 45 treated with irradiation and surgery, the 10-year survival rates were comparable, and the pelvic tumor control rates were 90% and 87%, respectively.

Eifel et al.¹⁶⁸ evaluated 1,526 patients, of whom 371 had tumors 6 cm or greater. There were biases in treatment selection, but a statistically significantly higher 10-year survival rate was noted in patients treated with irradiation and surgery (64% vs. 45%). Tumor diameter was highly significant as a prognostic factor, and the authors concluded that only patients with lesions >8 cm in diameter benefited from adjuvant hysterectomy. In the same study, 98 patients with stages IB and IIB bulky endocervical carcinomas (≥6 cm in diameter) were treated with RT alone. Twenty-four patients received <6,000 mgh of intracavitary treatment, and 73 received higher doses. Despite having somewhat more favorably treated tumors, patients who received <6,000 mgh had a higher rate of pelvic recurrence at 5 years (33%) than those who received higher doses (16%; p = .03). Actuarial 5-year survival rates were 44% and 60% for low- and high-dose groups, respectively (p = .14).

Kim et al.⁵¹⁸ assessed the prognostic factors for pelvic tumor control in 40 patients with FIGO stage IB or IIA carcinoma and 25 patients with stage IIB carcinoma classified as barrel shaped (i.e., at least 5 cm in diameter) treated with curative intent. Seventy-two percent were treated with RT alone and 28% with RT and extrafascial hysterectomy. The extent of tumor regression after external-beam radiation therapy correlated with the likelihood of local tumor control (p = .02). For patients treated with radiation therapy alone, increased brachytherapy dose was associated with better local tumor control. The 10-year overall and cause-specific survival rates were 53% and 68%, respectively, and did not differ significantly between treatment groups.

Paley et al.⁵¹⁹ reported on 57 patients with barrel-shaped (mean diameter, 5 to 9 cm) cervical carcinoma treated with preoperative EBRT and BT (mean dose to point A, 79.6 Gy) followed by extrafascial hysterectomy 6 to 8 weeks later. Residual disease was present in 35 (61%) of the hysterectomy specimens; tumor sterilization correlated significantly with the mean dose to point A (p = .016). Ninety-five percent of the patients with negative specimens remained clinically free of disease at their last follow-up versus 31% of those with residual disease (p < .001).

The GOG and RTOG conducted a randomized phase III clinical trial in which 282 patients with carcinoma of the cervix measuring 4 cm or greater (exophytic or barrel shaped) were treated with either external-beam and intracavitary irradiation or a slightly lower dose of intracavitary irradiation and the same pelvic EBRT followed by an extrafascial hysterectomy.⁵²⁰ The survival rates were 61.4% for irradiation alone and 64.4% for the combined irradiation and surgery group. The incidence of recurrences was 43.3% in the irradiation group compared to 34.5% with combined therapy (p = .081). The incidence of local recurrences was 25.8% and 14.4%, respectively. The incidence of grade 3 and 4 sequelae of therapy was 10.5% and 9.8%, respectively. Thus, the addition of hysterectomy to standard irradiation did not significantly affect survival, although there was a small reduction in the local recurrence rate. When combined therapy is used, the dose of irradiation delivered to the lymph nodes, the time of the operation, and the pathologic examination of the specimens are critical in determining the presence of postirradiation residual tumor.

Perez et al.³⁶ noted that in patients with primary carcinoma of the uterine cervix who had endometrial stromal invasion or tumor only in the curettings, the addition of a hysterectomy did not improve the survival rate because most of the patients failed at distant sites.

For stage IIB tumors treated with irradiation alone, the 5-year survival rate is 60% to 65%. The pelvic failure rate ranges from 18% to 39%. In an analysis of the Patterns of Care Study in 157 patients who had stage IIB disease, Coia et al.⁵²¹ reported a better 4-year survival rate (67% and 54%) and in-field tumor control rate (78% and 68%) in patients with unilateral versus bilateral parametrial involvement, respectively. Similarly, in a review of 1,178 patients with stage IIB disease, the 5-year survival rates were 70% with medial parametrial and 58% with lateral parametrial involvement (p = .004).⁵²² Kim et al.,⁵²³ in patients with stage IIB disease, found a correlation of point A dose and incidence of pelvic failures.

In stage IIIB carcinoma, the 5-year survival rates range from 25% to 48%, and pelvic failure rates range from 38% to 50%.¹⁶⁵^,⁵²⁴ Hanks et al.,⁵²⁵ reporting on the Patterns of Care Study, noted a 28% probability of 5-year survival in patients with stage III carcinoma of the cervix treated in a large number of facilities in the United States versus 60% survival in selected large centers (extended survey). Later, Komaki et al.⁵²⁶ reported a significant increase in local pelvic tumor control (69%) in patients with stage III carcinoma of the cervix treated in 1983, compared with 37% and 49% in earlier periods (p = .03). The 5-year survival rate increased from 25% to 47% (p = .02). The improvement in pelvic tumor control may be associated with higher external-beam doses but more likely is related to the substantial increase in the percentage of patients receiving brachytherapy (96%) and more careful dosimetry and dose calculations for intracavitary therapy. They noted a decrease in major complications from 15% in the 1973 and 13% in the 1978 Patterns of Care Surveys to 7% in 1983. Montana et al.⁵²⁷ reported that calculation of doses to the bladder and rectum were performed in 80% and 76% of patients, respectively, in the 1983 survey, which may also have resulted in decreased toxicity.

Arthur et al.,⁵²⁸ in 89 patients with stage IIIB carcinoma of the cervix treated with external irradiation and brachytherapy, observed a locoregional tumor control rate of 22.5% and a disease-free survival rate of 15% in 16 patients treated with 78 Gy or lower doses to point A, in comparison with 53% and 47%, respectively, in 24 patients receiving higher doses.

Horiot et al.⁵²⁹ reported the results of a French cooperative study of 1,383 patients with invasive carcinoma of the uterus treated with irradiation alone following the MD Anderson Hospital treatment guidelines. Survival and locoregional tumor control were similar in both groups, except in stage III, in which the pelvic and central failure rates were lower in the French patients, may be because of different tumor volumes or socioeconomic factors. Major urinary complications were noted in 2% of the patients. Grade 3 bowel complications occurred in 3% of the patients with stages I and IIA disease and in 7% of patients with stages IIB and III disease. Barillot et al.⁵³⁰ updated the results in 642 patients; the analysis was divided into three periods: 1970 to 1978 (use of standard prescriptions), 1979 to 1984 (implementation of individual adjustments), and 1985 to 1994 (systematic individual adjustments). There was a significant reduction of the external radiation dose (>40 Gy in 47% of patients before 1979 vs. 36% after 1984), use of parametrial boost (55% vs. 39%), use of vaginal cylinder (28% vs. 11.5%), and combined intracavitary and external irradiation volume (842 vs. 503 cm³ on average). The 5-year actuarial toxicity rates were as follows: grade 2, 23.5%; grade 3, 10%; and grade 4, 3%. The three main predictive factors for rectal and bladder sequelae were increased external radiation dose, higher dose rate at reference points, and whole-vagina brachytherapy.

Marcial et al.⁵³¹ described results of a randomized trial in 301 patients with stages IIB, III, and IVA carcinoma of the uterine cervix treated with split-course irradiation (10 fractions of 2.5 Gy, five weekly doses up to 25 Gy, followed by a rest period of 2 weeks, and an additional 25 Gy delivered in the same manner) or continuous irradiation (30 fractions of 1.7 Gy daily, five times per week, total dose 51 Gy) combined with LDR brachytherapy for 30 Gy to point A. There was no significant difference in tumor control, acute or late complications, or survival in the two groups.

In patients with stage IVA disease, the 5-year survival rates range from 18% to 34%, and pelvic failures from 60% to 80% after definitive irradiation.²⁶⁰ Million et al.²⁶¹ reported 18 of 53 patients (34%) with bladder involvement surviving without disease after definitive irradiation, results comparable with those obtained with exenteration. Kramer et al.²⁶⁰ reported on 48 patients with stage IVA carcinoma of the cervix treated with definitive RT. Patients with minimal parametrial involvement had a 5-year survival rate of 46%, compared with only 5% for those with extensive parametrial tumor. The major complication rate was 22%, consisting mostly of vesicovaginal fistula in 5 patients.

Crozier et al.⁵³² described equivalent 5-year survival rates after salvage pelvic exenteration (37% in 35 patients with adenocarcinoma and 39% in 70 patients with squamous cell carcinoma). In the adenocarcinoma group, 14 of 22 patients, and in the squamous cell-carcinoma group, 14 of 30 patients had distant metastases after pelvic exenteration.

Combination of Irradiation and Surgery

Preoperative Chemoirradiation

Bulky endocervical tumors and the so-called barrel-shaped cervix have a higher incidence of central recurrence, pelvic and para-aortic lymph node metastasis, and distant dissemination.⁵³³ In the setting of plain x-ray, point-based planning for brachytherapy, because of the inability of intracavitary sources to encompass the entire tumor in a high-dose volume, larger doses of external radiation to the whole pelvis or extrafascial hysterectomy, or both, have been advocated to improve therapeutic results.⁴ Alternatively, the use of 3D planning for the brachytherapy component significantly improves survival,⁵³⁴ and the ability to dose escalate due to more precise dose delivery improves local control.⁵³⁵ In rare cases with large residual after 45 Gy external beam, an extrafasical hysterectomy may be considered 6–12 weeks after completion of preoperative irradiation (45 Gy to the whole pelvis and one intracavitary LDR insertion for 5,500 mgh, delivering approximately 50 Gy to point A, with a total dose to point A of 70 Gy, or the equivalent dose in HDR, approximately three fractions of 6 Gy per fraction). Higher doses of irradiation alone yield equivalent pelvic tumor control and survival rates.¹⁶⁸^,³⁰²

Keys et al.⁴⁵⁰ reported on 183 women with bulky (≥4 cm) stage IB carcinoma of the cervix with negative pelvic and para-aortic nodes radiographically treated with pelvic EBRT and brachytherapy, followed by extrafascial hysterectomy, or EBRT and brachytherapy (to 70 Gy) with weekly cisplatin followed by extrafascial hysterectomy. A significant survival advantage was seen with the combination of concurrent chemoradiation. However, in comparison to other trials, the survival was not significantly improved with the addition of a hysterectomy. The use of PET scanning to determine residual disease allows selection of patients who may be appropriate candidates for a hysterectomy after completion of external-beam treatment.⁹⁰ Therefore, patients should receive definitive doses of chemoradiation, with hysterectomy reserved for salvage in patients with either gross residual disease or PET-positive disease that is biopsy proven at 3 months after completion of radiation. A subsequent reanalysis including GOG 123 and GOG 71 analyzed 464 patients allocated to pelvic radiation (75 Gy, n = 291) plus hysterectomy or to pelvic radiation (75 Gy) and cisplatin (40 mg/m², n = 176) plus hysterectomy. A benefit to chemoradiation was seen for patients who had a poor response.⁵³⁶

Morice et al.⁵³⁷ reported a randomized trial of 61 patients treated with adjuvant hysterectomy versus none after EBRT with concurrent weekly cisplatin and vaginal brachytherapy (15 Gy to intermediate-risk CTV) for stage IB2 or II cervical cancer. Hysterectomy increased the number of deaths, with an 11% nonsignificant survival advantage in the no-hysterectomy arm (86% vs. 97%). As a result of this trial, routine adjuvant hysterectomy is no longer practiced for patients who have no residual disease at 6 weeks after chemoradiation.

Motton et al.⁵³⁸ retrospectively reviewed 171 patients treated with chemoradiation followed by simple extrafascial hysterectomy or extended hysterectomy. There was no difference in survival or complication rate based on type of surgery. Leguevaque et al.⁵³⁹ reported on 111 patients treated with or without adjuvant hysterectomy after chemoradiation; there was no advantage to overall survival, but there was a significant difference in recurrence rates.

Touboul et al.⁵⁴⁰ reported on toxicities for 150 patients with stages IB2 to IVA cervical cancer treated at Institut Gustave Roussy with extrafascial versus modified radical hysterectomy after chemoradiation. After a median follow-up of 3.6 years, 15% had grade 2 or greater side effects, including lymphedema, ureteral fistula, bowel fistula, iliac and vessel rupture. There were 2 postoperative deaths. Modified radical versus extrafascial hysterectomy had a higher odds ratio (OR) for complications of 2.4 (p = .04), as did the presence of residual disease.

Elective Para-Aortic Lymph Node Irradiation

Rotman et al.⁴¹² updated results of an RTOG randomized study of 337 patients with stage IIB carcinoma of the uterine cervix with no clinical or radiographic evidence of para-aortic lymphadenopathy who, in addition to standard pelvic irradiation, were randomized to electively receive or not 45 Gy to the para-aortic region (1.6- to 1.8-Gy fractions). The 10-year survival rate was 55% for patients receiving elective para-aortic irradiation and 44% for those treated to the pelvis only (p = .02). The locoregional tumor control rate was similar (69% in the para-aortic node–irradiated group and 65% for the pelvis-irradiated group). The 10-year grade 4 or 5 (major) complication rate was 8% in the group receiving para-aortic irradiation, compared with 4% in patients treated with pelvic irradiation alone (p = .06).

A similar randomized study was reported by Haie et al.⁵⁴¹ and the European Organization for Research and Treatment of Cancer (EORTC) on 441 patients with cervical carcinoma, including stage III, who had no evidence of para-aortic lymph node involvement. In the study group, the para-aortic area either received or did not receive 45 Gy with external-beam irradiation. No statistically significant difference was found between the two treatment arms with regard to local tumor control, distant metastases, or survival. However, the incidence of para-aortic and distant metastases without pelvic failure was significantly higher in patients receiving pelvic irradiation alone. The incidence of small-bowel injury was 0.9% in the pelvic irradiation group and 2.3% in the pelvic plus para-aortic irradiation group. A severe complication rate of 9% was observed in patients receiving para-aortic irradiation, compared with 4.8% in those treated to the pelvis only.

Sood et al.⁵⁴² treated 54 patients with cervix cancer using extended fields (45 Gy) and HDR brachytherapy; 44 received concurrent cisplatin (20 mg/m² per day for 5 days during week 1 and 4 and once after the second HDR insertion). During a median follow-up of 28 months, 6 patients had died. The 3-year local tumor control was 100% and 85%, respectively. Late toxicity was 10% and 6%, respectively.

Huang et al.²³⁵ assessed 758 patients and found that 38 (5%) and 42 (6%) had isolated and nonisolated para-aortic lymph node (PALN) recurrences after a median follow-up of 50 months (range, 2 to 159 months), respectively. The 3-year and 5-year overall survival rate after PALN recurrence was 35% and 28%, respectively, with those with isolated recurrences faring better than those with a nonisolated recurrence (p < .001). An SCC-Ag level of >40 ng/mL (p< .001), advanced parametrial involvement (score 4 to 6; p = .002), and the presence of pelvic lymphadenopathy (p = .007) were independent factors associated with PALN relapse on multivariate analysis. This group subsequently identified pretreatment CEA of ≥10 ng/mL as an additional risk factor of PALN relapse after definitive concurrent chemo-radiation therapy (CCRT) for SCC of the uterine cervix in patients with pretreatment SCC-Ag levels of <10 ng/mL.²³⁶ The role of prophylactic para-aortic radiation, particularly in patients with large tumor size, parametrial involvement, or involved pelvic lymph nodes, must be carefully weighed against the potential toxicities of para-aortic radiation.

METASTASES TO PARA-AORTIC LYMPH NODES

Para-aortic lymph node metastases are frequently combined with distant dissemination but are clinically apparent in only 10% to 20% of patients who have recurrences.

Varia et al.⁵⁴³ reported on GOG Protocol 125, in which 87 patients with biopsy-confirmed para-aortic lymph nodes from cervical cancer were treated with extended-field irradiation (45 Gy in 1.5-Gy fractions) and higher doses to the pelvis (approximately 80 Gy to point A) in combination with 5-FU and cisplatin. The 3-year progression-free survival rate was 33%, and the overall survival rate was 39%. Grades 3 and 4 hematologic toxicity were noted in 13 patients (15%) and chronic proctitis in 3 (3.5%), and 4 patients (4.6%) required surgery for rectal complications.

Nelson et al.³⁹⁰ reported on 104 patients with stages II and III cervical carcinoma who had exploratory laparotomy and para-aortic lymph node biopsies; 12.5% of patients had stage IIA disease, 14.9% had stage IIB disease, and 38.4% had stage III disease had para-aortic lymph node metastases. They were treated with 60 Gy to the para-aortic region. Within 4 years, 50% of these patients had distant metastases, and only 1 out of 13 was alive. There was no significant increase in complications in the patients receiving para-aortic irradiation (39% and 32%). The authors concluded that the main goal of exploratory laparotomy and para-aortic lymph node biopsy is to define the extent of disease.

Lovecchio et al.⁵⁴⁴ noted a 50% 5-year survival rate in 36 patients with stages IB and IIA cervical carcinoma who had histologically confirmed para-aortic lymph node metastases treated with RT (including 45 Gy to the para-aortic lymph nodes). Fourteen of 31 evaluable patients had pelvic recurrences (12 combined with distant metastases). Unfortunately, the authors did not specify how many patients had para-aortic recurrences, although they reported 4 abdominal failures.

Stryker and Mortel⁵⁴⁵ determined survival after extended-field treatment of para-aortic lymph node metastasis plus brachytherapy or pelvic boost in 35 patients; 5-year survival was 41.7% for 12 patients with microscopic para-aortic lymph node metastasis and 26.1% for 23 patients with grossly enlarged lymph nodes. Three patients (8.6%) had grade 4 morbidity.

Grigsby et al.⁵⁴⁶ reviewed 43 patients with cervical cancer and biopsy-proven positive para-aortic lymph nodes treated with external irradiation to the pelvis and para-aortic regions (45 to 50 Gy) combined with brachytherapy. The 5-year overall survival rate was 32%, and the cause-specific survival rate was 49%. Tumor recurrence occurred in 20 patients (3 in the pelvis, 9 in pelvis and distant metastasis, and 8 in distant metastasis only). Severe grade 3 complications occurred in 2 patients (1 had an enterovaginal fistula and the other had radiation myelitis).

Hacker et al.,⁵⁴⁷ in 437 patients with invasive cervical carcinoma, 222 of whom were treated with radical hysterectomy and lymphadenectomy, identified 34 in whom resection of bulky pelvic or para-aortic lymph nodes was carried out without a complete lymphadenectomy. Thirty-three patients received pelvic external irradiation, and 28 combined pelvic and para-aortic extended-field irradiation (50.4 Gy in 1.8-Gy fractions using a four-field technique). Four cycles of cisplatin were administered to 23 patients. The 5-year survival was 80% in patients with pelvic and common iliac nodes and 48% in those with positive para-aortic lymph nodes. Serious long-term morbidity occurred in 6 patients (18%). Radiation enteritis was observed in 5 patients, leading to small-bowel obstruction necessitating resection.

Grigsby et al.⁵⁴⁸ evaluated twice-daily external irradiation to the pelvis and para-aortic nodes (1.2 Gy at 4- to 6-hour intervals, 5 days/week) combined with brachytherapy and concurrent chemotherapy in 29 patients with carcinoma of the cervix and positive para-aortic lymph nodes. EBRT doses were 24 to 48 Gy to the whole pelvis, 12 to 36 Gy parametrial boost, and 48 Gy to the para-aortics, with additional boost to a total dose of 54 to 58 Gy to known metastatic para-aortic sites. One or two LDR brachytherapy applications were performed to deliver a total dose of 85 Gy to point A. Cisplatin (75 mg/m², days 1 and 22) and 5-FU (1,000 mg/m² per 24 hours for 4 days, days 1 and 22) were given for two or three cycles. Hyperfractionated external radiation therapy was completed in 86% (25 of 29). Radiation therapy toxicity was grade 2 in 34%, grade 3 in 21%, and grade 4 in 28%. An unacceptably high rate (31%, 9 of 29) of grade 4 nonhematologic toxicity was recorded. With a median follow-up of 18.9 months, at 2 years the overall survival rate was 47%, and the probability of locoregional failure was 49%.

Malfetano et al.⁵⁴⁹ treated 67 patients with carcinoma of the cervix (44 with stage IIB and 23 with stage III disease) with cisplatin (1 mg/kg up to 60 mg weekly) and extended-field radiation therapy, including the para-aortic nodes, and brachytherapy; 75% were alive without evidence of disease with a mean follow-up of 47.5 months.

Chou et al.⁵⁵⁰ treated 19 patients with isolated para-aortic lymph node metastasis from cervix cancer, 14 of them with chemoradiation, 4 with chemotherapy, and 1 with irradiation alone. Seven of the 14 patients receiving chemoradiation survived.

Goodman et al.⁵⁵¹ compiled survival statistics on patients with para-aortic lymph node metastasis and found an average 5-year survival rate of approximately 40% (Table 69.14).

TABLE 69.14 RESULTS OF EXTENDED-FIELD IRRADIATION FOR PARA-AORTIC LYMPH NODE METASTASES

CARCINOMA OF THE CERVICAL STUMP

A supracervical hysterectomy, which removes the uterus and leaves the cervix behind, may be performed for benign conditions of the uterus. The use of subtotal hysterectomy has declined, given the persistent risk of cervical cancer arising in the remnant tissue and the difficulty of managing cancer of the cervical stump.

It is important to divide carcinoma of the cervical stump into true, when the first symptom occurs 3 or more years after subtotal hysterectomy, or coincidental, when the symptoms are noticed before the third postoperative year. This separation is important because the prognosis for true carcinoma of the stump is significantly better than for coincidental lesions, in which carcinoma was probably present when the hysterectomy was performed.³⁰²

The natural history and patterns of spread of carcinoma of the cervical stump are similar to those of the cervix in the intact uterus. The diagnostic workup, clinical staging, and basic principles of therapy are the same. Treatment also follows similar paradigms. When surgery is indicated for early stage I tumors, it may be more difficult because of the previous surgical procedures and the presence of adhesions in the pelvis. With radiation therapy, external-beam treatments are identical, although small bowel may be adherent to the superior portion of the cervix due to scar tissue, and using the prone position, as well as having the patient maintain a full bladder for treatment, may aid in attempting to move the small bowel out of the radiated field. Whole-pelvic radiation is recommended, with the superior border set at the level of the bifurcation of the common iliac nodes as determined by a CT simulation, or at the L4–5 interspace for those planned with plain film radiographs. A dose of 45 Gy in 1.8-Gy fractions over 5 weeks is the most commonly recommended dose, with concurrent weekly cisplatin at 40 mg/m² given for five doses. For brachytherapy, if >2 cm of the endocervical canal remain, it is best to insert a short tandem surrounded by ovoids, a ring, or, if indicated due to vaginal extension or lateral extension, interstitial catheters. For low–dose-rate insertions, as many sources as technically feasible should be inserted in the remaining cervical canal. For HDR brachytherapy, the tandem should extend from the cervical os superiorly to the full extent of the canal. When there is no opportunity to insert any sources in the cervical canal, an interstitial implant to bring the tumor dose to approximately 80 to 90 Gy for brachytherapy after completing a standard dose of 45 Gy to the whole pelvis is recommended while monitoring the radiation dose to the organs at risk (OAR). The use of external-beam radiation alone is not recommended due to the significant mobility of the cervix due to bladder motion, the low dose tolerance of the surrounding small bowel, and the high dose of radiation necessary for cure in patients with bulky disease. Total dose (external and LDR intracavitary brachytherapy) to the upper vaginal mucosa should not exceed 150 Gy, and tolerance doses to small volumes (D_2cc) of the bladder (90 to 100 Gy) or rectum and sigmoid (70 to 75 Gy) should be carefully monitored.

The 5-year survival rate for carcinoma of the cervical stump treated with irradiation is similar to that reported for patients with carcinoma of the intact uterus.⁵⁵²^,⁵⁵³ The anatomic sites of failure and the incidence of recurrences are similar to those of patients in whom the uterus is intact. Distant metastases also follow the same distribution. In 253 patients with carcinoma of the cervical stump treated at MD Anderson Cancer Center, median survival was 203, 140, and 32 months for stages I, II, and III, respectively.⁵⁵⁴ Kovalic et al.⁵⁵² reported on 70 patients with carcinoma of the surgical stump treated with irradiation; 16 also underwent a surgical procedure. The 10-year disease-free survival was 79% for stage IB, 66% for stage IIB, and 39% for stage IIIB disease. The pelvic failure rates were 10%, 9%, and 50%, respectively. Major gastrointestinal complications were noted in 9% of patients and urinary complications in 3.8%. The results are comparable with those seen in patients treated for invasive carcinoma of the cervix with an intact uterus.

Hannoun-Levi et al.⁵⁵⁵ published results in 77 patients treated for carcinoma of the cervical stump. Treatment consisted of a combination of EBRT and brachytherapy, and, in a few cases, patients underwent surgery or interstitial brachytherapy. Three-year pelvic tumor control was achieved in 59 of 77 patients (76.6%); tumor control probabilities were 77%, 73.7%, and 56% in patients with stage I, II, and III tumors, respectively. Late complications were grade 2 in 5 patients (6.5%); grade 3 in 1 patient (1.3%), and grade 4 in 2 patients (2.6%).

Hellstrom et al.⁵⁵⁶ published a retrospective study of 145 patients treated for carcinoma of the cervical stump, representing 2.2% of all cervical cancers. Three control cases to each case were matched from the cohort of cases with cervical carcinoma with intact uterus. The dose of irradiation from the intracavitary application given to the stump cancers was lower than for comparable cases with intact uterus. Long-term prognosis for squamous cell carcinoma of the uterine stump was comparable to that of the ordinary cervical carcinomas. Stump adenocarcinomas had a worse prognosis compared with adenocarcinoma of the intact uterus (p < .07) and with squamous cell carcinoma stump (p= .05). The complication rate was higher for stump cancer cases compared with that for cervical cancers with an intact uterus.

Because of the close proximity of the bladder, rectum, and small intestine to the intracavitary sources and to the often higher doses of external-beam irradiation given to the whole pelvis, complications are somewhat more frequent than in carcinoma of the cervix with an intact uterus. Care in brachytherapy treatment planning, including the use of 3D-based treatment planning to minimize dose to the normal tissues, should be considered.

SMALL-CELL CARCINOMA OF THE CERVIX

Small-cell carcinoma of the cervix, like its counterparts in the lung and other anatomic locations, has a high proliferation rate and marked propensity for regional lymph node and distant metastases. Miller et al.⁵⁵⁷ demonstrated that all small-cell carcinomas of the cervix are aneuploid, compared with only 30% of large-cell nonkeratinizing squamous carcinomas. The incidence of lymphatic vascular space invasion is 80% to 90%, and that of lymph node metastases has been reported to be 40% to 67%.⁵⁵⁸ These patients must be evaluated in conjunction with a medical oncologist; the workup should include bone marrow aspiration biopsy of the iliac crest and other tests to rule out metastatic spread. Furthermore, the basic therapy should include a combination of cytotoxic agents with pelvic EBRT and intracavitary brachytherapy to doses similar to those used in squamous cell carcinoma, although some patients have been treated with radical surgery. If bleeding is present, prompt institution of radiation therapy with concurrent chemotherapy is necessary. Patients have extremely poor outcomes, with the only reported survivors having had triple-modality therapy of small tumors treated by radical hysterectomy, concurrent chemoRT, and adjuvant chemotherapy. Prophylactic cranial irradiation is not indicated because cervix cancer will most commonly spread first to lung and then to brain.

Patients with small-cell carcinoma of the cervix are treated with the same irradiation techniques as outlined for other histologic varieties of cervical carcinoma in combination with multiagent chemotherapy, including external beam radiation to 45 Gy, followed by nodal boost if PET-positive nodes are identified, followed by brachytherapy. The most frequently prescribed drugs are cisplatin and etoposide (VP-16) every 3 weeks.⁵⁵⁹ Hoskins et al.⁵⁶⁰ used a multimodality regimen of four cycles of cisplatin and etoposide with concurrent locoregional RT in 11 women with small-cell carcinoma of the cervix. The 3-year overall and failure-free survival rates were 28%. Four patients were alive in first remission; the remaining 7 died (2 from toxicity, 5 from cancer). Toxicity of therapy was significant, with 70% experiencing severe neutropenia; 40% were admitted to the hospital for emesis control.

Twelve patients with small-cell carcinoma of the cervix were treated with radical hysterectomy (5 received postoperative RT for lymph node metastases and 2 for close margins). With a mean follow-up of 73 months, the disease-free survival rate was 36.4%, compared with 71.6% for patients with non–small-cell carcinoma.⁵⁵⁸ Four of five patients who received postoperative irradiation died with pelvic recurrence, and 3 also had disseminated metastases. However, only those with small lesions or those who received adjuvant irradiation were cured.

Delaloge et al.⁵⁶¹ reported only 2 of 10 patients with neuroendocrine small-cell carcinoma of the cervix surviving at 13 and 53 months after treatment, which included surgery, irradiation, and cisplatin/etoposide combination chemotherapy.

Boruta et al.⁵⁶² reviewed results in 11 of their and 23 other patients with early-stage neuroendocrine cervical carcinoma identified by a Medline search. Lymphovascular space invasion was present in 21 of 27 patients (78%) (7 unknown), and 15 of 29 (52%) had lymph node metastases. Fifteen patients were treated with cisplatin/etoposide (PE), 7 with vincristine/doxorubicin/cyclophosphamide (VAC), 2 with alternating cycles of VAC and PE, and 10 with other chemotherapy regimens. Twenty women were treated with radiation therapy. The presence of lymph node metastases was a poor prognostic factor (p < .001). PE and VAC chemotherapy were associated with increased survival (p < .01).

ADENOCARCINOMA OF THE CERVIX

Squamous cell carcinoma accounts for 80% of cervical cancers, adenocarcinoma for 15%, and adenosquamous carcinoma for 3% to 5%. SEER data from 1972–2002 suggest that the incidence of cervical adenocarcinoma is rising, but, based on SEER data, cause-specific mortality is not significantly different than that for SCC.⁵⁶³ Adenocarcinoma has been linked to HPV 18, which has a higher rate of nodal and distant metastases than HPV 16.¹⁵⁹ Despite a slower regression after irradiation, reflecting cellular kinetics and slow growth, no difference in tumor control or survival has been observed in adenocarcinomas compared with squamous cell carcinomas,⁵⁶⁴^,⁵⁶⁵ although prognosis is related to clinical stage, volume of disease, and dose of irradiation.⁵⁶⁶ Because of the predilection for endocervical involvement in adenocarcinoma, a combination of irradiation and conservative hysterectomy has been advocated by some authors,⁵⁶⁷ although results are comparable with those obtained with irradiation alone.⁵⁶⁴ Given a lower toxicity profile with chemoRT, this is preferable to a planned course of RT alone followed by hysterectomy upfront. Patients who have residual disease after chemoRT may be candidates for adjuvant hysterectomy.

Grigsby et al.⁵⁶⁴ found no difference in 5-year DFS in patients with adenocarcinoma of the cervix (AC) compared with SCC treated with RT alone or combined with surgery. In contrast, Eifel et al.⁵⁶⁸ reported that overall 5-year survival rates for patients with SCC and AC were 81% and 72%, respectively (p < .01). Patients with AC had a maximum cervical diameter of <4 cm more often than did those with SCC (53% vs. 47%). For 903 patients with tumors of ≥4 cm, 73% of those with SCC survived ≥5 years, compared with only 59% of those with AC (p < .01). Although there was no significant difference in the rate of pelvic disease recurrence for patients with AC or SCC tumors of ≥4 cm (17% vs. 13%; p = .16), the rate of distant metastases was greater for patients with AC (37% vs. 21%; p < .01). For patients with tumors of ≥4 cm, prognosis was strongly correlated with tumor size (p < .01) and lymphangiogram findings (p < .01) but not with age (p = .58) or tumor morphology (exophytic vs. endocervical; p = .33); a trend toward better survival in 165 patients who underwent adjuvant hysterectomy (78% vs. 71%) was not significant (p = .09). Multivariate analysis confirmed a highly significant independent association between histology and survival; patients with tumors ≥4 cm in diameter that were AC had an estimated risk of death 1.9 times that of patients with SCC (p < .01).

Nakano et al.⁵⁶⁹ studied 58 patients with adenocarcinoma of the cervix treated with LDR or HDR brachytherapy and external pelvic irradiation. The 10-year survival rates for stages I, II, III, and IV were 85.7%, 60%, 27.6%, and 9.1%, respectively. The local tumor control rate with HDR treatment was 45.5%, significantly lower than with LDR (85.7%) or mixed–dose-rate treatments (72.7%). Kilgore et al.,⁵⁶⁵ in a study of 162 patients with adenocarcinoma compared with matched patients with squamous cell carcinoma, found that clinical stage and lesion size were the most important prognostic factors. In patients with stage I tumors, no significant difference in survival was found when they were treated with radical surgery, irradiation alone, or irradiation combined with hysterectomy. In contrast, Kjorstad et al.⁵⁷⁰ reported a worse 5-year survival rate in 102 patients with adenocarcinoma (51%) compared with that of 1,900 patients with squamous cell or other differentiated carcinomas (68%).

A Cochrane database review⁵⁷¹ found only one randomized trial, the Landoni study, in which a small subgroup analysis that was not powered to detect a difference showed an apparent improvement with surgery, although the majority of patients required adjuvant RT, rather than chemoradiation, which increases the rates of toxicity. Adenocarcinoma predicts worse OS on multivariate analysis (HR = 2.68, 95% CI = 1.9 to 3.8). Primary chemoradiation is considered the standard regimen for patients with locally advanced cervical adenocarcinoma.

Huang et al.⁵⁷² reported on 318 stage IB to IIB postoperative cervical cancer patients, 202 (63.5%) with SCC and 116 (36.5%) with AC/atypical squamous cells (ASC), treated by radical hysterectomy and adjuvant RT/concurrent chemo-RT (CCRT). The 5-year relapse-free survival rates for SCC and AC/ASC patients were 83.4% and 66.5%, respectively (p < 0 .001). Distant metastasis was the major failure pattern in both groups. After multivariate analysis, prognostic factors for local recurrence included younger age, parametrial invasion, AC/ASC histology, and positive resection margin; for distant recurrence they included parametrial invasion, lymph node metastasis, and AC/ASC histology. Compared with SCC patients, those with AC/ASC had higher local relapse rates for the intermediate-risk group but a higher distant metastasis rate for the high-risk group. Postoperative CCRT tended to improve survival for intermediate-risk but not for high-risk AC/ASC patients.

TREATMENT OF ELDERLY PATIENTS

Oguchi et al.⁵⁷³ reported on 23 patients 90 years of age or older treated for cervix carcinoma. Definitive radiation therapy was completed in 13 of the patients, and local tumor control at 6 months was attained in 9 patients. Palliative RT was completed in 7 of 11, and palliation was observed in 9 patients (81%). Seven patients were alive for 15 to 67 months. Fourteen patients died because of intercurrent disease or senility associated with active cancer and 2 because of senility without evidence of cancer. The 2-year overall and relapse-free survival rates were 30% and 21%, respectively.

CARCINOMA OF THE CERVIX AND PREGNANCY

The concurrent presence of carcinoma in situ or invasive carcinoma of the uterine cervix and pregnancy, although rare, poses a therapeutic dilemma to gynecologic and radiation oncologists. Reported incidence is approximately 1 to 10 per 10,000 pregnancies.⁵⁷⁴ In the United States, the incidence has decreased. Norstrom et al.,⁵⁷⁵ in Sweden, found that cervical cancer was diagnosed in 33 women in association with pregnancy (incidence, 11.1 cases per 100,000 deliveries and 7.5 per 100,000 pregnancies). Abnormal bleeding was the symptom that led to diagnosis in 54.5% of the women; 45.5% were asymptomatic but had an abnormal cervicovaginal cytologic test result (39.4%) or abnormal vaginal examination (6.1%) in association with pregnancy. During the follow-up, 1 of 12 women with cervix cancer in the first trimester, 4 of 12 in the third trimester, and 2 of 9 postpartum died of the disease. Primary surgery was used more frequently than radiation therapy.

For carcinoma in situ, if the pregnancy is allowed to reach full term, confirmation of the diagnosis by colposcopy and conservative management with monthly Pap smears constitutes the best approach. Conization has frequently been performed. Punch biopsies can be obtained, but the diagnostic accuracy is less reliable. As many as 50% of the patients have residual carcinoma in situ after delivery.

In patients with invasive carcinoma, the lesion is usually clinically apparent. Multiple punch biopsies are adequate to confirm the diagnosis. Management is individualized based on tumor size and stage, patient age, and desires of the patient (or couple) regarding the pregnancy. The majority of patients with cervical cancer diagnosed during pregnancy (approximately 75%) have stage I tumors.⁵⁷⁴^,⁵⁷⁶^,⁵⁷⁷

Women with tumors diagnosed early in pregnancy are often recommended to abort the fetus. Because there is a greater need to institute therapy as soon as possible, the accepted method of treatment in patients in the first 6 months of pregnancy is to carry out definitive surgery or radiation therapy, as indicated by the stage of the disease, with resultant loss of the fetus. An abortifacient may be administered before initiating radiation to ensure fetal demise and delivery of the placenta prior to initiation of treatment. The whole pelvis is irradiated (40 to 45 Gy in 4 to 5 weeks). However, in one series of 45 patients, 27% did not abort spontaneously and surgical evacuation was required;⁵⁷⁸alternatively, misoprostol may be administered as an alternative to surgical evacuation after failed spontaneous abortion.⁵⁷⁹ After this dose of radiation, careful evacuation of the uterus and LDR (or equivalent-dose HDR) brachytherapy may be performed under general anesthesia. If a radical hysterectomy is performed and positive pelvic lymph nodes are found, the usual postoperative irradiation, including external beam with or without intracavitary insertion, should be carried out.

If the woman refuses abortion, serial MRI scans at 2- to 3-month intervals to ensure no growth or spread to lymph nodes is recommended. Neoadjuvant chemotherapy may be considered in selected patients.⁵⁸⁰ Sorosky et al.⁵⁸¹reported on eight pregnant women with stage I carcinoma of the cervix who had declined immediate therapy and followed until the late third trimester; a cesarean section–radical hysterectomy was performed, with delay in therapy ranging from 3 to 40 weeks during the pregnancies. There was no clinical progression of the disease with follow-up of 33 months.

When patients are diagnosed in mid-pregnancy (second trimester), consideration to keeping the pregnancy and treating with chemotherapy is given. A French series reported five cases between 2002 and 2009.⁵⁸² Three patients received neoadjuvant chemotherapy; 1 patient died of cancer. A Chinese report described treatment of two patients with neoadjuvant paclitaxel and cisplatin as feasible.⁵⁸³

Occasionally in late pregnancy (final trimester), if tumors are small and an MRI confirms no lymph node involvement, definitive therapy is postponed until after imminent delivery. In a review of the literature intentional treatment delay was associated with a recurrence rate of 4%.³⁶² Greer et al.⁵⁸⁴ noted that in 600 infants without congenital abnormalities, when stage IB cervical carcinoma was diagnosed during pregnancy and fetal survival was chosen, the neonatal mortality rate decreased from 30% when the fetus was delivered at 26 to 27 weeks to 2.7% when the fetus was allowed to mature to 34 to 35 weeks. In the third trimester of pregnancy, when the fetus may be salvaged, some gynecologic oncologists prefer a postpartum cesarean section, combined with a radical hysterectomy and lymphadenectomy followed by radiation of high risk features are present. However, some authors report that vaginal delivery has no detrimental effect on the prognosis.⁵⁸⁵

Patients who require high doses of pelvic irradiation should be counseled regarding the permanent loss of reproductive capability, not only because of ovarian ablation (which happens with doses of 8 Gy or higher), but as a consequence of radiation effects in the uterus.⁵⁸⁶^,⁵⁸⁷

Survival is the same regardless of the trimester of the pregnancy in which definitive treatment is instituted. Creasman et al.⁵⁸⁵ reported on 48 patients treated by irradiation, 45 by irradiation followed by surgery, and 5 with radical hysterectomy alone. The survival was comparable with that of nonpregnant patients for similar stages. The survival rate for patients with stage I disease was comparable whether vaginal delivery was allowed or a cesarean section was performed (approximately 85% in stage I and 50% to 64% in stage II). In addition, the percentage of infants surviving (>80%) was the same in both groups.

Sood et al.⁵⁸⁷ performed a retrospective analysis of 26 women with cervical carcinoma diagnosed during pregnancy and treated primarily with radiation therapy (mean dose, 46.7 Gy) and LDR intracavitary radiation (mean dose, 56.5 Gy to point A). These cases were matched with 26 nonpregnant control patients based on age, histology, stage, treatment, and year of treatment. There were no statistically significant differences in recurrence rates or survival between the pregnant group and the control patients. Short-term toxicity was comparable in pregnant and nonpregnant patients. Long-term complication rates were 12% in pregnant patients and 27% in control patients, but this difference was not statistically significant. Most complications were likely related to radiation techniques (particularly the predominance of ⁶⁰Co).

Sood et al.⁵⁸⁸ compared the prognosis of 56 women who had cervical cancer diagnosed during pregnancy and 27 who were diagnosed within 6 months after delivery. Control patients (cervical cancer diagnosed at least 5 years since last delivery) were matched one-to-one with cases based on age, histology, stage, treatment, and time of treatment. Among the postpartum women, 11 were treated with radical hysterectomies and 14 with radiation therapy, and 2 with stage IA1 disease were treated with vaginal hysterectomies. One of 7 patients who had cesarean sections had a local and distant recurrence. In contrast, 10 of 17 (59%) patients who delivered vaginally had recurrences (p = .04). In multivariate analysis, vaginal delivery was the most significant predictor of recurrence, followed by high tumor stage. Survival for patients diagnosed in the postpartum period was significantly worse than for control patients and for those diagnosed during pregnancy. The authors concluded that pregnant women with cervical cancer should be delivered by cesarean section.

Jones et al.⁵⁸⁹ published a survey by the American College of Surgeons that evaluated management of invasive cervical carcinoma in 161 pregnant patients; 86 were treated with surgery alone, 30 with radiation therapy alone, and 45 with a combination of the two modalities. Approximately one-third of patients were diagnosed in each trimester. The 5-year survival was 94.6% for patients diagnosed in the first trimester, 76.9% for the second, and 68.9% for the third. The prognosis of patients with invasive carcinoma of the cervix associated with pregnancy was similar to that of nonpregnant patients. There was no significant difference in 5-year survival between the patients delivered by cesarean section and by normal vaginal delivery.

Senekjian et al.⁵⁹⁰ reported no difference in survival or patterns of failure in 24 women who were pregnant at the time of diagnosis of clear-cell adenocarcinoma of the cervix and vagina compared with 408 who had never been pregnant. The 5- and 10-year actuarial survival rates were 86% and 68% for the pregnant patients and 87% and 79% for the patients who had not been pregnant, respectively.

The practice popularized 30 years ago of administering a “restraining dose of radium” and deferring definitive radiation therapy until delivery is carried out should be strongly rejected. Strauss⁵⁹¹ reported 2 of 11 infants being born with microcephaly in addition to other complications such as alopecia, facial deformity, eye damage, and chromosomal abnormalities after this procedure.

BRACHYTHERAPY

After the discovery of radium in 1898 by the Curies, publications followed describing use of the first glass radium capsule in 1904 and a metal brachytherapy applicator for cervical cancer in 1905.⁵⁹² The incorporation of brachytherapy after external-beam treatment arose from the recognition that tumor control probability correlated with radiation dose and cancer volume.⁵⁹³ Evidence confirms that brachytherapy as used for dose escalation after external-beam treatment for cervical cancer significantly improves survival.⁵²⁵^,⁵⁹⁴^–⁵⁹⁷ Therefore, brachytherapy is a standard part of the treatment of locally advanced (stages IB2 to IVA) cervical cancer after external beam radiation; brachytherapy alone may be used as primary treatment for selected cases with early-stage (stages IA to IB1) cervical cancer.⁵⁹⁸ The increasing complexity of brachytherapy administration, including the use of complex imaging, mandates implementation of careful quality assurance measures and a culture of open communication to ensure safe practices in the clinic.⁵⁹⁸

Dose Rate

The ICRU in its Report 38⁵⁹⁹ defines brachytherapy dose rate as follows: LDR, 0.4 to 2 Gy/hr; medium dose rate (MDR) or PDR, 2 to 12 Gy/hr; and HDR, >12 Gy/hr. For LDR, the most commonly used isotope is ¹³⁷Cs, and for PDR and HDR it is ¹⁹²Ir. The use of HDR has significantly increased in the United States, from 13% in the 1996–1999 Quality Research in Radiation Oncology (formerly known as the Patterns of Care) survey to 62% in the 2007–2009 survey.³⁶⁹^,⁶⁰⁰ In other U.S., European, and Japanese surveys of gynecologic brachytherapy practitioners, approximately 85% state that they use HDR brachytherapy,⁶⁰¹^–⁶⁰²^,⁶⁰³ whereas in Canada the reported use is 68% HDR, 10% PDR, and 23% LDR.⁶⁰⁴ The dose delivered per fraction for HDR and proportion of dose delivered with external beam versus brachytherapy vary substantially in different centers around the world.⁶⁰²

Most institutions in the United States have either LDR or HDR brachytherapy available. Larger centers may have LDR, PDR, and/or HDR. Overall, outcomes are similar regardless of dose rate, with the caveat that for HDR, 3D imaging should be incorporated to ensure coverage of the tumor, particularly for large-volume disease.⁶⁰⁵ Several studies demonstrate worse survival for stage IIIB cervical cancer treated with HDR due to initiating the treatment early in the course of external beam therapy,⁶⁰⁶ when the tumor mass was >4 cm and therefore a prescription to point A did not cover the tumor volume, or by not using 3D planning to cover large residual disease.⁶⁰⁷

TABLE 69.15 MEAN VALUES OF THE NUMBER OF FRACTIONS, DOSE/FRACTION TO POINT A (FOR HIGH DOSE RATE) AND TREATMENT TIME, DOSE RATE FOR LOW DOSE RATE (WITH STANDARD ERRORS) AND THE RATIO OF TOTAL DOSES

FIGURE 69.20. Relationship between number of high–dose-rate (HDR) fractions and late normal tissue effects. Solid lines show the increase in normal-tissue late effects as the number of HDR fractions used to treat cervical cancer decreases. Dotted lines indicate the maximum level of late damage calculated for conventional low–dose-rate brachytherapy of 70 Gy at 0.5 Gy/hour for 140 hours and an arbitrary level 5% above this. The intersection of the solid lines with the dotted lines indicates the number of HDR fractions needed to give equal late normal-tissue effects. In this model, the dose to late-responding tissues should be kept at 83% of the tumor dose when treating with four to six HDR fractions. (Modified from Fowler JF. The radiobiology of brachytherapy. In: Martinez AA, Orton CG, Mould RF, eds. Brachytherapy HDR and LDR. Leersum, Netherlands: Nucletron International BV, 1990;121–137; with permission from Elsevier.)

Biology of High–Dose-Rate Brachytherapy for Cervical Carcinoma: Equivalent Dose in 2 Gy and Biologically Effective Dose

To achieve tumor control using HDR equivalent to that with LDR brachytherapy, attention to the dose/fractionation schedule and to normal tissue doses is mandatory.⁶⁰⁸^,⁶⁰⁹^–⁶¹⁰ The linear-quadratic (LQ) model provides calculation estimates of biologically equivalent dose taking into account dose rate, dose per fraction, and overall treatment time.⁶¹¹^,⁶¹² For comparison of LDR to HDR, the LQ model doses are normalized to an equivalent dose in 2 Gy (EQD2).⁶¹³ The α/β ratio is a critical component of the LQ model.⁶¹⁴ For cervix cancer, an α/β ratio of 10 Gy is used for tumor and an α/β of 3 Gy is used for normal tissues,⁶¹⁵ which may have inherent inaccuracies in generalizability,⁶¹⁶ although an α/β ratio of 3 Gy for the rectum has been correlated with late rectal complications.⁶¹⁷^,⁶¹⁸^–⁶¹⁹

Spreadsheets to assist with HDR EQD2 dose conversions are available from the American Brachytherapy Society (www.americanbrachytherapy.org/guidelines). The values derived are not actual doses but biologically effective ones that take into consideration dose rate and effect of fraction size.⁶²⁰

Although use of a detailed EQD2 conversion is preferred, an approximation of these values was proposed by Orton et al.,⁶¹⁰ with an LDR-to-HDR reduction factor of 0.54 to 0.6 (Table 69.15), and by Patel et al.,⁶⁰⁷ with a similar correction factor of 0.58. These conversion factors are valid when three to five HDR fractions are used, but with a higher number of fractions (six to eight), the conversion factor is closer to 0.75. Therefore, use of the EQD2 worksheet is recommended for consistency.

The importance of adopting biologically based equivalent doses when switching from LDR to HDR brachytherapy is exemplified in a report by Newman⁶²¹ on 115 patients treated with external irradiation (40 to 50 Gy) and manual afterloading cesium sources delivering 60 Gy to point A with a dose rate of 0.75 Gy/hour, or a Selectron device with 40-mCi sources, which delivered from 0.75 to 1 Gy/hour to point A. Because of the increased dose rate, the total intracavitary dose was reduced by 20%. Grade 3 genitourinary and gastrointestinal complications were observed in 3 of 87 patients (3.4%) treated with LDR, in contrast to 30 of 132 patients (22.7%) treated with the Selectron HDR sources. No significant differences in local tumor control and survival were found.

Figure 69.20 illustrates the late normal-tissue effect, which is proportional to log cell kill, and the relationship to the number of HDR treatment fractions.⁶²² Each solid curve is calculated assuming the same log cell kill. Late damage rises sharply as the number of HDR fractions is decreased. When these curves are above the dashed lines that represent the maximum late effect of 70 Gy of LDR brachytherapy given at 0.5 Gy/hour, the risk of late complications increases. Displacing the bladder and rectum away from the HDR sources for the short duration of therapy may offset the radiobiologic disadvantage of using a few brachytherapy fractions.⁶¹⁰

Brachytherapy Process: Preparation and Timing

Standard procedures for pretreatment evaluation, imaging, anesthesia use, and treatment duration should follow accepted general principles in the guidelines published by the American Brachytherapy Society in 2012.⁵⁹⁸^,⁶²³^,⁶²⁴Planning the course of brachytherapy should begin at the time of initial presentation. An examination at diagnosis assessing disease extension and tumor size should be recorded. Periodic examinations during external beam treatment should be performed to monitor response. For patients receiving concurrent chemoradiation, rapid shrinkage should be expected because treatment may regress the tumor to 70% to 80% of the pretherapeutic volume. Therefore, a clinical gynecologic examination at the time of brachytherapy is also important.⁶²⁵^,⁶²⁶ Inserting radiopaque marker seeds (“fiducials”) at the time of diagnosis that mark the inferior, lateral, and superior extension of a vaginal tumor may aid in identifying regions requiring dose escalation with brachytherapy even after complete regression during external-beam treatment.

Treatment schedules integrating external-beam irradiation and brachytherapy were initially designed with regard to the disease stage and volume.⁶²⁷ For LDR, insertion of the applicator may be done after all external beam finishes, with the caveat that one or two insertions may be required, approximately 1 week apart. All treatment, including external-beam treatment and brachytherapy, should finish 8 weeks from the initiation of radiation.¹⁸⁴

The optimal time–dose–fractionation scheme and the technique for remote-control afterloading intracavitary brachytherapy for cervical cancer have yet to be established through systematic clinical trials. For HDR or PDR brachytherapy, the applicator insertion and treatment may commence after external-beam treatment finishes, to ensure optimal geometry with normal tissues far from the applicator. Alternatively, the physician may choose to insert the applicator for treatment as early as during the second week of external radiation if the tumor is small enough, to minimize total treatment time. However, brachytherapy and external-beam treatments are not given on the same day.

FIGURE 69.21. Ultrasound used during intrauterine tandem insertion can ensure proper placement into the intrauterine canal and shorten overall procedure time. A: Ultrasound depicts that the tandem is placed in the posterior myometrium. B: Ultrasound directs the tandem into the intrauterine canal.

Applicator Selection

The most frequently used applicator for locally advanced cervical cancer patients worldwide is the tandem and ovoid applicator,⁶⁰² which provides radiation dose covering the cervix, uterus, inner parametria, and approximately 1 to 2 cm of the upper vagina. The tandem and ring applicator has a slightly narrower dose distribution, but with HDR the dose distribution may be optimized and mimics that obtained with the tandem and ovoid applicator. For patients with a very narrow vagina due to stricturing, a tandem and cylinder applicator may be the only option available. However, this applicator provides insufficient dosing to the parametrial tissue and should be used with caution. For patients with large tumors with residual bulky disease after external-beam radiation or those with vaginal extension, fistulae, or pelvic sidewall invasion, a combination of tandem/ring or ovoid with interstitial applicator or tandem/interstitial applicator alone may be inserted.

Applicator Insertion

General guidelines from the American Brachytherapy Society should be followed.⁵⁹⁸ The patient receives appropriate anesthesia for pain management. In the lithotomy position, the perineum is sterilely prepped and draped. The Foley catheter is inserted into the bladder. The catheter is clamped and the bladder filled with 150 to 200 cc of saline if ultrasound (US) is used. US with a transabdominal probe can significantly speed up the insertion process and assist with accurate placement because the uterine canal is often clearly visible after instilling fluid in the bladder (Fig. 69.21). Transabdominal US can measure uterine width and height in patients who do not have large fibroids or tumor volumes that greatly distort uterine configuration.⁶²⁸ US does not define the target volume as clearly as MRI but may be used to assist with 3D-based planning when CT or MRI is unavailable.⁶²⁹ Transrectal US may assist with interstitial brachytherapy when other imaging modalities are not available. For interstitial insertions, CT or MRI may be used during the insertion process iteratively using real-time guidance to ensure proper tumor coverage and no inadvertent insertions into the rectum or bladder.⁶³⁰ After tandem and ovoid or tandem and ring applicator placement, vaginal packing covered with lubricant gel is placed in the vagina to separate the bladder and rectum, which also helps to maintain applicator position.

Applicator Position

An experienced brachytherapist has greater familiarity with applicator insertion and evaluation.³⁶⁸ Applicator position is a critical determinant of dose specification⁶⁰⁰^,⁶³¹ and pelvic control.⁵⁷^,⁶³² As Fletcher⁵³³ emphasized, conditions for an adequate intracavitary insertion include the following:

1. The geometry of the insertion must prevent underdosing around the cervix.

2. Sufficient dose must be delivered to the paracervical areas.

3. Vaginal mucosal, bladder, and rectal tolerance doses must be respected.

For LDR Fletcher-Suit applicators, Potish et al.⁶³³ used linear least-squares regression to show that although there was a moderately good correlation between the milligram-hours and dose to point A, it was markedly affected by the position of the colpostats and the tandem. A review of plain films of 808 LDR intracavitary applications in 396 cervical cancer patients treated at MD Anderson⁶³⁴ quantified acceptable implant geometry. The median distance from the tandem to the sacrum was 4 cm, or one-third the distance from the pubis to the sacrum. The distance between the vaginal ovoids and cervical marker seeds was 7 mm, and the median distance between the tandem and the posterior edge of the ovoids was 50% of the ovoid length. In 92% of insertions, vaginal packing was posterior to or within 5 mm of a line that passed through the posterior edge of the ovoids, parallel to the tandem. The median doses to point A and rectal, bladder, and vaginal surface reference points were 87, 68, 70, and 125 Gy, respectively. Analysis of the LDR and HDR brachytherapy positions for 103 patients enrolled on RTOG trials 0116 and 0128 found that patients with unacceptable symmetry of ovoids to the tandem had a significantly higher risk of LR than patients in the acceptable group (HR = 2.67; 95% CI = 1.11 to 6.45; p = .03).⁵⁷ Patients with displacement of ovoids in relation to the cervical os had a significantly increased risk of LR (HR = 2.50; 95% CI = 1.05 to 5.93; p = .04) and a lower DFS rate (HR = 2.28; 95% CI = 1.18 to 4.41; p = .01). Inappropriate placement of packing resulted in a lower DFS rate (HR = 2.06; 95% CI = 1.08Y3.92; p = .03).

FIGURE 69.22. Definition of point A shown on a tandem and ovoid applicator based on the American Brachytherapy Society 2012 Guidelines for Cervical Cancer.

Imaging After Insertion

For LDR brachytherapy, active sources may be inserted after the films have been reviewed and the position of the applicators judged to be satisfactory.⁵⁷^,⁶³⁴ Placing a small amount of contrast into the bladder and rectum before CT or plain film may clarify the location of these structures.

When a CT scan is obtained after applicator insertion, it also verifies proper placement (no perforation) and analyzes cervix and normal-tissue location in relationship to brachytherapy dose distribution.⁶⁰¹ CT provides a reasonable estimate of the location of the uterus and cervix. The CT contours of the cervix overestimate the tumor contours compared to an MRI, although the additional width contoured on a CT may not be of detriment to the patient because cervical cancer tends to spread laterally along the parametrial tissues.⁶³⁵ CT depicts changes in the OAR related to tumor shrinkage, organ motion, and the location of the brachytherapy applicator in relation to the uterus. However, separating the OAR, such as the sigmoid or the small bowel from portions of the uterus or cervix, may be difficult on CT, given the lack of contrast. OAR dosimetry based on CT is similar to that based on MRI when optimized similarly.⁶³⁶ CT may not provide sufficient detail of the tumor if selected dose escalation is required, such as in cases with large residual tumors. In the vast majority of cases, however, it should suffice.⁶³⁷^–⁶³⁸^,⁶³⁹ The uterus and cervix cannot be distinguished as separate structures on a CT, whereas they can on an MRI. Therefore, CT-based contouring guidelines recommend delineating the entire cervix and uterus.⁶³⁵

In a multicenter study, MR imaging was significantly better than CT for tumor visualization and detection of parametrial involvement.⁶⁶ Other advantages of MR include multiplanar capability and excellent soft-tissue contrast resolution. The strength of a magnet in an MR scanner is expressed by a unit of measurement referred to as a tesla (T). Higher field strength produces a better overall signal-to-noise ratio and more accurate imaging.

Regardless of whether a plain film radiograph, CT, or MR is obtained after insertion to aid treatment planning, in order to properly visualize the apparatus, radiopaque markers should be inserted to identify source position to aid with dosimetric planning. For MRI, identifying the applicator using either a radiopaque marker inserted into the applicator, or, for interstitial cases undergoing MR, a special 3-T MR sequence may be used to create artifact that allows the tip of the needle to appear as a balloon on the sagittal image and as a cross on the axial images.⁶⁴⁰

Dose Specification

Point A

Several methods for specifying dose in brachytherapy evolved over the twentieth century.

Due to the limited availability of 3D imaging worldwide and a 100-year history of plain film radiography, the majority of institutions internationally use point-based dosimetry based on the ICRU 38 nomenclature,⁵⁹⁹ defining point A rather than prescribing dose to a tumor volume.⁶⁰¹ Other institutions use a system of milligram-hours, whereas others consider the volume of the region of interest. Based on the general principles guidelines for cervical cancer brachytherapy published by the American Brachytherapy Society and the ICRU report, the point A definition was updated in 2012.⁵⁹⁸ To determine point A, connect a line through the center of each ovoid or the lateralmost dwell position in the ring; extend this line superiorly along the radius of the ovoids (or ring), and then move an additional 2 cm superior along the tandem. From this point, extend out 2 cm on each side laterally on a line perpendicular to the tandem (Fig. 69.22). For tandem and cylinders, begin at the flange or cervical marking seed and move 2 cm superiorly along the tandem and then 2 cm laterally.

Three-dimensional image-based brachytherapy treatment planning precisely defines the tumor and aids with the precision of radiation dose delivery, which may reduce the dose to the normal tissues and reduce toxicity.⁶⁴¹ In the era of increasing use of HDR brachytherapy, proper applicator placement and precise estimation of the location of the normal tissue is critical. When 3D imaging is available, point-based radiographic dosimetry has limited utility for the dose adaptation required for HDR brachytherapy because point A may overestimate or underestimate the tumor dose based on 3D imaging.⁶⁴² Kim et al.⁶⁴³ found that dose to point A was significantly lower than the D₉₀ for HR-CTV calculated using 3D image-based optimization. With imaging, one may visualize the tumor volume and conform dose to the volume which may result in the dose to point A being lower than the prescription 100% isodose line (covering a smaller tumor volume) or a higher-than-prescription dose to point A due to a large tumor volume extending beyond the boundaries of point A. The tumor coverage relies on tumor volume at the time of brachytherapy, with larger tumors requiring greater optimization to be adequately covered by the prescribed isodose line.⁶⁴²^,⁶⁴⁴^,⁶⁴⁵ The dose to point A should be reported to ensure consistency in terminology between centers.⁶⁴⁶

Accurate delineation of the tumor and OAR is critical for precise treatment planning (Fig. 69.23). Due to the rapid fall-off of dose, imprecise contouring can dramatically change dosing to normal-tissue structures. Formal contouring education programs reduce the variability of interobserver contours.⁶⁴⁷

Computed Tomography Imaging for Brachytherapy Contouring

A CT scan can define a CTV with the lateral borders of the cervix and any parametrial extension defined based on suspicious regions seen on the scan. CT-contouring guidelines should be followed.⁶³⁵ Uterosacral ligaments may be visualized on CT, and, if detected, they should be included in the CTV contours. No GTV may be identified on CT. The superior border of the cervix is not defined, but instead the entire tandem length is planned and the top dwell is optimized off the sigmoid to reduce bowel dose.

FIGURE 69.23. Tandem and ovoid implant showing the use of three-dimensional (magnetic resonance or computed tomography) imaging to adequately cover the high-risk clinical target volume (HR-CTV) while minimizing dose to the organs at risk (OAR)—the rectum, sigmoid, and bladder. Dose–volume histograms record the D_2cc limits to the OAR. The dose at point A is recorded but varies between patients based on optimization of the HR-CTV and OAR.

Magnetic Resonance Imaging for Brachytherapy Contouring

For MR-based contouring, the Groupe Europeen Curietherapy-European Society for Therapeutic Radiation Oncology (GEC-ESTRO) guidelines⁶²⁵^,⁶²⁶ delineate volumes for MR. The recommended volumes include the GTV, including all T2-bright areas of enhancement; the HR-CTV, which is the entire cervix, any regions of high to intermediate signal intensity in the parametria, uterus, or vagina, and any residual disease detected on clinical examination at the time of brachytherapy; and, the intermediate-risk clinical target volume (IR-CTV), which subtracts out the OARs but includes the tumor extension at the time of diagnosis, adding 1 cm to the HR-CTV volume. The IR-CTV defines regions with potential microscopic seeding of tumor cells (Fig. 69.24).⁶⁴⁸ Lang et al.,⁶⁴⁹ in a multicenter study, confirmed the feasibility of these recommendations, with total doses to point A from both BT and EBRT ranging from 85 to 91 Gy and to CTV from 69 to 73 cGy. Doses to organs at risk were comparable to those obtained with standard dosimetric methods, although they were more accurately determined with dose–volume histograms.

Dose–Volume Histogram Reporting

With MR-planned brachytherapy, the most common dose–volume parameters reported for target structures of the entire cervix and any residual disease at the time of brachytherapy, the HR-CTV, are D₉₀, defined as the dose received by at least 90% of the target volume, D₁₀₀, and V₁₀₀, based on the GEC-ESTRO recommendations.⁶⁵⁰^,⁶⁵¹ The cumulative D₉₀ equals the sum of D₉₀ values from the individual fractions plus the dose from a homogeneous 3D conformal external-beam treatment. D₁₀₀, the minimum target dose, may be more sensitive to inaccuracies in contouring and dose calculation. V₁₀₀ assesses dose coverage of the whole target volume and is 100% when the entire target is covered by the prescribed dose. V₁₅₀ and V₂₀₀ are often reported in interstitial brachytherapy. One may report these for CT, although the dimensions of the target will differ significantly from the absolute dimensions on MR, and the CT contour of the HR-CTV will include the cervix, residual areas in the parametria or uterosacral ligaments, and part of the uterus because the superior border of the cervix is not visible.⁶³⁵ CT contours are more accurate if an MRI can be performed immediately before or with the first fraction of brachytherapy.⁶⁵² In both CT and MRI, prescribed dose is based on the physician’s directive of the dose intended for the target volume, that is, the volume covered by the 100% isodose line, and point A should be recorded. Several institutions have validated the use of these guidelines with HDR, LDR, or PDR brachytherapy.⁶⁴⁵^,⁶⁵²^,⁶⁵³^,⁶⁵⁴^,⁶⁵⁵^,⁶⁵⁶

With 3D imaging, one may define the surrounding normal tissue structures as the OAR, including the rectum, sigmoid, and bladder. With 2D imaging, the ICRU 38 report requires only reporting point estimates for the rectum and bladder because the sigmoid cannot easily be visualized.⁵⁹⁹ However, the ICRU bladder point may underestimate maximum doses to the OAR, in particular for the bladder⁶⁵⁷^,⁶⁵⁸; it is less likely that rectal doses will be incorrectly estimated. Numerous publications correlate the ICRU point dose and the probability of late complications for bladder and rectum.⁶⁵⁹^,⁶⁶⁰ Nevertheless, DVH metrics may provide a more reliable predictor of long-term complications.⁶⁶¹ In a review of 50 patients treated with LDR or HDR brachytherapy who then had a CT for treatment planning, the closest point of the sigmoid was related to sigmoid dose but varied in proximity to the tandem up to 40% between fractions, with a median distance of 1.7 cm. No sigmoid toxicity was noted after a median follow-up of 31 months.

FIGURE 69.24. Diagrammatic representation of gross tumor volume (GTV) and clinical target volume (CTV) for three-dimensional treatment planning in carcinoma of uterine cervix. Coronal (A,C) and transverse (B,D) sections for limited (A,B) and advanced (C,D) disease (gray zones in left parametrium). (From Potter R, Haie-Meder C, Limbergen EV, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): Concepts and terms in 3D image-based treatment planning in cervix brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67–77; with permission from Elsevier.)

Kapp et al.⁶⁶² analyzed 720 ¹⁹²Ir HDR applications in 331 patients with gynecologic tumors to evaluate the dose to normal tissues. CT-based dosimetry showed that the maximum doses to bladder and rectum were generally higher than those obtained from orthogonal films, with an average ratio of 1.44 for the bladder neck, 2.42 for the bladder base, and 1.37 for the rectum. The ratio of bladder-base dose to bladder-neck dose was 1.5 for intracervical and 1.46 for intravaginal applications. If conventional methods are used for dosimetry, the authors recommended that doses to the bladder base should be routinely calculated because single-point measurements at the bladder neck seriously underestimate the dose to the bladder. In addition, the rectal dose should be determined at several points over the length of the implant because of the wide range of anatomic variations.

Eich et al.,⁶⁶³ in 11 applications of HDR brachytherapy for cervical carcinoma, calculated doses to ICRU points on orthogonal radiographs, and the doses at rectum reference points were compared with in vivo measurements. The in vivo measurements were 1.5 Gy below the doses determined for the ICRU rectum reference point (4.05 ± 0.68 vs. 6.11 ± 1.63 Gy). The advantage of in vivo dosimetry is the possibility to determine rectal dose during radiation. The advantages of computer-aided planning at ICRU reference points are that calculations are available before radiation and they can be taken into account for treatment planning.

Pelloski et al.⁶⁶⁴ compared CT-based volumetric calculations and ICRU reference point radiation doses in 60 patients with cervix cancer treated with LDR brachytherapy. Of 118 insertions performed, 93 were evaluated, and the minimal doses delivered to the 2 or 3 cm of bladder or rectum (DBV2 and DRV2, respectively) were determined on a dose–volume histogram (DVH). They concluded that the ICRU dose was a reasonable surrogate for the DRV2 but not for the DBV2. Furthermore, these calculations may not be applicable to other treatment guidelines or intracavitary applicators.

Patil et al.⁶⁶⁵ found significant correlations between ICRU point doses to the bladder and rectum and volumetric doses, particularly the D_2cc. However, there was significant variability, and they concluded that 3D imaging is essential to properly assess doses to the OAR.

Both CT- and MR-based OAR dosimetry report similar cumulative DVH parameters, including D_2cc and D_0.1cc. The D_2cc is the minimum dose received by the most exposed 2-cm³ volume of the analyzed organ. For CT-based brachytherapy, contrast placed in the OAR may cause some artifact, resulting in some variation in contouring the wall of the organ. MR-based brachytherapy relies less on contrast because the organ wall may be more clearly visualized. Wachter-Gerstner et al.⁶⁶⁶ analyzed the correlation between dose–volume histograms for bladder and rectum and found that D_2cc served as a good estimate for doses to the organ wall, whereas D_5cc was less reliable because is changed based on filling status. Rectal wall thickness did not significantly affect D_2cc.⁶⁶⁷

Based on CT-dosimetry, Koom et al.⁶⁶⁸ showed that more-severe rectal side effects (endoscopy score >2) occurred in patients with a higher D_2cc. Seventy-one patients with FIGO stages IB to IIIB uterine cervical cancer had CT-based HDR intracavitary brachytherapy. The mean values of the DVH parameters and ICRU rectal point [α/β = 3] were significantly greater in patients with a score of >2 than in those with a score of <2 at 12 months after brachytherapy (ICRU, 71 Gy vs. 66 Gy [p = .02]; D_0.1cc, 93 vs. 85 Gy [p = .04]; D_1cc, 80 vs. 73 Gy [p = .02]; D_2cc, 75 vs. 69 Gy [p = .02]). The probability of a score of >2 was significantly correlated with the DVH parameters and ICRU rectal point (ICRU, p = .03; D_0.1cc, p = .05; D_1cc, p = .02; D_2cc, p = .02).

For MR-based dosimetry, Georg et al.⁶⁶¹ tested the predictive value of dose–volume parameters for late effects of the rectum, sigmoid colon, and bladder using the D_2cc, D_1cc, and D_0.1cc of these three OARs for 141 cervical cancer patients treated with tandem and ring HDR brachytherapy after EBRT. The mean D_2cc values for bladder, rectum, and sigmoid were 95 ± 22, 65 ± 12, and 62 ± 12 Gy,_, respectively. This study confirmed that D_2cc was a predictor of late toxicity for the rectum and bladder. A rectoscopy study⁶⁶⁹ was done in 35 patients in which EQD2 (α/β = 3 Gy) of the D_0.1cc, D_1cc, and D_2cc of the rectum was recorded. After a mean follow-up time of 18 months, telangiectasia was found in 26 patients (74%), and 5 had ulceration that corresponded to the D_0.1ccof the anterior rectal wall. The D_2cc was higher in patients with rectoscopy score of >3 compared to <3 (72 ± 6 vs., 62 ± 7 Gy; p < .001) and in symptomatic versus asymptomatic patients (72 ± 6 vs. 63 ± 8 Gy; p < .001). Based on these two studies, a dose limit of 70 to 75 Gy EQD2 is recommended for the rectal dose constraint.

For interstitial brachytherapy, in which a much longer portion of the anterior rectal wall is treated as part of the target volume, D_2cc > 62 Gy predicted for late toxicity.⁶⁷⁰ The development of mucosal and clinical changes in the rectum seems to follow a clear dose effect and volume effect. For patients receiving interstitial brachytherapy who require treatment to the entire vaginal length, the dose to the rectum should be reduced as much as possible without compromising target coverage.

3D Treatment Planning for Pulse- and High–Dose-Rate Brachytherapy

Treatment planning for PDR and HDR brachytherapy can be accomplished by a variety of techniques. Treatment planning for LDR is covered in a separate chapter. For cervical cancer, customized optimization of source loading for each HDR insertion is recommended (Fig. 69.25), given significant changes in tumor and OAR dosimetry between fractions.⁶²⁷^,⁶⁷¹ Himmelmann et al.⁶⁷² described individualized computer treatment optimization of source position and the dwell time for each position. Customized planning does increase the time needed for planning and requires experience on the part of the physics and dosimetry staff.⁶⁷³

CT-Based Treatment Planning

Fellner et al.⁶⁷⁴ compared treatment planning for cervical carcinoma based on CT sections and 3D dose computations or, when these techniques were not available, dose evaluation based on orthogonal radiographs. The CT-based planning provides information on target and organ volumes and dose–volume histograms. The radiography-based planning provides dimensions and doses only at selected points. For the study, 28 patients with 35 applications receiving HDR treatment with ¹⁹²Ir were investigated. For a dose prescription of 7 Gy at point A, 83% (44 cm³) of the CTV received at least 7 Gy.

Gebara et al.⁶⁷⁵ estimated the external, internal, and common iliac dose rates using 3D CT-based dose calculations in tandem and ovoid brachytherapy in 30 patients with carcinoma of the uterine cervix treated with LDR brachytherapy using a CT-compatible Fletcher-Suit-Delclos device. Thirty-six implants were performed, and the authors concluded that the point B dose is similar to the maximum common iliac nodal dose. With HDR brachytherapy, the dose to the pelvic lymph nodes is approximately 25% of the per-fraction dose.³⁴⁴

Dewitt et al.,⁶⁷⁶ in 15 patients with cervical cancer, defined target and organs at risk for planning of HDR brachytherapy and established guidelines for volume and dose constraint parameters using image-guided inverse treatment planning.

Careful assessment of the quality of brachytherapy and dose distributions is critical. Suyama et al.⁶⁷⁷ analyzed the minimal radiation dose to the peripheral area of the cervix in relation to local tumor failure using CT images taken at the time of intracavitary brachytherapy in 80 patients with carcinoma of the cervix. After CT scanning, isodose curves were superimposed on the CT images. Histograms of both the minimum percentage peripheral dose and the dose to the cervical area showed significant correlation in the local tumor control and local failure groups (p < .001).

With HDR intracavitary applicators the use of a rectal retractor has been shown to substantially reduce the rectal dose.⁶¹⁰ Lee et al.,⁶⁷⁸ in a study of 15 patients, found that this reduction was significant only in the subgroup who received >70% of the prescription dose (p < .05).

Wanderas et al.⁶⁷⁹ reviewed data from 19 patients (72 fractions) retrospectively. Standard library plans were compared to individually optimized plans using a Fletcher HDR applicator. For standard treatment planning, the tolerance dose limits were exceeded in the bladder, rectum, and sigmoid in 26%, 4%, and 15% of the plans, respectively. This was observed most often for the smallest target volumes. The individualized planning of the delivered treatment gave the possibility of controlling the dose to critical organs to below certain limits. The dose was still prescribed to point A. An increase in target dose coverage was achieved when additional individual optimization was performed while keeping the dose to the OARs below predefined limits. Relatively low average target coverage was seen, however, especially for the largest volumes.

MR-Based Treatment Planning

Basic principles of MR imaging during brachytherapy have been described.⁶⁸⁰ Several institutions have reported the dosimetric advantages of MR-based brachytherapy, with reduction in OAR doses with optimization.⁶⁴⁵^,⁶⁵⁴^,⁶⁸¹^–⁶⁸³Tanderup et al.⁶⁸¹ showed that point A dose was a poor surrogate of HR-CTV dose, and MR-based planning improved target coverage and reduced OAR dose. Starting with a standard plan is important for consistency because relative uniformity of the dose distribution should be maintained.⁶⁸⁴

A comparison of MR to ultrasound was reported by Van Dyk et al.⁶²⁹ for 71 patients, showing comparability between the two modalities in terms of target volume and rectal point dose. Mahantshetty et al.⁶⁸⁵ similarly confirmed the feasibility of US for institutions that do not have easy access to MR or CT.

Recommended Doses

Stage IA (microinvasive) tumors are treated with intracavitary therapy only. LDR dose is approximately 60 Gy in one insertion or 75 to 80 Gy in two insertions to point A, or with HDR an equivalent dose, with one or two fractions per week. This may be given in approximately 5 Gy per fraction for 10 fractions or other regimens based on normal-tissue exposure.

For stages IB to IVA cervical cancer in the United States, the most common EBRT dose treats the elective pelvic nodes to 45 to 50 Gy given in 1.8 Gy per fraction.⁵⁹⁸ Some institutions instead use lower doses of whole-pelvis external irradiation (20 to 40 Gy) in addition to parametrial doses to complete 50 to 60 Gy to the involved parametrial tissues or nodal regions for more advanced stages. Brachytherapy follows, with a goal EQD2 dose of 80 to 90 Gy to point A or to the HR-CTV. For LDR, intracavitary treatment for approximately 4,000 to 5,000 mgh (36 to 50 Gy to point A at 60 cGy/hour) is given, depending on the tumor volume and stage and age of the patient. Fyles et al.¹³⁷identified FIGO stage as the most significant prognostic factor in 965 patients with invasive carcinoma of the cervix, followed by dose of irradiation to point A and overall time of radiation therapy. The 10-year survival rate was 62% in 743 patients receiving doses to point A of 85 Gy or higher, in contrast to 53% for 222 patients receiving lower doses.

For HDR, one study found that a dose to the HR-CTV of >87 Gy resulted in a local recurrence rate of 4% compared to 20% for D₉₀ < 87 Gy when the tumor was >5 cm and using an HDR tandem/ring or tandem/ring/interstitial approach. They concluded that local control rates of >95% can be achieved for patients with a poor response after EBRT if D₉₀ for the HR-CTV is 87 Gy or higher.⁵³⁵ The IR-CTV intended dose should be approximately 60 Gy EQD2. In the United States the most common regimen uses five fractions (5 to 6 Gy per fraction), with two fractions per week 24 to 48 hours between fractions.

FIGURE 69.25. A: Coronal view of a CT planned tandem and ring applicator with standard HDR loading (to point A). B: Tandem and ring treatment plan optimized to maximize tumor coverage and minimize the dose to the organs at risk (OAR) including the rectum (brown), sigmoid (blue) and bladder (yellow). C: Sagittal CT of the standard plan at point A. D: Sagittal CT image of the optimized plan showing the reduction in OAR dose. E: Cervical stump cancer showing an MR-planned tandem and interstitial brachytherapy implant without HDR optimization. F: Optimized tandem and interstitial plan cover the posterior border of the cervical stump while minimizing dose to the bladder and rectum.

DVH constraints for both PDR and HDR are 90 Gy (EQD2) for bladder and 70 to 75 Gy (EQD2) for both rectum and sigmoid as minimal doses to the most exposed D_2cc of the OAR. There are no generally accepted constraints for the 0.1-cm³ level. Given the rapid regression of the tumor and the dramatic change in the location and size of the normal tissues, it is recommended to replan and determine the doses to the OAR with each fraction if the patient is treated on an outpatient basis.⁶⁷¹

Dose Fractionation in High–Dose-Rate Brachytherapy

The relationship between dose and fractionation for HDR and LDR intracavitary irradiation of stage I and II carcinoma of the cervix was examined by Arai et al.⁶⁴⁴ The dose rate at point A was 2 to 3 Gy/minute (120 to 180 Gy/hour) for HDR and 0.6 to 0.9 Gy/hour for LDR irradiation. Concurrent EBRT was given to the whole pelvis (23 to 30 Gy), followed by 25 to 30 Gy with central shielding, along with brachytherapy. The authors concluded that the optimal dose fractionation schedules for HDR brachytherapy were 28 ± 3 Gy in 4 to 5 fractions, 34 ± 4 Gy in 8 to 10 fractions, or 40 ± 5 Gy in 12 to 14 fractions at point A. Petereit and Pearcey,⁶¹⁹ based on their preliminary results and published reports in the literature, recommend doses of 45 to 50.5 Gy in a 1.8-Gy/fraction external beam followed by HDR with either 5.5 or 6 Gy per fraction in the era before the standardization of chemoradiation. Since the implementation of concurrent chemoradiation, several institutions in the United States have standardized the use of 5.5 Gy for five fractions, given some concerns about rectal toxicity with 6 Gy per fraction.⁶⁸⁶

Chatani et al.⁶⁸⁷ described a study in which 165 patients with carcinoma of the cervix were randomized to a HDR brachytherapy point A dose of 6 Gy (group A) or 7.5 Gy (group B) per fraction, both combined with external irradiation. The 5-year local failure rate was 16% in both groups, and distant failure rates were 23% and 29%, respectively (p = .2955). Moderate to severe complications requiring treatment were comparable (6 patients, 7%) in the two groups.

Hama et al.⁶⁸⁸ compared the effectiveness and safety of once- versus twice-weekly HDR brachytherapy for cervical cancer in 124 patients treated with EBRT (50 Gy); 74 patients (group A) were treated with one HDR brachytherapy insertion weekly (three fractions of 7 Gy each to point A), and 50 patients (group B) were treated twice weekly (six fractions of 4.5 Gy each to point A). Overall survival rates were 65.2% and 65.3%, respectively (p = .96). Local recurrence-free survival rates were 69% for group A and 90% for group B (p < .001). The rate of grade 2 (moderate) and grade 3 (severe) complications was significantly lower for group B (6%) versus 32% in group A (p< .001).

Mayer et al.⁶⁸⁹ compared HDR BT in two schedules used to treat 210 patients with cervix cancer—one sequential (SRT), consisting of four fractions of 8 Gy followed by EBRT, and the other continuous (CRT), consisting of five fractions of 6 Gy one session per week integrated with EBRT (four fractions per week). Total dose to point A was 68 to 70 Gy. Progression-free survival was 71% with CRT versus 56% with SRT (p > 0.05). Late bladder and rectal morbidity were 13% in the CRT group and 25% in the SRT group (p = .037), related to the higher dose per fraction (8 Gy).

Nam and Ahn⁶⁹⁰ compared, in a randomized study of 46 patients, two schedules of HDR BT (10 fractions of 3 Gy or five fractions of 5 Gy) followed by a small BT boost to residual tumor in combination with EBRT (30.6 Gy to whole pelvis and 14.4 Gy to parametria with midline block). Three-year pelvic tumor control was 90% in both groups, and disease-specific survival was 90.5% and 84.9% (p = .64), respectively. Late grade 2 and greater bladder or rectal morbidity was 23.8% and 9.1%, respectively (p = .24).

Liu et al.,⁶⁹¹ based on the linear-quadratic model, developed isoeffect tables to convert traditional LDR doses and number of fractions to point A to HDR brachytherapy; depending on dose rate, different dose values can be calculated for various fractionation schedules. They predicted that, using therapeutic gain ratio, similar results would be obtained with either brachytherapy modality with two to four fractions of LDR and four to seven fractions of HDR.

TABLE 69.16 HIGH–DOSE-RATE BRACHYTHERAPY DOSE AND FRACTIONATION REGIMENS WORLDWIDE

The optimal time–dose–fractionation scheme for HDR brachytherapy for cervical cancer has yet to be established. In an international survey from the Gynecologic Cancer Intergroup, 28 different fractionation regimens were used by international cooperative group members (Table 69.16); the most common was 6 Gy for five fractions after 45 Gy.⁶⁰² The American Brachytherapy Society published recommendations for HDR brachytherapy for carcinoma of the cervix.⁶²³ Each institution should follow a consistent treatment policy, including complete documentation of treatment parameters and correlation with clinical outcome (pelvic tumor control, survival, and complications). The goals are to treat point A to at least a total LDR equivalent of 80 to 85 Gy for early-stage disease and 85 to 90 Gy for advanced-stage disease. The pelvic sidewall dose recommendations are 50 to 55 Gy for early lesions and 55 to 65 Gy for advanced ones. As with LDR BT, every attempt should be made to keep the bladder and rectal doses to <100 Gy and 75 Gy LDR-equivalent doses, respectively. Interstitial brachytherapy should be considered when the tumor cannot be optimally encompassed by intracavitary brachytherapy. Some suggested dose and fractionation schemes for combining the external-beam radiation therapy with HDR brachytherapy for each stage of disease have been presented by the American Brachytherapy Society, although they have not been thoroughly tested. The responsibility for the medical decisions ultimately rests with the treating radiation oncologist. Petereit and Pearcy,⁶¹⁹ in a review of 24 HDR dose fractionation schedules published in the last three decades, found no dose relationship for either tumor control or late morbidity. Viswanathan et al.,⁶⁰² for the Gynecologic Cancer Intergroup, found significant international variation in the HDR dose/fractionation regimens reported, but aside from Japan, where the ratio of HDR brachytherapy dose to external beam is higher, there was consistency in converted EQD2 doses administered.

TABLE 69.17 RANDOMIZED TRIAL RESULTS OF TOXICITY AND OVERALL AND DISEASE-FREE SURVIVAL COMPARING HDR AND LDR

Clinical Outcomes of Brachytherapy

Randomized Studies Comparing HDR to LDR Using Plain X-Ray Dosimetry

Four randomized trials (Table 69.17) and a meta-analysis summarizing the results of these have been published comparing HDR and LDR brachytherapy for carcinoma of the cervix.⁶⁹²^,⁶⁹³ Teshima et al.⁶⁹⁴ reported on a prospective, randomized study of 430 patients with carcinoma of the uterine cervix treated with either LDR (171 patients) or HDR (259 patients) brachytherapy combined with external irradiation. Cause-specific and overall survival rates were comparable for each clinical stage with either modality, except for stage I overall survival. The conversion factor of total intracavitary dose from LDR to HDR was 0.5 to 0.53. With HDR, four fractions usually were delivered, and with LDR, two fractions. The incidence of pelvic failures was comparable in both groups. The incidence of grade 2 and 3 morbidity was somewhat higher in the HDR group (~10%) than in the LDR group (4%; p = .002).

Patel et al.⁶⁰⁷ published a randomized trial of 482 patients with invasive squamous cell carcinoma of the cervix. The overall local tumor control rate with LDR brachytherapy was 79.7%, compared with 75.8% with HDR. The 5-year survival rates were 73% with LDR and 78% with HDR in stage I, 62% and 64%, respectively, in stage II, and 50% and 43% in stage III. The only statistically significant difference was the incidence of overall rectal complications, which was 19.9% for LDR, compared with 6.4% for HDR. However, the incidences of more severe grade 3 and 4 complications were not significantly different (2.5% and 0.4%, respectively). Bladder morbidity was similar in both groups.

Hareyama et al.⁶⁹⁵ conducted a randomized study in 132 patients with stage II or IIIB cervical carcinoma treated with LDR or HDR BT and identical pelvic EBRT. The conversion factor from LDR to HDR was 0.588. The 5-year DSS with HDR for stages II and IIIB was 69% and 51%, respectively, and with LDR it was 87% and 60%, respectively. Pelvic tumor control for stage II and III was 89% and 73% with HDR and 100% and 70% with LDR, respectively, and grade 3 or greater morbidity was 10% and 13%, respectively (differences were not statistically significant).

Lertsanguansinchai et al.⁶⁹⁶ randomized 237 patients with cervical cancer to be treated with LDR (109 patients) or HDR (112 patients) brachytherapy and EBRT. Median follow-up was 40 and 37 months, respectively. Three-year pelvic tumor control was 89% and 86.4%, respectively, and relapse-free survival was 69% in both groups. Grade 3 or 4 morbidity was noted in 2.8% of LDR and 7.1% of HDR patients (p = .23).

A meta-analysis⁶⁹³ in-cluding these four trials reported a pooled RR for HDR versus LDR of 0.95 (95% CI = 0.79 to 1.15), 0.93 (95% CI = 0.84 to 1.04), and 0.79 (95% CI = 0.52 to 1.20) for 3-, 5- and 10-year overall survival rates and 0.95 (95% CI = 0.84 to 1.07) and 1.02 (CI = 0.88 to 1.19) for 5- and 10-year DSS rates. For local control rates the RR was 0.95 (95% CI = 0.86 to 1.05) and 0.95 (95% CI = 0.87 to 1.05) at 3 and 5 years, respectively. For bladder, rectosigmoid, and small-bowel complications, the RR was 1.33 (95% CI = 0.53 to 3.34), 1.00 (95% CI = 0.52 to 1.91), and 3.37 (95% CI = 1.06 to 10.72), respectively, indicating no significant differences except for increased small-bowel complications with HDR (p = .04). Of note, none of the randomized studies used 3D imaging to optimize away from normal tissues.

The use of 3D imaging to guide brachytherapy treatment planning has allowed optimization of HDR and PDR brachytherapy, thereby reducing the high per-fraction doses to the normal tissues that might potentially cause significant side effects. A retrospective comparison of LDR and HDR with pretreatment MRI used for tumor volume determination showed a significant reduction in complications with HDR when image-based planning was implemented.⁶⁹⁷ Similarly, the use of 3D imaging optimizes tumor coverage, which is critical with fractionated HDR therapy.

Prospective Data Using Point A Dosimetry

Haie-Meder et al.,⁶⁹⁸ in 204 patients with cervical cancer randomized to receive one of two preoperative LDR brachytherapy procedures (0.4 or 0.8 Gy/hour), noted similar local tumor control (93%) and overall survival (85%) rates at 2 years with either dose rate. Grade 3 late complications were observed in 7% of patients treated with 0.4 Gy/hour and in 13% of patients treated with 0.8 Gy/hour. There was 1 small-bowel obstruction in the 0.4-Gy/hour group (1%), in contrast with 5 (5%) in the 0.8-Gy/hour group. Vesicovaginal fistulas were observed in 2% and 4%, respectively.

A prospective study in Japan of stage I and II cervical cancer with tumors <4 cm (by T2 MRI) and no lymphadenopathy treated 60 patients with whole-pelvis EBRT 20 Gy/10 fractions with midline block followed by 30 Gy/15 fractions and HDR 24 Gy/4 fractions (at point A).⁶⁹⁹ The cumulative BED was 62 Gy (α/β = 10) at point A, lower than that reported by any other institution worldwide. Median tumor diameter was 28 mm (range, 6 to 39 mm). Median overall treatment time was 43 days. Median follow-up was 49 months (range, 7 to 72 months). Seven patients developed recurrences: 3 patients had pelvic recurrences (2 central, 1 nodal), and 4 patients had distant metastases. The 2-year disease-free and overall survival rates were 90% (95% CI = 82% to 98%) and 95% (95% CI = 89% to 100%), respectively. The 2-year late complication rates (according to RTOG/EORTC grade ≥ 1) were 18% (95% CI = 8% to 28%) for large intestine/rectum, 4% (95% CI = 0% to 8%) for small intestine, and 0% for bladder. No cases grade ≥3 were observed for genitourinary/gastrointestinal late complications.

The prospective French STIC trial⁵³⁴ reported patients treated with x-ray simulation compared to 3D-based planning. A total of 705 patients with stages IB to IIIB cervical cancer were enrolled. Toxicity and survival were significantly improved with 3D-based treatment planning. Plain film–based 2-year local control was 74% for patients treated with chemoradiation and LDR or PDR brachytherapy. Detailed results are shown in Table 69.18.

TABLE 69.18 CLINICAL OUTCOMES WITH THREE-DIMENSIONAL PLANNED BRACHYTHERAPY

Retrospective Data Using Point A Dosimetry for Low–Dose-Rate Brachytherapy

Fowler⁷⁰⁰ analyzed results in 270 patients with carcinoma of the cervix treated with either 75 cGy/hour from manually loaded cesium or 150 cGy/hour by remote afterloading. There was an increase in grade 3 late complications from 4% to 22%, in spite of a reduction of 20% in dose, implying a rather large difference in biologic effect between the two systems. The effect of the increased dose rate was also described by Leborgne et al.⁷⁰¹ Linear-quadratic modeling was used to calculate biologically effective doses in the clinical protocols used. When the LDR was doubled, it was called MDR. The maximum ratios calculated for the biologic effective doses of 16 Gy at MDR to 20 Gy at LDR were 1.06 to 1.15, assuming α/β = 4 to 2 Gy, the latter being an unlikely extreme for rectal or urinary complications. The theoretically ideal dose reduction factors, calculated using the t_1/2 values derived from the clinical data, are in the range of 24% to 29% instead of 20%.

Rodrigus et al.⁷⁰² analyzed late complications in 143 patients with cervical cancer treated with two different brachytherapy schedules and external radiation. Seventy-seven patients had two intracavitary applications with a dose rate of 0.54 Gy/hour and 66 patients with that of 1.07 Gy/hour. Because of the expected increase in complications with the higher dose rate, the latter dose per application was reduced from 25 to 20 Gy. Late intestinal and urinary complications were scored in 49 of 77 and 46 of 68 patients, respectively. Actuarial estimates at 5 years showed 42% and 54.1% late intestinal complications and 16.9% and 24.1% late urinary complications, respectively. Thus, despite the dose reduction, there was a clear dose-rate effect on late morbidity. These studies emphasize the importance of the dose rate of brachytherapy in carcinoma of the cervix.

Rotmensch et al.⁷⁰³ compared the outcome in 140 patients with early-stage cervical cancer undergoing whole-pelvis radiation therapy with one versus two LDR intracavitary brachytherapy applications. The two groups had similar 5-year local tumor control (p = .83), disease-free (p = .23), and cause-specific (p = .29) survival. Late complications were similar in the two groups. These results support the use of a single LDR application in patients with early-stage disease undergoing definitive radiation therapy after 45-Gy external-beam pelvic irradiation.

In a retrospective analysis, Perez et al.,¹⁶⁹ noted that in patients with cervical cancer treated with radiation therapy alone for stage IB tumors <2 cm in diameter, the pelvic failure rate <10% with LDR doses of 70 to 80 Gy to point A, whereas for larger lesions, even doses of 85 to 90 Gy resulted in 25% to 37% pelvic failure rates. In stage IIB with LDR doses of 70 Gy to point A, the pelvic failure rate was approximately 50%, compared with 20% in nonbulky and 30% in bulky tumors with doses >80 Gy. In stage III unilateral lesions, the pelvic failure rate was approximately 50% with 70 Gy or less to point A versus 35% with higher doses, and in bilateral or bulky tumors it was 60% with doses <70 Gy and 50% with higher doses.

A study from France reported on preoperative LDR followed by radical surgery with lymph node dissection for 257 patients with stages IB1, IIA, and IIB cervical cancer of <4 cm.⁷⁰⁴ Residual tumor was identified in 44% of patients, whereas 4.3% of patients had parametrial invasion and 17.9% of patients had lymph node involvement. Late complications of grade 2 occurred in 7.4% and of grade 3 in 2.7% of patients. Five-year actuarial overall survival and disease-free survival were 83% (CI = 78.3 to 87.5) and 80.9% (CI = 76.3 to 85.7), respectively. In multivariate analysis, lymph node involvement, parametrial involvement, and smoking factors significantly affected overall survival and disease-free survival rates.

Retrospective Results Using Point A with Pulse–Dose Rate Brachytherapy

Rogers et al.⁷⁰⁵ treated 52 patients with cervical carcinoma, 31 of whom had staging laparotomy before radiation therapy. Brachytherapy was interstitial in 18 patients and intracavitary in 28. The median EBRT pelvis dose was 45 Gy in 25 fractions. Median total doses were 75.8 Gy to the implant volume with interstitial and 84.1 Gy to the A points with intracavitary at a median dose rate of 0.55 Gy per pulse per hour. Six patients had laparotomy-documented para-aortic node involvement and received EBRT to this site (45 Gy in 25 fractions). Thirty patients received concomitant weekly cisplatin chemotherapy (40 mg/m²). With a median follow-up of 25 months, the actuarial 4-year disease-free survival rates were 66% for the entire group (100% for stage IB, 69% for stage II, 68% for stage III/IVA, and 43% in patients treated for recurrences after surgery). Grade 4 complications occurred in 2 patients (4.3%). One patient (2.2%) had a grade 3 complication (frequent hematuria), and 5 (10.9%) had grade 2 complications.

Kaneyasu et al.⁷⁰⁶ treated 419 patients with squamous cell carcinoma of the cervix from 1969 to 1999 with LDR or MDR. LDR required overnight admission, whereas MDR was given over approximately 5 hours on an outpatient basis. The 5-year overall survival rates for stages I, II, III, and IVA in the LDR group were, respectively, 78%, 72%, 55%, and 34% versus 100%, 68%, 52%, and 42% in the MDR group (not statistically different). The actuarial rates of late complications of grade 2 or greater at 5 years for the rectum, bladder, and small intestine in the LDR group were 11.1%, 5.8%, and 2.0%, respectively, whereas for the MDR group they were 11.7%, 4.2%, and 2.6%, respectively (not significantly different).

El-Baradie et al.⁷⁰⁷ published a prospective study in which 45 patients with carcinoma of the uterine cervix were randomly allocated to either HDR or MDR. The external-beam radiation dose was the same in the two groups. The point A dose rate correction factor from LDR to HDR was 0.53, and that from LDR to MDR 0.6. The 3-year survival and locoregional tumor control rates for both modalities were equivalent (respectively 62% and 67% for HDR and 68% and 74% for MDR). The rectal and bladder complication rates were the same in both groups (29% at 3 years). Tanaka et al.⁷⁰⁸ also compared HDR and MDR brachytherapy in 150 and 56 patients, respectively. The survival was equivalent in the two groups; grade 2 or greater late toxicity tended to be higher in the HDR group (14% vs. 6%, respectively).

Bachtiary et al.⁷⁰⁹ reported on 109 patients treated with LDR BT and 57 who received PDR BT. The 3-year overall survival and disease-free survival rates were 70% and 57% for the LDR group and 82% and 70% for the PDR group, respectively (p = .25 and .19). The 3-year probability rate for late grade 3 or worse toxicity was 7.4% for LDR BT patients and 7.6% for PDR BT patients (p = .69) and was 6.9% and 7.6%, respectively, for concurrent chemotherapy versus none (p = .69).

Rath et al.⁷¹⁰ reported on 48 patients treated with PDR brachytherapy (ICRT) and pelvic irradiation. A single session delivered a dose of 27 Gy to point A by PDR (hourly pulse, 70 cGy). Ten patients had disease recurrence (5 each in stage IIB and stage IIIB). Eight patients had pelvic failure, 1 had bone metastases, and 1 had supraclavicular node metastases. Overall the grades III to IV late toxicity rate at 50 months was 6%. For the median follow-up period of 15 months, the actuarial recurrence-free survival in stages I to II was 82% and in stages III to IV was 78%.

Retrospective Results with Point A Using High–Dose Rate Brachytherapy

Many nonrandomized studies compared the results of HDR with those of historic or concurrent control patients receiving LDR at the same institution.⁶⁰⁸^,⁶²⁷^,⁶⁷²^,⁷¹¹^–⁷¹³ HDR in patients with stage IIIB disease or large tumors must be used cautiously because the brachytherapy prescription dose should cover the tumor volume and avoid the normal tissues as much as possible (Table 69.19). Although it is generally recommended not to give concurrent chemotherapy on the day of HDR brachytherapy,⁵⁹⁸ several studies indicate that HDR does not increase toxicity in patients treated with chemoradiation (Table 69.20). Most studies used point A as a reference point, although the definition of point A may have differed from center to center.

A retrospective population-based cohort study of all uterine cervix cancer cases in Saskatchewan diagnosed between 1985 and 2001 had 107 LDR and 37 HDR cases with similar stage distribution. The 5-year cause-specific survival rate was 56% for HDR and 67% for LDR (p = .72). Acute toxicities were diarrhea (60%) and abdominal cramps (12.5%), and chronic toxicities were vaginal stenosis (5.5%) and small-bowel obstruction (4%).⁷¹⁴

TABLE 69.19 STAGE III OVERALL SURVIVAL, PELVIC CONTROL, AND TOXICITY IN RETROSPECTIVE SERIES

TABLE 69.20 FRACTIONATION AND TOXICITY OF HIGH–DOSE-RATE AND CONCURRENT CHEMOTHERAPY

Petereit et al.⁶⁰⁶ reported on 191 patients receiving LDR brachytherapy and 173 receiving HDR brachytherapy with equivalent external-beam radiation therapy techniques. Pelvic tumor control and survival rates were comparable with the two techniques, except in stage III; in this subgroup, outcome was better with LDR brachytherapy, but this may have been related to a lower HDR equivalent dose administered. In an analysis of 198 patients treated with LDR brachytherapy, the 3-year survival rate was 66% versus 77% for 40 patients treated with HDR brachytherapy.⁷¹⁵ Pelvic tumor control rates were 80% and 77%, respectively. The incidences of complications requiring hospitalization or surgery were 10% (20 of 198) and 2.5% (1 of 40), respectively.

Kapp et al.,⁷¹⁶ in a study of 181 patients with FIGO stages IB to IV carcinoma of the cervix, documented that prognostic factors for patients treated with HDR are similar to those in previous series with LDR brachytherapy. In multivariate analysis, tumor size was the most powerful factor for pelvic tumor control and incidence of distant metastasis.

Ferrigno et al.⁷¹⁷ carried out a retrospective study of 190 patients treated with LDR and 118 with HDR brachytherapy in combination with pelvic EBRT for cervical cancer. For stage I or II patients, there was no difference in outcome; however, in the stage III group local tumor control was 58% with LDR and 50% with HDR (p = .19), and DFS was 49% versus 37% (p = .03). At 5 years, rectal sequelae were 16% versus 8% (p =.03), bladder sequelae were 6% and 3% (p = .13), and small-bowel sequelae were 4.6% and 8.9% (p = .17).

Falkenberg et al.⁷¹⁸ reviewed 160 patients, 103 treated with LDR and 57 treated with HDR from 1990 to 2000. Locoregional control was 78% for LDR and 76% for HDR (p = .96); overall survival was 60% for LDR versus 55% for HDR (p = .48) at 3 years. Late complications were reported in 2 HDR patients (3.5%) and 5 LDR patients (4.8%).

Orton et al.⁶¹⁰ noted that dose per fraction of HDR brachytherapy significantly influenced toxicity. Morbidity rates were significantly lower for point A doses/fractions of 7 Gy or less for both severe (1.28% vs. 3.44%; p <.0001) and moderate plus severe injuries (7.58% vs. 19.51%; p <.001). The effect of dose/fractionation on cure rates was equivocal.

Kuske et al.⁷¹⁹ described a method to improve target coverage and locoregional tumor control with HDR tandem and ovoid applications by which HDR endocavitary and interstitial brachytherapy are applied in the same session for tumors with a lateral expansion of 25 mm or more from the axis of the cervical canal. Seventy-six combined applications were given to 41 patients. With a follow-up average of 23 months, in stage IIB tumors, 3-year DFS was 75%. No severe early or persistent late complications were observed. Combined applicators with the tandem and ring with interstitial⁷²⁰ and tandem and ovoid with interstitial⁶⁵⁶^,⁷²¹ are now available for HDR brachytherapy.

Forrest et al.⁶⁸⁶ presented the results of 122 patients treated with EBRT followed by 6 Gy per fraction for five fractions of HDR. They reported a 2-year disease-free survival rate of 70% and grade 3/4 toxicity rate of 14% (13 patients). The median time to recurrence was 8 months (range, 2 to 22 months) and to toxicity was 10 months (range, 4 to 27 months). They concluded that the high toxicity of this regimen should prompt consideration of dose reduction in BT dose or use of 3D imaging to shape the dose. Several institutions in the United States now report 5.5 Gy é five fractions instead of 6 Gy per fraction for patients treated with chemoradiation. ^601,⁶⁰²

Anker et al.⁷²² treated 65 patients with HDR with 6 Gy é fractions, and 45 patients had the top dwells retracted as the tumor regressed. With a median follow-up of 24.5 months, the 3-year overall, disease-free distant metastases–free survival, and local control rates were 67%, 76%, 79%, and 97%, respectively. Acute and actuarial 3-year late grade 3 toxicity or greater occurred in 24.6% and 17% of patients, respectively.

Le Pechoux et al.⁷²³ treated 130 patients with cervical cancer with HDR brachytherapy (for stage I, 30 Gy in six weekly sessions) in combination with EBRT (50-Gy mean dose with midline shielding). Patients with more-advanced disease received four sessions of biweekly brachytherapy for a total dose of 18 to 24 Gy and external irradiation (20 to 30 Gy to the whole pelvis, 50 to 66 Gy to parametria with midline shielding). The 5-year survival rates were 82% for patients with stage IIB and 47% with stage IIIB disease. There were 4 rectovaginal or vesicovaginal fistulas and 1 case of proctitis requiring colostomy. Survival, local tumor control, and morbidity were equivalent in 76 patients treated with 6 Gy once a week and in 54 patients receiving twice-weekly brachytherapy of 5 Gy per session.

Hsu et al.⁷²⁴ dosed 92 patients with cancer of the cervix with HDR brachytherapy, six fractions of 7 Gy per fraction (42 Gy) at point A (HDR-6); 57 received four fractions of 8 Gy per fraction (32 Gy) at point A (HDR-4). A twice-daily program was used for all patients receiving HDR in two split courses. A historic control group of 259 patients was treated with LDR brachytherapy (40 Gy in two split courses). All patients received whole-pelvis external irradiation of 36 to 45 Gy (mostly 40 Gy) before brachytherapy. Five-year local tumor control rates were equivalent in the three groups (82%, 85.5% for HDR, and 89.5% for LDR). Five-year survival rates were also comparable (67.7%, 77.9%, and 74.1%, respectively). However, late complications were lower in the HDR-4 group, which received treatment more biologically equivalent to the LDR regimen, than in patients in the HDR-6 group (11% vs. 25.6%).

Selke et al.⁷²⁵ published results in 187 patients with primary carcinoma of the cervix treated with whole-pelvis irradiation (46 Gy) and HDR brachytherapy with a dose rate to point A of 1.6 Gy/minute, decreasing to approximately 0.8 Gy/minute at the end of the 5-year study. Three HDR fractions (8 to 10 Gy to point A per fraction) were concurrently administered with the last 2 to 3 weeks of external irradiation. The 5-year actuarial survival rates were 72% for stage IB, 65% for IIA, 66% for IIB, 66% for IIIA, and 45% for stage IIIB. With a median follow-up of 54 months, 23 patients had 25 complications; 13 (7.6%) were grade 3 or 4. Rectal complications were significantly higher in patients who received a total rectal dose of >54 Gy (p = .045).

Choi et al.⁷²⁶ treated 136 patients with carcinoma of the cervix with external-beam whole-pelvis irradiation (46 Gy in 23 fractions) and three weekly applications of HDR brachytherapy of 7 or 8 Gy per fraction to point A. The actuarial 5-year survival was 85% in stage IB, 64% in stage IIA, 70% in stage IIB, and 53% in stage IIIB. Grade 3 or higher complications occurred in 3% to 7% of the patients. The most significant determinants of severe rectal complications were the addition of a lower vaginal tandem (p < .01), uterine tandem length >5 cm, a total biologically effective dose to the rectum of >120 Gy, and stage III disease.

Kagei et al.⁷²⁷ reported on 217 patients with carcinoma of the cervix (71 patients with stage II and 146 with stage III disease) who received whole-pelvis EBRT (40 Gy in 20 fractions or 39.6 Gy in 22 fractions) and an additional 10 Gy in five fractions to the parametria followed by HDR brachytherapy. Cause-specific 5-year survival rates were 77% for stage II and 50% for stage III. Pelvic failure rates were 13% and 36%, respectively. The rates of severe (grade 4) late complications were 2% for the rectum, 1% for the small intestine or sigmoid colon, and 1% for the bladder.

Takeshi et al.⁷²⁸ treated 265 patients with stage III cervical carcinoma with external-beam radiation therapy (50.3 Gy) and intracavitary HDR brachytherapy (19.8 Gy). The 5-year overall survival, relapse-free survival, and locoregional event–free rates were 50.7%, 57.1%, and 71.2%, respectively. The 5-year incidence of major complications was 2.6% for bladder and 8.3% for rectum. The radiation dose in the subgroup with rectal complications was significantly greater than that in the subgroup without complications.

Wang et al.⁷²⁹ reported treatment results in 173 patients with cervical carcinoma treated with HDR brachytherapy and whole-pelvis irradiation (40 to 44 Gy in 20 to 22 fractions) followed by pelvic wall boost (6 to 14 Gy in three to seven fractions with central shielding). HDR brachytherapy delivered 7.2 Gy to point A in each of three applications 1 to 2 weeks apart. Five-year pelvic tumor control rates were 94%, 87%, and 72% for stages IIA, IIB to IIIA, and IIIB to IVA, respectively. Five-year actuarial survival rates were 79%, 59%, and 41%, respectively. Sixty-six patients (38%) had rectal complications, and 19 (11%) had bladder complications. The 5-year actuarial rectal complication rates were 15%, 4%, and 3% for grades 2, 3, and 4, respectively.

Lorvidhaya et al.⁷³⁰ reported the results in 1,992 patients with carcinoma of the cervix treated by external irradiation and HDR brachytherapy. There were 211 patients with stage IB, 225 with stage IIA, 902 with stage IIB, 14 with stage IIIA, 675 with stage IIIB, 16 with stage IVA, and 16 (0.8%) patients with stage IVB. With a median follow-up of 96 months, the actuarial 5-year disease-free survival rates were 70%, 59.4%, 46.1%, 32.3%, 7.8%, and 23,1%, respectively. The late complication rates (RTOG) for bowel and bladder combined were 7% for grade 3 and 1.9% for grade 4 complications.

Leborgne et al.⁷³¹ described a 4-year pelvic control rate of 93% and a disease-free survival rate of 88% for 59 patients with stage IB to IIA disease. All were treated with 18 Gy to the whole pelvis and 22 Gy to the parametria combined with six HDR fractions (14 Gy/hour to point A) of 7 Gy to point A, two in each treatment day, with 6-hour interfraction intervals. The corresponding parameters for 29 patients with stage IIB disease were 79%, 75%, and 75%. The actuarial 4-year late grade 2 and 3 complication rate was 4.7%.

In 1,148 patients with squamous cell cervical cancer treated with external RT and HDR brachytherapy with 22 years median of follow-up, the 10-year pelvic tumor control was 93% for stage IB, 82% for stage II, and 75% for stage III.⁵⁶⁹ Cause-specific survival was 89%, 74%, and 59%, respectively. Major sequelae were 4.4% in the rectosigmoid, 0.9% in the bladder, and 3.3% in the small intestine. Nakano et al.⁷³² subsequently presented a study of 210 patients with stage IIIB cervical cancer from eight Asian countries treated from 1996 to 1998 with radiation and brachytherapy. Though follow-up was difficult to obtain, the reported 5-year major complication rates were 6% in the HDR group and 10% in the LDR group. The 5-year overall survival rates were 51.1% in the HDR group and 57.5% in the LDR group.

Novetsky et al.⁷³³ presented data on 77 patients treated with external beam with concomitant cisplatin followed by two HDR brachytherapy fractions of 9 Gy each. Median follow-up was 3.5 years. The local control rate was 88% for stages IB2/II and 68% for stages III/IV. Grade 3/4 gastrointestinal acute symptoms occurred in 47%. Grade 3/4 late toxicities occurred in 5 (6%) patients. Patel et al.⁷³⁴ describe 104 cervical cancer patients treated with external beam and HDR, either 9 Gy for two fractions or 6.8 Gy for three fractions, each fraction 1 week apart. Median follow-up was 31 months. The 3-year actuarial local control was 81.35% with 9 Gy versus 65.18% with 6.8 Gy (p = .04). The 3-year actuarial risk of developing any grade 3 or worse late toxicity was 7.47% with 9 Gy and 3.57% with 6 Gy (p = 0.3).

Prospective Trial with CT or MR Compared to X-Ray

The clinical outcome results from institutions using CT- or MR-based treatment planning for cervical cancer brachytherapy are listed in Table 69.18. The French STIC trial⁷³³ collected data from 20 centers prospectively and stratified to 2D versus 3D (mainly with CT) brachytherapy. A total of 705 patients were treated with one of three arms: (a) brachytherapy followed by surgery (stage IB1, 165 patients); (b) EBRT plus chemotherapy, BT, then surgery (305 patients); or (c) EBRT plus chemotherapy and then BT (235 patients). For the 235 patients treated with concurrent chemoradiation and then brachytherapy, 2-year overall survival was 74% for 3D versus 65% for 2D (p = .27); disease-free survival was 60% versus 55% (p = .09); local regional relapse–free survival was 70% versus 61% (p = .001), and local-only relapse–free survival was 79% versus 74% (p = .003). Toxicity was reduced overall from 23% with 2D to 2.6% with 3D (p = .002); urinary from 9% in 2D to 1% with 3D (p = .02), gastrointestinal from 9% to 0% (p = 0.17), and gynecologic from 15% to 1% (p = .01).

Retrospective Comparison of CT to MR-Planned Brachytherapy

Three studies compared CT to MRI contouring for HDR tandem and ring brachytherapy. Wachter-Gerstner et al.⁷³⁵ compared MR-based plans in 15 patients to those derived with either CT or orthogonal films. CT and MR enabled higher dose to the target volume with similar OAR dosing. Viswanathan et al.⁶³⁵ compared CT contours to MR contours based on a standard set of guidelines; the CT contours were larger in width, but no other significant differences in DVHs were identified. A report by Eskander et al.⁶³⁶ of 10 patients had an MR for the first fraction only and showed that CT volumes had a greater length on the coronal plane, whereas MR images had a greater height on the sagittal plane. No differences were found in DVH parameters after optimization.⁶³⁶ Similar to the Eskander et al.⁶³⁶ study, using an MR for the first fraction and CT for subsequent fractions, Beriwal et al.⁶⁵² treated 44 patients with 5- to 6-Gy per fraction HDR after EBRT. Ninety-three percent had a complete response by PET at 3 months. Of those with a CR, 2 had a local recurrence at 6 and 8 months. With a median follow up of 8 months (range, 2.5 to 38 months), 2-year local control, disease-specific, and overall survival rates were 88%, 85%, and 86%, respectively.

Retrospective Results with CT-Planned Brachytherapy

Potter et al.⁷³⁶ reported results in 189 patients treated with HDR brachytherapy and EBRT (48.6 to 50 Gy). Small tumors were treated with five to six fractions of 7 Gy at point A (25 Gy in the brachytherapy volume), which is isoeffective to 76 to 86 Gy at point A. Large tumors received three to four fractions of 7 Gy after 50 Gy of EBRT, which is isoeffective to 82 to 92 Gy at point A. Three-dimensional treatment planning for brachytherapy was based on conventional x-rays and in 181 of 189 patients on CT scan. The mean brachytherapy dose was 16.2 Gy at the ICRU rectum reference point and 14.4 Gy at the ICRU bladder point. Taking into account the dose for EBRT, the mean isoeffective dose at the ICRU rectum reference point was 69.9 Gy. After a mean follow-up of 34 months, the actuarial pelvic control rate was 78% and the late complication rate for grades 3 and 4 was 2.9% for bladder, 4% for bowel, 6.1% for rectum, and 30.6% for the vagina (shortening and obliteration).

CT-based clinical outcomes were reported by the Addenbrooks Hospital. Twenty-eight patients had HDR, 8 Gy é 3, CT-planned brachytherapy.⁷³⁷ The 3-year actuarial cancer-specific survival rate in this group was 81%, with a pelvic control rate of 96%. Five of the 28 patients died of para-aortic or other distant disease, 1 of them being the only one with local recurrence presenting as a malignant vesicovaginal fistula. In 24 patients, D₉₀ ≥74 Gy was achieved. The only patient with local recurrence had D₉₀ = 63.8 Gy, which was a 20% improvement over historical non–image-guided controls.

At Brigham and Women’s Hospital, 115 stages IB to IVA cervical cancer patients had CT-planned brachytherapy and were treated with 595 fractions of 5.5- to 6-Gy per fraction HDR brachytherapy.⁷³⁸ The 2-year local relapse rate was 6.9%. The 2-year disease-specific survival was 83%, and overall survival rate was 78%.

Retrospective Results with MR-Planned LDR Brachytherapy

An initial report of MRI during intracavitary gynecologic brachytherapy was published in 1992 from the University of Michigan by Schoeppel et al.⁷³⁹ Three patients had CT and MRI with their first of two intracavitary implants. A CT- and MR-compatible Fletcher applicator was used. CT could not distinguish the tumor with as much clarity as MR. Tardivon et al.⁷⁴⁰ at Institut Gustave Roussy (IGR) treated 10 patients with MR evaluation of the tumor during intracavitary brachytherapy for cervical and vaginal cancer and found that in 7 cases MR findings were concordant with clinical examination. MR was useful to determine the tumor/applicator relationship and distinguish the adjacent OAR.

A review was published of 39 patients treated at IGR with MRI-guided LDR brachytherapy in the preoperative setting.⁷⁴¹ A total dose of 60 Gy to the IR-CTV was followed 6 weeks later by extrafascial hysterectomy and bilateral salpingo-oophorectomy with pelvic node dissection. Adjuvant chemoradiation was delivered to patients with pelvic lymph node involvement. After a median follow-up of 4.4 years (range, 2.6 to 6.6 years), there were no central recurrences; 1 local recurrence occurred in the lateral pelvis (2.6%). The 4-year actuarial overall and disease-free survival rates were 94% and 86%, respectively. The 2- and 4-year actuarial local relapse–free survival rates were 94% and 91%, respectively. Haie-Meder et al.⁶⁵⁵ subsequently published a series of 84 patients treated with LDR MR-planned brachytherapy after chemoradiation. With a median follow-up of 53 months (range, 31 to 79 months), the 4-year overall survival and disease-free survival rates were 57 (95% CI = 43 to 69) and 52% (95% CI = 40 to 64), respectively. Thirty-nine late complications occurred in 28 patients (33.3%): 13 bladder, 7 rectal, 5 small bowel, 4 urethral, 3 colic, 2 vaginal, 1 pelvic fibrosis, and 4 others. Four grade 3 delayed complications were observed, and no grade 4 complication occurred.

Retrospective Results with MR-Planned PDR or HDR Brachytherapy

With a 0.2-T MRI at the Medical University of Vienna, 145 patients with stage IB to IVA cervical cancer were treated with four fractions of 7-Gy HDR from 1998 to 2003.⁷⁴² Complete remission was achieved in 138 patients (95%), with 7 patients having locally persistent or progressive disease in the central (n = 5) or noncentral (n = 2) pelvis. With a median follow-up of 40 months, the 4-year local control rate was 83%, compared to 63% for historical controls. A subsequent analysis of 156 patients treated from 2001 to 2008 with MR-based brachytherapy was reviewed.⁶⁵³ Local control was 98% for tumors 2 to 5 cm and 92% for tumors >5 cm. Overall survival, however, was 72% for tumors 2 to 5 cm and 65% for tumors >5 cm, indicating that despite the increase in local control with MR-based brachytherapy, death from distant metastases remains a problem in patients with large-volume cancer.

Investigators at the IGR reported on 45 patients treated between 2004 and 2006 with a tandem and mold technique using PDR brachytherapy and MR-based contouring.⁶⁵¹ Until recently at IGR, surgery was often performed after brachytherapy if disease was suspected on clinical examination. A dose of ≥15 Gy (after EBRT) was prescribed to the IR-CTV. The dose to the HR-CTV was approximately 250% of the dose to the IR-CTV (i.e., 80 Gy to the HR-CTV). With a median follow-up of 26 months, the 2-year overall and disease-free survival rates were 78% and 73%, respectively. At Tata Memorial Hospital in India, 24 patients with squamous cell carcinoma were treated with MRI-based HDR. With a median follow-up of 12 months,⁷⁴³ 2 patients had local failures.⁶¹⁶ Other European centers⁶⁴⁵^,⁶⁵⁴^,⁶⁵⁶ and one Canadian center⁷⁴⁴ reported feasibility data for MR-based cervical cancer brachytherapy, showing a reduction in the normal-tissue toxicity rate. When implementing 0.5- to 1.5-T MR-based tandem/ring or tandem/ovoid brachytherapy with MRI, specific guidelines for MR use should be followed.⁶⁸⁰

Toxicities

Table 69.18 lists general toxicities in series using CT- or MR-planned brachytherapy. In the Medical University of Vienna series reporting patients treated from 2001 to 2008, 73% received concurrent cisplatin chemotherapy.⁶⁵³ A total of 11 grade 3 and 4 late events were recorded in 143 patients. With a median follow-up of 3.5 years, the actuarial grade 3 and 4 late morbidity at 3 and 5 years was respectively as follows: gastrointestinal, 4% and 4%; urinary, 2% and 3%; and vaginal, 1% and 3%. Two patients developed massive rectal bleeding requiring transfusions. Three patients required stoma (grade 4) for rectal wall ulceration, resulting in a fistula, a rectal perforation, and a rectovaginal fistula. Three patients developed grade 3 urinary frequency or urgency. Three patients experienced grade 3 or 4 coaptation of the vagina.

At IGR, of the 45 patients studied,⁶⁵¹ 23 and 2 developed acute grade 1 or 2 and grade 3 complications, respectively; 21 patients presented with delayed grade 1 or 2 complications. One other patient presented with a grade 3 vesicovaginal fistula. No grade 4 or greater complications, whether acute or delayed, were observed. In the IGR experience with LDR brachytherapy from 2000 to 2004, 39 late complications were reported; 13 bladder, 7 rectal, 5 small bowel, 4 urethral, 3 colic, 2 vaginal, 1 pelvic fibrosis, and 4 others. Grade 3 complications were 1 rectal, 2 bladder, and 1 urethral. Tan et al.⁷³⁷ reported on 28 patients treated with CT-guided brachytherapy for stage IB to IIIB cervix cancer. Their overall actuarial 3-year grade 3 and 4 morbidity rate was 14%,. Two patients had grade 3 abdominal pain and 1 had a colovaginal fistula. Overall, the data indicate that a potential reduction in morbidity appears to be a benefit of image-guided brachytherapy.

Template-Based Interstitial Brachytherapy

Interstitial implants with ²²⁶Ra, ¹³⁷Cs needles, or ¹⁹²Ir afterloading plastic catheters to limited tumor volumes are helpful in specific clinical situations. Indications include large residual bulky cervical tumors after external-beam treatment, residual tumor with sidewall invasion, vaginal extension, presence of a fistula and/or adjacent organ invasion, or a prior supracervical hysterectomy (Fig. 69.26). Syed-Neblett⁷⁴⁵ and Martinez⁷⁴⁶ perineal applicators are the most commonly selected. Methods for insertion have been described.⁵⁹⁸^,⁷⁴⁷ A tandem should be inserted when a uterus is present.⁷⁴⁸ If the os is not visible, ultrasound guidance to determine the proper placement of the tandem is advised.⁷⁴⁹ A ring applicator modified to allow simultaneous insertion of interstitial needles⁷⁵⁰ and ovoid application with interstitial needles have been described.⁶⁵⁶

Traditionally, plain x-ray films are used for brachytherapy treatment planning. Determination of normal tissue doses and optimization is not feasible, and the risk of complications is high. In these cases, consideration of laparoscopic approaches is recommended.⁵⁹⁸ Syed et al.⁷⁵¹ reported on 185 locally advanced cervical cancer patients treated with LDR interstitial brachytherapy from 1977 to 1997. Patients received external-beam treatment to 50.4 Gy, followed by interstitial brachytherapy to 40 to 50 Gy. Local control was 82%; 5-year disease-free survival rates were 65%, 67%, 49%, and 17% for patients with stage IB, II, III, and IV disease, respectively. Eighteen (10%) of the 185 patients developed RTOG grade 3 or 4 late complications.

Clinical outcomes using traditional techniques have been reported by several institutions. Thirty patients with stage IIB and 37 patients with stage III carcinoma received interstitial irradiation in the parametrium to supplement the dose delivered by external-beam treatment and intracavitary brachytherapy. Despite the fact that the patients treated with interstitial implant were in a high-risk group, local tumor control was comparable to that of patients treated with standard techniques.¹⁶⁹ Pierquin et al.⁷⁵² described locoregional recurrences in 6% of 53 patients with T1, 11% in 47 patients with T2, and 42% of 19 patients with T3 primary tumors of the uterine cervix treated with a combination of external-beam irradiation and the Creteil method for interstitial implantation of ¹⁹²Ir sources in a plastic cervical-vaginal moulage and a uterine tandem. Prempree⁷⁵³ reported a 96% local tumor control rate and 61% 5-year disease-free survival rate in 23 patients with stage IIIB carcinoma of the cervix treated with a combination of external irradiation and intracavitary and interstitial implants to the parametrium. Overall, major complications were noted in 8% of the patients. Martinez et al.,⁷⁴⁶ using the Martinez Universal Perineal Interstitial applicator, treated 37 patients with advanced or recurrent carcinoma of the cervix and 26 with vaginal-urethral tumors. Doses of approximately 35 Gy were given, in addition to external irradiation (36 Gy to the whole pelvis and 14 Gy to the pelvic sidewall). They reported 6 local failures in the patients with cervical lesions and 5 in the group with vaginal-urethral tumors. The overall complication rate was 5.1%. Nag et al.⁷⁵⁴ reported on 31 patients with carcinoma of the cervix treated with external-beam radiation therapy and fluoroscopically guided interstitial brachytherapy. With a median follow-up of 36 months, 16 patients (51%) with cervical had local tumor control. The 5-year actuarial survival rate was 34%. Only 1 patient experienced grade 3 complications (2.5%).

FIGURE 69.26. A: Picture of anterior scout computed tomography showing a template-based interstitial brachytherapy application. B: Magnetic resonance imaging during interstitial needle insertion in a patient with stage IIIB cervical cancer ensures proper placement of the catheters adjacent to the tandem. The 100% isodose line is in yellow.

Recio et al.⁷⁵⁵ used laparoscopy at the time of interstitial brachytherapy in six patients with FIGO stages IIB to IVA cervical carcinoma after completion of whole-pelvis radiation; a total of 98 needles were inserted to deliver a median interstitial brachytherapy dose of 20 Gy. Eleven perforations in the pelvic peritoneum or bladder were identified during surgery in five of the six patients, leading to immediate repositioning of needles. No acute or short-term morbidity related to the procedure was noted.

Sharma et al.⁷⁵⁶ presented results on 42 patients treated from 2005 to 2007 in a prospective study of two weekly sessions of 10Gy, 1 week after finishing external-beam radiation. Median follow-up was 23 months. Delayed toxicity was 9%. The 3-year overall survival for all stages was 47% and the 3-year recurrence-free survival for stages IIB, IIIB, and IVA was 67%, 34%, and 20%, respectively. Sharma et al.⁷⁵⁷ also reported on the use of transrectal ultrasound to assist with insertion of the interstitial needles.

With image-based planning including either a CT^637,⁶³⁸ or an MRI⁶³⁰ the physician evaluates the placement of the needles and may choose either to not treat specific catheters or to lower the dose given through catheters close to normal-tissue structures. An approximate 11% rate of bowel insertion and a long-term fistula rate of 4% to 10% have been reported in studies using CT for planning after insertion.⁶³⁷^,⁶³⁸ When a physician has the facility to insert the applicator in a CT or MR suite while the patient is under anesthesia, an iterative process of image-guided needle insertion ensures proper placement of the catheters and prevents an inadvertent insertion into a surrounding normal-tissue structure, such as the rectum, sigmoid, or bladder.⁶³⁰

Dose optimization with either PDR or HDR may improve the normal-tissue doses for interstitial therapy for some patients. The University of Pittsburgh reported on 11 cervical cancer patients treated with CT-guided HDR interstitial brachytherapy (5 fractions of 3.5 Gy per fraction).⁷⁵⁸ From 1998 to 2004 interstitial brachytherapy was chosen for cases with distorted anatomy or extensive vaginal disease. The 5-year actuarial local control rate was 63%. No patient had acute grade 3 or 4 toxicity. Grade 3 or 4 late toxicity occurred in 1 patient, with a 5-year actuarial rate of 7%. Three patients had late grade 2 rectal toxicity, and 1 patient had grade 2 small-bowel toxicity.

Dimopoulos et al.⁷²⁰ reported on the use of tandem/ring with short interstitial needles and MR-planned HDR brachytherapy for 22 cervical cancer patients followed for a median of 20 months; no grade 3 or 4 toxicities were noted, and 1 patient had a local recurrence. Nomden et al.⁷²¹ described the use of tandem/ovoid application with short interstitial needles for the second insertion with MR-planned PDR brachytherapy for 20 cervical cancer patients. They compared the first insertion with just a tandem and ovoid applicator to the second insertion, which included the addition of interstitial needles. There was an average increase in dose of 4.4 Gy (SD 2.3), with better coverage of the HR-CTV with the second insertion.

Mikami et al.⁷⁵⁹ analyzed needle applicator displacement in 10 patients treated with 30 Gy HDR in five fractions and found on daily CT scans an average of 1 to 2 mm of caudal displacement. Shifts of >3 mm were replanned. Shukla et al.⁷⁶⁰ presented data on 20 patients with cervical cancer treated with interstitial brachytherapy who underwent every-other-fraction CT imaging. The mean needle displacement was 2.5 (range, 0 to 7.4), 17.4 (range, 0 to 27.9), 1.7 (range, 0 to 6.7), 2.1 (range, 0 to 9.5), 1.7 (range, 0 to 9.3), and 0.6 mm (range, 0 to 7.8 mm) in cranial, caudal, anterior, posterior, right, and left directions, respectively. The mean displacement in the caudal direction was higher between days 1 and 2 than that between days 2 and 3 (13.4 vs. 3.8 mm; p = .01). Damato et al.,⁷⁶¹ in a study of 10 patients treated with interstitial brachytherapy, found on average, that <1-cm displacements and deformations of the implant occurred over the course of treatment. The most significant dosimetric consequences were due to changes in organ filling rather than catheter shifts. Proper quality assurance methodologies should be in place to detect shifts that can potentially result in inadvertent insertion into normal tissue.

Brachytherapy in the Elderly

Magné et al.⁷⁶² reported on 113 patients with median age of 76 years (range, 70.7 to 94.4 years) treated by conventional LDR BT as a part of their treatment. For rectal complications, grades 1/2, 3/4, and 5 (fatal) crude incidences were 19.4% (22 of 113), 1.8% (2 of 113) and 0.9% (1 of 113), respectively. Acute toxicity death occurred in 1 patient with major diarrhea associated with a hemodynamic shock. For small-bowel complications, grades 1/2 and 3/4 crude incidences were 3.5% (4 of 113) and 0.9% (1 of 113), respectively. For urinary tract complications, grades 1/2 and 3/4 crude incidences were 11.5% (13/113) and 2.7% (3/113), respectively. With a median follow-up of 3.1 years, 10 patients developed distant metastases, and 10 others had local relapses. The 3-year specific overall survival rate was 88.6% (95% CI = 77 to 92), and the corresponding disease-free survival rate was 81% (95% CI = 72 to 88). Age did not influence the effectiveness of BT in elderly patients, and BT should be considered whenever possible, even in elderly patients presenting with a cervix cancer.

TABLE 69.21 CARCINOMA OF THE UTERINE CERVIX: INCIDENCE OF CENTRAL/PELVIC RECURRENCES CORRELATED WITH METHOD OF THERAPY

Image-Guided Brachytherapy Versus External-Beam Boost

Studies of external-beam treatment as an alternative boost instead of brachytherapy demonstrate significantly inferior survival rates compared to those that use brachytherapy. The use of ultrasound enables tandem placement in most cases, even when the os cannot be identified, and should be attempted for difficult cases. Barraclough et al.⁷⁶³ reported on 44 patients with cervical cancer who did not receive brachytherapy and were treated with EBRT to 54 to 70 Gy via a three-dimensional conformal boost. After a median follow-up of 2.3 years, 48% relapsed, with 16 of 21 developing a central recurrence. The 5-year overall survival rate was 49%, which is much lower than for brachytherapy-treated patients.

The dosimetry of brachytherapy cannot be adequately mimicked by external-beam techniques. A treatment planning report compared inversely planned EBRT with photons (IMRT) and protons (IMPT) to 3D MRI-guided brachytherapy.⁷⁶⁴ EBRT was planned to deliver the highest possible doses to the PTV while respecting D_2cc limits from brachytherapy, assuming the same fractionation. Volumes receiving 60 Gy (in equivalent dose in 2-Gy fractions) were approximately twice as large for IMRT compared with brachytherapy, and the high central tumor dose was lower than that seen with brachytherapy. Both IMRT and protons were inferior to 3D image-based brachytherapy.

With IMRT, there is a need for replanning due to rapid tumor regression³¹⁷^–³¹⁹ and an increase in integral dose, with normal tissues throughout the pelvis receiving more radiation than with brachytherapy. Given the large movement and the increased dose to the normal tissues resulting in an increase in normal-tissue toxicity, highly conformal (IMRT, IGRT, SBRT) methods for boosting the cervix are not routinely recommended. Every effort should be made to use image guidance to insert a tandem into the uterus in order to provide adequate brachytherapy doses for all cervical cancer cases receiving radiation.

External-Beam Irradiation Alone

Occasionally, brachytherapy procedures cannot be performed because of medical reasons or unusual anatomic configuration of the pelvis or the tumor (i.e., extensive lesion, inability to identify the cervical canal). These patients may be treated with higher doses of external-beam irradiation alone, although survival is significantly worse than when brachytherapy is implemented, and normal-tissue toxicity is higher due to the excessive dose to the rectum and bowel. Therefore, every attempt to treat with brachytherapy should be made because brachytherapy moves with the patient and provides high regions of dose in the central regions of the tumor. With IMRT, a significantly higher normal-tissue dose is administered, and the desired high central regions of radiation cannot safely be administered.

Coia et al.,⁵²¹ in an analysis of 565 patients with various stages of cervical carcinoma treated in the Patterns of Care Study, reported better survival (67%) and pelvic tumor control (78%) for patients treated with external irradiation and brachytherapy than for patients who had no intracavitary brachytherapy applications (36% 4-year survival rate and 47% in-field failure rate). Patients treated with two intracavitary applications had a higher 4-year survival rate (73%) and in-field tumor control rate (83%) than those receiving only one application (60% 4-year survival rate and 71% in-field tumor control rate).

Hanks et al.⁵²⁵ and Montana et al.⁵²⁴ reported a higher incidence of central pelvic recurrences in patients with stage III cervical carcinoma treated with external-beam therapy alone than in patients receiving brachytherapy in addition to external-beam irradiation (Table 69.21). The incidence of major complications was similar in both groups of patients.

Akine et al.⁷⁶⁵ treated 104 patients with carcinoma of the uterine cervix with external irradiation alone (anteroposterior–posteroanterior or four-field box techniques) because of inability to perform intracavitary brachytherapy. Average doses delivered were 50 Gy to the whole pelvis, followed by additional doses with reduced portals to deliver a total of 60.8 Gy in 6 weeks, 72.3 Gy in 7.5 weeks, or 80.5 Gy in 8 weeks, with a daily dose of 1.9 or 2 Gy. The local tumor control rate was 27% for stage II, 19% for stage III, and 15% for stage IVA disease. The 5-year survival rates were 36%, 17%, and 5%, respectively. Four patients had major complications (usually proctitis) that required surgical treatment, and 1 patient died of rectal bleeding. Eight of 23 patients treated with conformal therapy had control of the tumor and survived 5 years without major complications. Saibishkumar et al.⁷⁶⁶ treated 146 patients with cervix cancer with EBRT alone (60 to 66 Gy) because of unsuitability for brachytherapy; 5-year pelvic tumor control was 21.9% and DFS was 11.6%.

Cost-Effectiveness of LDR Versus HDR Brachytherapy

Wright et al.⁷⁶⁷ developed a questionnaire to elicit patient preference for two brachytherapy methods (one LDR or three HDR fractions and two HDR or five HDR fractions, assuming both methods to be isoeffective). The questionnaire was completed by 90 female staff members at their center, 18 previously treated patients, and 20 newly diagnosed patients. When both methods were assumed to be isoeffective, only 34% of the 38 patients preferred three HDR fractions to one LDR fraction. However, when HDR was assumed to be 2% more curative or 6% less toxic, 50% said they would prefer the HDR therapy. Both preference and strength of preference for LDR were significantly associated with a greater traveling distance for treatments. More studies on resource utilization⁷⁶⁸ are needed.

Alternative Isotopes

Californium has been proposed as an alternative to iridium as the radioactive isotope. Maruyama and Muir⁷⁶⁹ reported on 41 patients with stage IB cervix cancer treated with 40 to 50 Gy to the whole pelvis followed by a 5- to 15-Gy boost to the lateral pelvic wall and a single ²⁵²Cf-neutron brachytherapy insertion in approximately 8 hours. Nearly total tumor clearance was achieved in >90% of the patients; tumor regression was more rapid in the ²⁵²Cf group than in similar patients treated with ¹³⁷Cs and the same external-beam irradiation dose.

FOLLOW-UP

After treatment, patients should be regularly followed by both the radiation and the gynecologic oncologist. Careful history taking and a complete physical and pelvic/rectal examination usually are performed every month for the first 3 months after completion of irradiation, every 3 months for the remainder of the first year, every 4 months the second year, every 6 months during the third through the fifth year, and yearly thereafter. The use of Pap smears for cervical and vaginal cytology as a follow-up study is controversial because of postirradiation cellular morphology that renders it difficult to distinguish postirradiation changes from residual or recurrent malignant cells.⁷⁷⁰^,⁷⁷¹ DNA analysis of postirradiation cytologic smears demonstrating atypia or dysplasia may provide ancillary information.⁷⁷²

Rintala et al.⁷⁷³ evaluated the reliability of cytologic analysis and atypia after radiation therapy in 89 patients treated for cervical carcinoma. A total of 697 Pap smears were taken; during the follow-up, 44 patients had recurrent disease, which was local in 17 (39%) cases. The rate of false-positive samples was only 3%. Radiation-induced atypia was detected in 28% of the Pap smears taken during the first 4 months after radiation therapy, and its incidence decreased thereafter. In 1,000 patients treated with either surgery or radiation therapy at the MD Anderson Cancer Center for stage IB cervical cancer posttreatment, Pap smears did not detect a single asymptomatic recurrence among 133 patients with recurrent disease.⁷⁷⁴

The presence of apparently viable tumor cells in the cytologic smear 3 months after irradiation should be evaluated with cervical biopsies, dilation and curettage, and careful examination under anesthesia, as indicated.

Complete blood counts and chemistry profile tests are obtained as clinically indicated. Chest radiography is commonly obtained on a yearly basis, usually for the first 5 years posttreatment, although its value to detect curable lung metastasis is not proven. If radiographs are consistently negative, obtaining them every other year thereafter may be sufficient.

Other imaging studies, such as CT, MRI, PET scanning, or bone scans, are obtained when clinically warranted. When persistent or recurrent tumor is suspected, biopsies should be obtained for histologic confirmation. If a biopsy is positive, immediate treatment should be instituted, as is discussed later.

Usually, hematometra after radiation therapy for cervical carcinoma is related to recurrent disease but occasionally may be related to estrogen replacement therapy, endometrial activity, or fibrosis and obliteration of the endocervix.⁷⁷⁵

TREATMENT OF RECURRENT CARCINOMA OF THE CERVIX

After Previous Surgery

Radiation may salvage approximately 50% of patients with localized pelvic recurrences after surgery alone. A combination of whole-pelvis external irradiation (45 to 50 Gy) with concurrent chemotherapy followed by interstitial brachytherapy is recommended. If the tumor lies outside of an accessible region for brachytherapy, dose escalation with conformal or IMRT techniques may be attempted, depending on the location of the tumor and the need to protect bowel, with at least 65 to 70 Gy necessary for adequate control. In the setting of recurrent disease, the total mucosal dose from the external and brachytherapy can approach 140 Gy to the upper vagina and 95 Gy to the distal vagina without a high risk.⁷⁷⁶ With interstitial brachytherapy, doses of 20 to 35 Gy are administered with single, double-plane, or volume implants, for a total tumor dose of approximately 80 Gy, depending on the extent of the tumor.

Larson et al.⁷⁷⁷ observed 27 recurrences (11%) in 249 patients treated with radical hysterectomy and pelvic lymphadenectomy for stage IB carcinoma of the cervix; 17 (63%) had tumor recurrence in the pelvis or vulva; the other 10 patients had recurrences outside the pelvis. Eight of 15 patients (53%) treated with irradiation for an isolated recurrence in the pelvis or vulvar region were tumor free between 10 and 126 months after treatment of the recurrence (median, 48 months).

Ijaz et al.⁷⁷⁸ reported on 50 patients treated with RT for an isolated pelvic recurrence of cervical carcinoma after radical hysterectomy; 7 patients were treated with palliative intent using hypofractionated RT. The remaining 43 patients were treated with curative intent, 33 with RT only and 10 with cisplatin-based chemoirradiation. The overall 5-year survival rate was 33% for all 50 patients, 39% for the 43 patients treated with curative intent, and 25% for patients with isolated sidewall recurrences treated with curative intent. Three patients experienced late treatment complications.

Hille et al.⁷⁷⁹ described results in 17 patients with recurrent cervix cancer (9 had a complete microscopically incomplete resection) treated with EBRT and brachytherapy to 50 to 65 Gy. The 5-year pelvic tumor control was 48%, and relapse-free survival was 24%.

After Definitive Irradiation

Reirradiation of previously irradiated patients must be undertaken with extreme caution. It is very important to analyze the techniques used in the initial treatment (beam energy, volume, doses delivered with external or intracavitary irradiation). In addition, the period of time between the two treatments must be taken into consideration because it is postulated that some repair of the initial damage may take place in the interval. In general, external irradiation for recurrent tumor is given to limited volumes (40 to 45 Gy, 1.8-Gy tumor dose per fraction, preferentially using lateral portals). Occasionally, intracavitary or interstitial irradiation can be used to treat relatively circumscribed recurrences.

Sommers et al.⁷⁸⁰ described the results of retreatment in 376 patients with recurrent carcinoma of the uterine cervix. Ninety-one patients received irradiation, mostly external (86.8%), occasionally combined with brachytherapy (7.7%) to control bleeding of central recurrences; brachytherapy alone was administered in 5.5% of patients. The usual dose for recurrent pelvic masses was 40 to 45 Gy, and for para-aortic lymph node metastases it was 45 to 50 Gy in 5 weeks. Other metastatic sites were treated with 35 to 40 Gy in 3 to 4 weeks. Pelvic exenteration was attempted in 23 patients, only 10 of whom were deemed to be operable (43.5%), but it was completed in only 7. The probability of 5-year survival after treatment for recurrence was 30% with combined surgery and external irradiation, 12% with surgery alone, and 4% with external irradiation alone. The 5-year survival rate for 10 patients who underwent pelvic exenteration was 16%. Only 1% of the untreated patients survived 5 years. Six of 140 patients (4.3%) experienced grade 2 or 3 complications.

Selected patients with limited pelvic recurrences not fixed to the pelvic wall and without evidence of extrapelvic metastases can be potentially salvaged by radical hysterectomy or pelvic exenteration. Coleman et al.⁷⁸¹ described results in 50 patients who underwent radical hysterectomy for persistent (18 patients) or recurrent (32 patients) cervical cancer after primary radiation therapy. Lymph node metastases were identified in 5 of 39 patients (13%) in whom the lymph nodes were evaluated. The 5- and 10-year survival rates were 72% and 60%, respectively.

In 65 patients on whom pelvic exenteration was carried out at Memorial Sloan-Kettering Cancer Center, the 5-year survival rate was 23%.⁷⁸² The operative mortality rate was 9.2%. The authors pointed out that the significant mortality and morbidity associated with this procedure preclude its use as palliative therapy.

Urinary diversion, either by nephrostomy or ileal bladder, may be of palliative value in patients with either recurrent carcinoma in the pelvis or complications. It must be kept in mind that diversion may prolong life but runs the risk of denying a terminally ill patient with cancer the oblivion and insensibility of uremia.

Kastritis et al.⁷⁸³ treated 200 patients with stage IV or recurrent cervix cancer with cisplatin-based chemotherapy; response rate was 43.5% in 142 patients with squamous cell and 53.5% in 58 patients with nonsquamous tumors (p= .79). Median survival was 11.57 and 19 months, respectively. Tinker et al.⁷⁸⁴ treated 25 women for recurrent cervical cancer with carboplatin–paclitaxel and noted a 20% cure rate and 20% progression rate, with median survival of 21 months. Brewer et al.⁵¹¹ in 32 women, all of whom had previous chemotherapy and 29 of whom had previous RT, used cisplatin and gemcitabine, with a progression rate of 22% and median time to progression of 3.5 months.

Para-Aortic Lymph Node Recurrences

Isolated recurrences in the para-aortic nodes after pelvic irradiation have been described in about 3% of patients, and some may be salvaged with aggressive therapy. The advent of IMRT makes treatment easier, with less morbidity.

Kim et al.⁷⁸⁵ treated 12 patients with isolated para-aortic lymph node metastasis with hyperfractionated RT (60 Gy in 1.2-Gy fractions twice a day) and concurrent cisplatin–paclitaxel. Fields extended from the superior plate of T12 to the lower plate of L5. Three-year survival was 19%. Grade 3 or 4 hematologic toxicity developed in two patients. Singh et al.⁷⁸⁶ detected 14 isolated para-aortic lymph node metastases in 816 patients previously treated with RT; these women were subsequently treated with RT to the para-aortic lymph nodes combined with concurrent chemotherapy. Seven patients survived 5 years.

In a review of 1,955 patients treated with RT for cervix cancer, Jhingran et al.,⁷⁸⁷ identified 120 patients with recurrent tumor above the pelvic fields. Initially, 10 had common iliac and 5 had para-aortic node involvement. In 104 patients, recurrences were immediately adjacent to the upper borders of the RT fields. In 15 patients treated with curative intent for the para-aortic lymph node recurrence, 5-year survival was 25%.

Intraoperative Irradiation

Intraoperative radiation therapy (IORT) has been used for treatment of locally advanced and recurrent carcinoma of the cervix, with 3-year survival rates of 8% to 21% as reported by Mahé et al.⁷⁸⁸ and Garton et al.,⁷⁸⁹ and a 5-year survival rate of 33% in 14 patients described by Kinney et al.⁴²³ Patient selection may have had an impact on the different results. Abe and Shibamoto⁷⁹⁰ noted that central recurrences, particularly in nonirradiated patients, and resection of the gross recurrent tumor in irradiated patients improve the benefit from IORT. Significant toxicity included peripheral nerve injury and ureteral stenosis (with doses >15 to 20 Gy).

IORT was used in 70 patients with pelvic recurrences in a European cooperative study.⁷⁹¹ Complete tumor resection was carried out in 30 patients, partial in 37, and unspecified in 3. Sixty-five patients had electron beam therapy (12 to 25 MeV), with mean doses of 18 Gy (10 to 25 Gy) after gross complete resection and 19 Gy (10 to 30 Gy) after partial resection. The 3-year overall survival rate was 8%. Grade 2 or 3 toxicity was observed in 19/70 patients (27%), with 10 complications being related to IORT.

Martinez-Monge et al.⁷⁹² reported a study of IORT in 26 patients with recurrent gynecologic tumors, some relapsing after full-dose radiation therapy (group 1) or after surgery (group 2). Cervical carcinoma was the initial tumor site of involvement in 18 patients. Treatment consisted of maximal surgical resection and IORT (10 to 25 Gy) to high-risk areas. Patients not previously irradiated also received external-beam irradiation (with or without chemotherapy) before or after surgery. There was 1 IORT-related incidence of motor neuropathy. The local tumor control rates were 33% and 77%; the 4-year actuarial survival for group 1 was 7%, and the 6-year actuarial survival rate for group 2 was 33%.

In another study, 42 patients with stages IIA to IVA cervical cancer initially received 50.4 Gy of pelvic external-beam radiation with concurrent cisplatin and 5-fluorouracil.⁷⁹³ Patients then underwent radical surgery 6 to 8 weeks later with IORT. The 5-year DFS and OS were 46% and 49%, respectively, which are inferior to reported results with standard concurrent chemoradiation followed by brachytherapy without surgery or IORT. Therefore, this regimen remains of questionable value in potentially curable patients.

URGENT BLEEDING AND PALLIATIVE IRRADIATION

Frequently, the radiation oncologist is faced with the challenge of treating a patient with stage IVB or recurrent carcinoma requiring palliation of pelvic pain or bleeding. Tumors respond rapidly to radiation, and bleeding usually resolves within a few days of treatment. If vaginal bleeding is the main concern, several possibilities may be effective. In a descriptive review of eight papers that presented palliative treatment data,⁷⁹⁴ five papers were found to report using 10 Gy per fraction, with the best resolution of bleeding and/or pain when each 10-Gy fraction was given at 3- to 4-week intervals for a total of three fractions. Alternatively, common palliative regimens used in other sites of the body, such as 4 Gy for five or six fractions or 3 Gy for 10 fractions, may be implemented. Patients who present with a new diagnosis may be treated with 3 to 4 Gy for two or three fractions, followed by standard 1.8 Gy to approximately 39.6 Gy and then brachytherapy. Alternatively, patients may receive 1 to 2 days of 1.8 Gy twice a day, switching to once-a-day treatment with 1.8 Gy per fraction after bleeding has stopped on day 2 or 3, completing treatment after 45 Gy and then commencing routine brachytherapy.

A single LDR intracavitary insertion with tandem and colpostats for approximately 6,000 mgh (55 Gy to point A) may be used for palliation. If irradiation was delivered previously, lower intracavitary doses should be prescribed (4,000 to 5,000 mgh). Grigsby et al.⁷⁹⁵ used two fractions of HDR brachytherapy with a ring applicator (once weekly) with control of bleeding in 14 of 15 patients.

Several high-dose fractionation schedules with external-beam radiation have been used. Spanos et al.⁷⁹⁶ reported on a phase II study of daily multifractionated split-course irradiation in 142 patients with recurrent or metastatic disease in the pelvis. Irradiation consisted of 3.7 Gy per fraction given twice daily for 2 consecutive days, repeated at 3- to 6-week intervals for a total of three courses, aiming at a total tumor dose of 44.4 Gy. Occasionally, this regimen was combined with an LDR intracavitary insertion (4,500 mgh), blocking the midline for the last 14.4-Gy external dose. Twenty-seven patients survived >1 year. There were only 2 recorded cases of grade 3 toxicity (lower gastrointestinal tract). This study was expanded to a phase III protocol randomizing 136 patients between a short (2 weeks) or a longer (4 weeks) rest period between the split courses of irradiation.⁷⁹⁷ There was a trend toward increased acute toxicity in patients with shorter rest periods (5 of 58 vs. 0 of 68; p = .07). Late toxicity was not significantly different in the two groups. Pelvic tumor response was comparable in both groups (34% vs. 26%). Spanos et al.⁷⁹⁸ reported a 6% complication rate in 290 patients treated in RTOG Protocol 85–02. No patient receiving <30 Gy experienced late toxicity. There was no significant difference in the incidence of complications for patients with a 2- or 4-week rest (p = .47).

IRRADIATION AND HYPERTHERMIA

Because of technical limitations in the delivery of adequate heat to large parts of the body such as the pelvis, the use of hyperthermia in the treatment of carcinoma of the uterine cervix has been rare. Hornback et al.⁷⁹⁹ described a nonrandomized study in which the combination of microwave hyperthermia (433 MHz) and irradiation resulted in improved pelvic tumor control (72%) in a group of 79 patients with stage IIIB carcinoma compared with previously irradiated historic control patients (53%). However, 5-year survival rates were comparable in both groups (22% to 30%).

Sharma et al.⁸⁰⁰ reported a 70% disease-free survival rate at 18 months in 20 patients with stage IIB or III carcinoma of the uterine cervix treated with a combination of irradiation and hyperthermia (13.5 MHz, 42°C to 43°C, 30 minutes before irradiation) in comparison with a 50% disease-free survival rate in 22 patients treated with irradiation alone. The grade 3 complication rate (8%) was similar in both groups.

Dinges et al.⁸⁰¹ treated 18 patients with advanced carcinoma of the cervix with RT plus hyperthermia (in the first and fourth weeks, two regional hyperthermia treatments were applied). The acute toxicity was low and similar to that with RT alone. The local tumor control was 48% at 2 years.

Harima et al.⁸⁰² evaluated radiation therapy or thermoirradiation (three sessions of hyperthermia) for stage IIIB cervical carcinoma; two groups of 20 patients each were randomly divided. A complete response was achieved in 50% (10 of 20) in the RT group versus 80% (16 of 20) in the thermoirradiation group (p = .048). The 3-year overall survival and disease-free survival rates for the patients who were treated with thermoirradiation (58.2% and 63.6%) were better than with RT (48.1% and 45%), but differences were not statistically significant. The 3-year local relapse-free survival rate of the patients who were treated with thermoirradiation (79.7%) was significantly better than that of the patients treated with irradiation alone (48.5%; p = .048). Thermoirradiation was well tolerated and did not add to either acute or long-term toxicity over radiation alone.

Vasanthan et al.⁸⁰³ reported on 110 patients with locally advanced cervix cancer randomized to treatment with RT alone or combined with hyperthermia (minimum five sessions, 60 minutes each, once weekly). Overall 3-year pelvic tumor control was 68.5% and survival was 73.2%, with no difference in either group, although survival was lower in the patients with stage IIB treated with hyperthermia. Acute toxicity was 18% (10 of 55) in the hyperthermia patients and 4% (2 of 55) with RT alone. Late toxicity was not different in the two arms.

A Cochrane database review identified six randomized, controlled trials published between 1987 and 2009 comparing RT versus combined hyperthermia and RT. The results show 74% of patients had stage IIIB cervical cancer. A significantly higher complete response rate (RR = 0.56, 95% CI = 0.39 to 0.79) and lower local recurrence rate (HR = 0.48, 95% CI = 0.37 to 0.63) and improved overall survival (HR = 0.67, 95% CI = 0.45 to 0.99) with no difference in acute or late grade 3 to 4 toxicity were seen for patients treated with combined therapy.⁸⁰⁴ Catheter-based ultrasound devices provide a method to deliver heat with HDR brachytherapy, but clinical results are not yet available.⁸⁰⁵

SIDE EFFECTS: SURGERY AND RADIATION

Descriptions of sequelae vary among institutions because toxicity-grading scales are not uniform and the scoring system for complications is not clearly stated in all reports. Surgical side effects alone depend on the extent of surgery and the amount of disease. Radical hysterectomy alone may cause long-term side effects such as urinary retention requiring chronic suprapubic catheter placement, sciatic nerve injury, postoperative seroma or hematoma formation, pelvic pain, or, when lymphadenectomy, is performed, life-long edema. Oophorectomy also may induce menopause; hysterectomy removes the ability to carry a pregnancy, and removal of a portion of the vagina may significantly change sexual function if vaginal shortening is severe.

With improved anesthesia, surgical techniques, and antibiotic therapy, the mortality rate for radical hysterectomy with pelvic lymphadenectomy has decreased to 1% or less. The most frequent sequela after radical hysterectomy is urinary dysfunction as a result of partial denervation of the detrusor muscle. Patients may have various degrees of loss of bladder sensation, inability to initiate voiding, residual urine retention, and incontinence.

In 375 patients treated with a modified radical hysterectomy for various gynecologic disorders, Magrina et al.,⁸⁰⁶ observed some form of postoperative (within 42 days of surgery) complications in 89 patients (24%). Patients who had a pelvic lymphadenectomy experienced a greater incidence of lower-extremity lymphedema than those who did not undergo this procedure. Preoperative or postoperative pelvic irradiation was a significant predisposing factor for urinary tract infection, lymphedema, and bowel obstruction in these patients compared with those who did not receive pelvic irradiation.

Some loss of defecatory urge associated with chronic rectal dysfunction was observed by Barnes et al.⁸⁰⁷ after radical hysterectomy. Manometric studies suggest a disruption of the spinal arcs controlling defecation.

Other complications include ureterovaginal fistula (the incidence of which has decreased to <3%), hemorrhage, infection, bowel obstruction, stricture and fibrosis of the intestine or rectosigmoid colon, and bladder and rectovaginal fistulas. Postsurgical complications are usually more amenable to correction than are late complications after irradiation.

When postoperative radiation therapy is given to selected patients, further complications of the additional therapy are expected. The main areas of side effects due to radiation are bowel, bladder, skin, and sexual function. Because of intestinal adhesions to denuded surfaces in the pelvis, enteric complications, such as obstruction, fistula, or dysfunction, were observed in 24% of patients reported by Fiorica et al.⁸⁰⁸ Other investigators, however, have reported no increase in the incidence of severe complications in patients treated with postoperative irradiation.³⁸⁷^,⁸²¹

Lower body mass index (BMI) is correlated with an increase in toxicity. A total of 404 patients with stage IB1 cervical cancer with positive lymph nodes or stage IB2 or higher were treated from 1998 to 2008. A BMI of <18.5 was associated with a decreased overall survival (HR = 2.37, p < .01). Grade 3 and 4 complications appeared to trend higher; overall, 17% versus 14%; specifically for fistula, 11% versus 9% (p = .05), for bowel obstruction, 33% versus 4% (p < .01), and for lymphedema, 5.6% versus. 1.2% (p= .0).⁸⁰⁹

Montz et al.⁸¹⁰ evaluated bowel obstruction in 98 patients undergoing radical hysterectomy for a nonadnexal gynecologic malignancy. The incidence of small-bowel obstruction was significantly higher (p < .05) in patients who received concomitant radiation therapy (20%). None of these patients had recurrent disease at the time of small-bowel obstruction. Findings at surgery consisted of minimal incisional adhesions but extensive matted small-bowel loops adherent to the pelvic operative sites.

When irradiation is combined with surgery, the complication rate tends to be somewhat higher, particularly because of injury to the ureter or the bladder (ureteral stricture or ureterovaginal or vesicovaginal fistula).⁸¹¹ The dose of irradiation, technique, and type of surgical procedure performed are important in determining the morbidity of combined therapy. Jacobs et al.,⁸¹² in 102 patients with invasive cervical carcinoma treated with low-dose preoperative irradiation and radical hysterectomy with lymphadenectomy or high-dose preoperative irradiation and conservative extrafascial hysterectomy, noted a major complication rate of 5%. After combined treatment, some degree of lymphedema may be observed (30% to 40%).

A significant number of complications are associated with pretherapy staging laparotomy, particularly if irradiation (>55 Gy) is given to metastatic para-aortic lymph nodes. The incidence of complications is between 5% and 20%, depending on the extent of the para-aortic lymph node dissection, use of transperitoneal or retroperitoneal approach for the operation, and dose of irradiation given.²⁷⁹

TABLE 69.22 CARCINOMA OF THE UTERINE CERVIX: GRADE 2 SEQUELAE (WASHINGTON UNIVERSITY, 1959–1989)

TABLE 69.23 CARCINOMA OF THE UTERINE CERVIX: GRADE 3 SEQUELAE (WASHINGTON UNIVERSITY, 1959–1989)

Late Sequelae—Overall

The incidence of major late sequelae of radiation therapy for stages I and IIA carcinoma of the cervix ranges from 3% to 5% and for stages IIB and III between 10% and 15%. The most frequent major sequelae for the various stages are listed in Tables 69.22 and 69.23. Injury to the gastrointestinal tract usually appears within the first 2 years after radiation therapy, whereas complications of the urinary tract are seen more frequently 3 to 5 years after treatment.⁵⁷⁰^,⁸¹⁶ Pedersen et al.,⁸¹³ in a review of morbidity of radiation therapy in 442 patients with cervical cancer stages IIB, III, and IVA, recommended that actuarial estimates rather than frequency of sequelae be reported to avoid underestimation of risks of late morbidity after radiation therapy in long-term survivors. In fact, Eifel et al.,⁸¹¹ in 1,784 patients with stage IB carcinoma of the cervix, noted that the greatest risk of sequelae is in the first 3 years after therapy. The risk of rectal complications declined after the first 2 years of follow-up to 0.6%/year, whereas the risk of major urinary tract complications for survivors continued at 0.3%/year, with a 20-year actuarial risk of major complications of 14.4%.

Montana et al.,⁵²⁴ Perez et al.,⁸¹⁴ and Pourquier et al.⁸¹⁵ noted a greater incidence of complications with higher doses of irradiation. Perez et al.⁸¹⁶ and Pourquier et al.⁸¹⁵ reported that with doses <75 to 80 Gy delivered to limited volumes, grade 2 and 3 complications in the urinary tract and rectosigmoid were approximately 5%. However, the incidence increased to >10% with higher doses of irradiation to these organs (Fig. 69.27). Doses >60 Gy were also correlated with a greater incidence of small-bowel injury (Fig. 69.28). The same analysis showed that patients who experienced sequelae of therapy had slightly better survival rates than patients without any complications. This was related to improved tumor control with higher doses of irradiation.⁸¹⁶

Perez et al.⁸¹⁴ quantitated the effect of total doses of irradiation, dose rate, and ratio of doses to bladder or rectum and point A on sequelae in 1,456 patients treated for cervical cancer with external-beam irradiation plus two LDR intracavitary insertions to deliver 70 to 90 Gy to point A. Median follow-up was 11 years. In stage IB, the frequency of grade 2 morbidity was 9%, and in grade 3 it was 5%; in stages IIA, IIB, III, and IVA, the frequency of grade 2 morbidity was 10% to 12% and that of grade 3 was 10%. The most frequent grade 2 urinary/rectal sequelae were cystitis and proctitis (0.7% to 3%). The most common grade 3 sequelae were vesicovaginal fistula (0.6% to 2% in patients with stage I to III tumors), rectovaginal fistula (0.8% to 3%), and intestinal obstruction (0.8% to 4%). In the bladder, doses <80 Gy correlated with a <3% incidence of morbidity, which was 5% with higher doses (p = .31). In the rectosigmoid, the incidence of significant morbidity was <4% with doses <75 Gy and increased to 9% with higher doses. For the small intestine, the incidence of morbidity was <1% with 50 Gy or less, 2% with 50 to 60 Gy, and 5% with higher doses to the lateral pelvic wall (p = .04). Multivariate analysis showed that dose to the rectal point was the only factor influencing rectosigmoid sequelae, and dose to the bladder point affected bladder morbidity.

In a review of the Patterns of Care Study, Lanciano et al.⁸¹⁷ observed a 5-year actuarial rate of 14% for major late complications in 1,558 patients treated with irradiation for invasive carcinoma of the cervix. Women <40 years of age or with a history of prior surgery or laparotomy for staging had a greater incidence of significant morbidity (15% to 18% vs. 8% to 9%). In addition, EBRT dose per fraction of >2 Gy, paracentral doses of 85 Gy or greater, and lateral parametrial doses >60 Gy were independently associated with a higher complication rate.

Lee et al.,⁸¹⁸ using 3-Gy fractions with EBRT, calculated the rectal point dose in the anterior wall at the level of the cervical os and noted that total higher BED (142.7 Gy) was associated with more frequent rectal sequelae compared with BED of <131 Gy.

Mitchell et al.¹²⁴ evaluated 398 patients with stages I to III cervical carcinoma treated with radiation therapy. Patients were divided into nonelderly (35 to 69 years of age; n = 338) and elderly (≥70 years of age; n = 60) groups. The frequency and severity of acute and chronic sequelae were equivalent in both groups.

FIGURE 69.27. Incidence of moderate or severe genitourinary (A) or rectosigmoid (B) complications in patients with carcinoma of uterine cervix (all stages) treated with irradiation alone (external and brachytherapy). A greater frequency of complications is noted with maximum doses of >75 to 80 Gy to the bladder or rectum.

FIGURE 69.28. Incidence of moderate or severe complications in small intestine correlated with doses of irradiation.

Gastrointestinal Toxicity

When late radiation proctitis occurs, initial treatment is the same as for acute proctitis. If the symptoms and rectal bleeding persist, laser treatment of rectal telangiectasis or ulcers is frequently beneficial. Roche et al.⁸¹⁹ treated six patients with hemorrhagic radiation-induced proctitis using outpatient intrarectal application of formaldehyde 4%. In four cases the bleeding ceased after the first formaldehyde application; two patients continued to bleed, but another application 3 weeks later definitively controlled the hemorrhage. There were no complications, such as burns or late stenosis of the deep layers of the rectum, and this technique was well tolerated. Rubinstein et al.⁸²⁰ and Seow-Choen et al.⁸²¹ also reported treatment of radiation proctitis with a similar technique. Patients are sedated, a local anesthetic block is administered, and a sponge moistened with 4% formalin is applied for 4 minutes to each bleeding area of the rectum. Care is taken to protect the perianal skin from any caustic effects of the formalin.

Occasionally, a colostomy is necessary if conservation management fails. The importance of performing colonoscopy in patients with rectal bleeding to exclude other lesions in the colon, including polyps or cancer, is emphasized. If routine screening colonoscopy is not urgent, unless there is a medical reason, the colonoscopy may be postponed until 1 year after pelvic radiation to ensure no issues with poor wound healing, bleeding, or ulceration secondary to biopsy performed at the time of colonoscopy.

Anal incontinence is occasionally observed. This sequela must be assessed in light of a report by Nelson et al.,⁸²² who in a survey of 6,959 nonirradiated patients, identified 153 (2.2%) who reported anal incontinence, without specific etiology. Thirty percent of incontinent subjects were >65 years of age, and 63% were women. Of those with anal incontinence, 36% were incontinent to solid feces, 54% to liquid feces, and 60% to gas.

Kim et al.⁸²³ investigated the effects of radiation on anorectal function using manometry in 24 patients with carcinoma of the uterine cervix who had late radiation proctitis. These data were compared with those from 24 age-matched nonirradiated female volunteers. Regardless of the severity of proctitis symptoms, 75% of irradiated patients exhibited abnormal manometric parameters for sensory or motor functions. Radiation damage to nerves and to the external sphincter muscle was considered to be an important cause of motor dysfunction.

Quilty⁸²⁴ noted a greater incidence of pelvic complications in patients treated with higher doses to the whole pelvis (40 to 50 Gy). The author commented that the intracavitary radium dose was not correlated with severe complications. Similar observations were made by Stryker et al.⁸²⁵ who recorded a 9% incidence of fistulas and a 14% incidence of grade 2 and 3 complications in 132 patients after delivery of 50 Gy or higher to the whole pelvis (1.8-Gy daily dose) combined with intracavitary insertion. They recommended that the whole-pelvis dose should not exceed 40 to 45 Gy when doses of approximately 40 Gy are delivered to point A with LDR intracavitary insertions.

Kuske et al.,⁷¹⁹ reported results of therapy in 99 patients with carcinoma of the cervix on whom minicolpostats were used, noted a 15% incidence of grade 2 and 3 complications, which was higher than the 8% incidence noted in a similar group of patients treated with regular colpostats during the same period (p = .08).

Perez et al.⁸¹⁶ reported that the incidence and type of complications with interstitial therapy were approximately the same as in patients treated with intracavitary technique only. In contrast, Kasibhatla et al.⁸²⁶ noted 6% small-bowel obstruction in 36 women with gynecologic cancer treated with EBRT and interstitial brachytherapy, which was aggravated by previous abdominopelvic surgery. The 3-year risk of rectovaginal fistula was 18%, and it was significantly higher in patients who received total doses of >76 Gy (100% vs. 7%; p = .009).

Irradiation of the para-aortic lymph nodes has been reported to cause increased morbidity, particularly if it is done after transperitoneal staging para-aortic lymphadenectomy. In a randomized study reported by Rotman et al.,⁸²⁷ a somewhat higher incidence of grade 2 and 3 complications was reported in 170 patients (10 complications) given 45 Gy to the para-aortic area in addition to standard pelvic irradiation, compared with 5 complications in 167 patients treated by pelvic irradiation only. The incidence of fatal (grade 5) complications was 4 and 1, respectively. In a similar randomized study by Haie et al.⁵⁴¹ for the EORTC, the incidence of grade 3 small-bowel injury was 2.3% in the para-aortic irradiation group and 0.9% in the pelvic irradiation–only group. The overall incidences of severe complications were 9% and 4.8%, respectively.

Willett et al.⁸²⁸ reported on 28 patients with inflammatory bowel disease (10 with Crohn’s disease, 18 with ulcerative colitis) who underwent external-beam abdominal or pelvic irradiation. Patients were treated either by specialized techniques (16 patients) to minimize small- and large-bowel irradiation or by conventional approaches (12 patients). The overall incidence of severe toxicity was 46% (13 of 28 patients), and 6 patients (21%) experienced severe acute toxicity necessitating cessation of radiation therapy. Late toxicity requiring hospitalization or surgical intervention was observed in 8 of 28 patients (29%). For patients treated with conventional approaches, the 5-year actuarial rate of late toxicity was 73% versus 23% for patients treated by specialized techniques (p = .02). In patients with inflammatory bowel disease abdominal or pelvic irradiation, must be used judiciously.

In contrast, Song et al.,⁴¹¹ in a review of 24 patients with a history of inflammatory bowel disease who received RT (median dose of 45 Gy in 1.8- to 3-Gy fractions) to fields encompassing some portion of the gastrointestinal tract, noted that 5 patients (21%) experienced acute intestinal toxicity of grade 3 or greater and 2 (8%) had grade 3 or greater late intestinal toxicity. Fifteen patients also received concurrent chemotherapy. The authors believed that the gastrointestinal toxicity in these patients was more modest than generally perceived. Tiersten and Saltz⁸²⁹ noted that five patients with inflammatory bowel disease and gastrointestinal malignancy completed planned radiation therapy (30 to 54 Gy), usually with concurrent 5-FU, without difficulty.

Salama et al.⁴⁴³ reported preliminary observations on acute toxicity with extended-field IMRT in 13 patients with gynecologic cancer. With median follow-up of 11 months, 2 patients treated with chemoradiation experienced grade 3 or higher morbidity and 1 (with a history of previous surgeries) developed small-bowel obstruction.

Levenback et al.⁸³⁰ identified 116 of 1,784 patients (6.5%) with stage IB carcinoma of the cervix treated with irradiation in whom hemorrhagic cystitis developed, 23% grade 2 (repeated minor bleeding) and 18% grade 3 (hospitalization required for medical management). The median interval to onset of hematuria was 35.5 months. The risk of severe hematuria requiring surgical intervention was 1.4% at 10 years and 2.3% at 20 years. Minor episodes of hematuria are managed by antibiotic therapy. Cystoscopic, laser, or cautery treatment of bleeding points is indicated. Clot evacuation and continuous bladder irrigation are important elements in the acute management of patients with heavy bleeding. Occasionally, a urinary diversion is required for intractable severe hematuria.

Genitourinary Toxicity

Ureteral stricture at 20 years was observed in 2.5% of 1,784 patients with stage IB carcinoma of the cervix treated with irradiation (274 followed for up to 20 years or longer).⁸³¹ The most common presenting symptoms were flank pain and urinary tract infection. In 5 patients, ureteral stricture was complicated by a vesicovaginal fistula. Seven of 43 patients who had no evidence of cancer and had hydroureter or hydronephrosis died of radiation complications. Treatment of ureteral stenosis may consist of stenting or resection of the fibrotic segment and reimplantation of the ureter with either ureteroneocystostomy or ureteroileocystostomy. In approximately half of the patients, diversion of urinary stream and ileal conduits are necessary. Occasionally, a nephrectomy is performed for removal of a nonfunctional kidney. Buglione et al.⁸³² reported a 10% incidence of late urinary morbidity and 1% ureteral fibrosis, grade III or IV, in 191 patients. They postulated the role of TGF-β₁ in the activation of fibroblasts and remodeling of extracellular matrix, which may be important in the induction of these sequelae.

Patients with gynecologic malignancies, including those receiving radiation therapy, are prone to development of urinary tract infections. Prasad et al.⁸³³ collected 216 urine samples from 36 patients receiving pelvic irradiation, 12 of whom had urinary tract infection. The most common organism isolated was Escherichia coli, followed by Enterococcus species. Appropriate urine bacterial studies and cultures are indicated in patients suspected of having superimposed urinary tract infection during the course of radiation therapy.

Parkin et al.⁸³⁴ reported a 26% incidence of severe urinary symptoms (urgency, incontinence, and frequency) in patients treated with irradiation alone for cervical carcinoma. They carried out urodynamic studies in 42 women and compared them with 28 women having urodynamic evaluations before and after treatment. There was no difference in the mean maximum flow rate or mean residual volume in the two groups. However, mean volume of full bladder sensation was significantly lower in the postirradiation group than in the pretreatment group, as was the mean maximum cystometric capacity. This same dysfunction may be noted in approximately 10% of the general female population, and the incidence increases in older women.³⁰²

Ureteroarterial fistula is a rare occurrence, and it is associated with a high mortality rate. When profuse urinary tract bleeding occurs in patients previously diagnosed with a gynecologic malignancy and treated with radiation therapy and extensive surgery, ureteroarterial fistula should be considered in the differential diagnoses.⁸³⁵

Neurologic Toxicity

Although extremely rare, lumbosacral plexopathy has been occasionally reported in patients treated for pelvic tumors with doses of 60 to 67.5 Gy. This syndrome was observed in 4 of 2,410 patients with cervical or endometrial carcinoma receiving 45 Gy to the para-aortic lymph nodes (without spinal cord shielding) or external pelvic irradiation (60 Gy to the parametria) and brachytherapy, with the lumbosacral plexus receiving total doses of 70 to 79 Gy.⁸³⁶ Lower-extremity paralysis secondary to lumbosacral plexopathy was reported in one patient after standard radiation therapy for cervical cancer.⁸³⁷

Patients previously reported as having radiation myelopathy to the lumbar spine may have suffered a lumbar and sacral nerve plexopathy instead of or in addition to the spinal cord injury. The differential diagnosis of plexopathy with recurrent tumors is sometimes difficult. In a comparison of 20 patients with lumbosacral plexopathy after irradiation and 30 patients with plexus damage from pelvic malignancy, Thomas et al.⁸³⁸ noted that indolent leg weakness occurred early in radiation-induced plexopathy (pain occurred initially in 10% of patients, although ultimately it was present in 50%), whereas pain was most frequently associated with tumor plexopathy. Muscular weakness, numbness, and paresthesia are common in both groups. Electromyography showed abnormal myokymic discharges in 57% of patients, whereas this finding was very unusual in tumor-induced plexopathy. CT is extremely helpful in the detection of pelvic masses or bone destruction caused by tumor. The authors also reported extensive retroperitoneal fibrosis of the lumbosacral plexus in 2 patients and femoral nerve fibrosis with plexopathy in 1 patient. Although cystometrograms have demonstrated bladder atonicity in some cases, several authors have failed to observe bladder or rectal sphincter disturbances. Unfortunately, as in radiation myelopathy, the neurologic deficit is irreversible, and no effective therapy other supportive care has been found.

Sexual Function

Other types of clinically significant sequelae have been described. Bruner et al.,⁸³⁹ in 90 patients treated with intracavitary irradiation for either carcinoma of the cervix (42 patients) or endometrial carcinoma (48 patients), 78 of whom also received external pelvic irradiation (44.5-Gy mean dose), noted that vaginal length decreased in most patients (at 24 months, in endometrial carcinoma from 8.8 to 7.8 cm, and in cervical carcinoma from 7.6 to 6.2 cm). Pretreatment sexual activity was reported by 31% of women in comparison with 43% after treatment. However, 22% of women reported a decrease in sexual frequency and 37% a decrease in sexual satisfaction. This was correlated with increased dyspareunia, which was noted in 31% of women treated for carcinoma of the cervix and 44% of those treated for endometrial carcinoma. Grigsby et al.⁸⁴⁰ described complex problems with sexual adjustment in women with gynecologic tumors treated with radiation therapy, with decreased frequency of sexual intercourse, desire, orgasm, and enjoyment of intercourse in 16% to 47% of patients.

Regular vaginal dilation is widely recommended to maintain vaginal health and sexual functioning; however, the compliance rate with this recommendation is not consistent. In a study to test the effectiveness of an “information-motivation-behavior skills” model, the intervention improved the use of vaginal dilation after radiotherapy, and decreased fear about sex after treatment⁸⁴¹ There was no evidence that the experimental intervention improved global sexual health. Jensen et al.⁸⁴² described persistent sexual dysfunction throughout 2 years after RT in 118 women; 85% had low or no sexual interest, 35% had lack of vaginal lubrication, and 55% had mild to severe dyspareunia. However, 63% of the sexually active patients before RT remained active, although with decreased frequency.

Radiation causes ovarian failure with a cessation of menses over a 6-month to 1-year period after treatment. Radiation also causes uterine fibrosis in a dose-dependent fashion. The dose required for radical cervical cancer treatment causes sufficient uterine fibrosis that even if a woman were to become pregnant through embryo donation, the pregnancy terminates as a stillbirth due to insufficient uterine distensibility.⁵⁸⁶^,⁸⁴³

Bone Toxicity

Grigsby et al.,⁸⁴⁴ in 1,313 patients with gynecologic tumors treated with radiation therapy, identified 207 who received pelvic irradiation to the inguinal areas, including the hips. Femoral neck fractures developed in 10 patients (4.8%); 4 were bilateral. The cumulative actuarial incidence of fracture was 11% at 5 years and 15% at 10 years. Most of the fractures occurred in patients receiving 45 to 63 Gy, and although radiation dose could not be correlated with the occurrence of fracture, no fractures were noted in patients receiving <42 Gy. Cigarette smoking and osteoporosis were significant prognostic factors for increased risk of fracture.

A retrospective cohort study using SEER cancer registry data linked to Medicare claims data analyzed 6,428 women of age 65 years and older diagnosed with pelvic malignancies from 1986 through 1999, and compared results for women who did (n = 2,855) with those who did not (n = 3,573) undergo radiation therapy. Results demonstrated that women who underwent radiation therapy were more likely to have a pelvic fracture than women who did not undergo radiation therapy. The cumulative 5-year fracture rate was 8.2% versus 5.9% in women with cervical cancer; the difference was statistically significant, and most fractures (90%) were hip fractures.⁸⁴⁵ Concurrent chemoradiation may result in a higher risk than for patients treated with RT alone because the highest fracture rates were seen in patients with anal carcinoma treated with concurrent chemoradiation.

Blomlie et al.⁸⁴⁶ reported radiation-induced insufficiency fractures of the pelvis on MRI (characterized by edema on T1-weighted images) in 16 of 18 women (9 premenopausal and 9 postmenopausal) with advanced cervical carcinoma. During the study, the fractures associated with edema subsided without treatment in 41 of 52 (79%) lesions in 15 of 16 (94%) patients. Moreno et al.⁸⁴⁷ described eight patients with pelvic cancer who developed insufficiency fractures after pelvic irradiation, with an average onset 13.7 months after treatment. The bone and CT scan showed abnormalities in the sacroiliac joint in all cases and in the pubis in three cases. In five patients, the initial diagnosis was incorrectly labeled as bone metastases.

Huh et al.⁸⁴⁸ reported on 463 patients treated for cervical cancer with RT alone, 1.7% of whom developed insufficiency fractures between 7 and 19 months (median, 12 months) after treatment. All had resolution of symptoms within <1 year with conservative therapy, including nonsteroidal anti-inflammatory medication and rest.

The most common complaint is persistent low back pain. Insufficiency fractures may be falsely diagnosed as metastases on PET/CT. The most common form of treatment is conservative management, followed by sacroplasty with polymethylmethacrylate. Bye et al.⁸⁴⁹ assessed health-related quality of life (HRQOL) at 3 to 4 years after pelvic radiation therapy for carcinoma of the endometrium and cervix in 94 survivors, 79 (84%) of whom answered a survey. The treated women scored lower than the general population on role functioning (81.5 vs. 90.6; p < .01) and higher on diarrhea (23.8 vs. 9.5; p < .01). Compared with pretreatment conditions, an increase in cases with pain in the lower back, hips, and thighs was seen and was associated with deterioration in HRQOL.

Toxicities Related to Brachytherapy

Descriptions of sequelae vary among institutions because toxicity-grading scales are not uniform and the scoring system for complications is not clearly stated in all reports. It is helpful to institute preventive measures when initiating radiation; for example, Dusenbery et al.⁸⁵⁰ reported 21 (6.4%) life-threatening complications in 327 of 462 patient implants. Lanciano et al.,⁸⁵¹ in 95 tandem and ovoid insertions for cervical cancer in 91 patients and for endometrial cancer in 4, observed 2 uterine perforations and a vaginal laceration in 2 patients. Twenty-four percent of implants in 16 patients were associated with temperatures >100.5°F. Five implants (5%) were removed because of presumed sepsis, pulmonary disease, arterial hypotension, change in mental status, and myocardial infarction.

Jhingran and Eifel,⁸⁵² in 4,043 patients with carcinoma of the cervix who had undergone 7,662 intracavitary procedures, observed 11 (0.3%) documented or suspected thromboembolisms, resulting in 4 deaths; the incidence of postimplant thromboembolism did not decrease significantly with the routine use of minidose heparin prophylaxis. Other life-threatening perioperative complications included myocardial infarction (1 death in 5 patients), cerebrovascular accident (2 patients), congestive heart failure (3 patients), and halothane liver toxicity (2 deaths). Intraoperative complications included uterine perforation (2.8%) and vaginal laceration (0.3%), which occurred more frequently in patients 60 years of age or older (p < .01).

Wollschlaeger et al.⁸⁵³ reported morbidity during hospitalization in 128 patients with cervical carcinoma undergoing 110 LDR intracavitary brachytherapy insertions. Forty-two implants (24.7%) were associated with acute problems; the most common were fever/infection (14.1%) or gastrointestinal problems (5.9%).

Acute gastrointestinal side effects of pelvic irradiation include diarrhea, abdominal cramping, rectal discomfort, and occasionally rectal bleeding, which may be caused by transient enteroproctitis. Patients with hemorrhoids may experience discomfort earlier than other patients. Diarrhea and abdominal cramping can be controlled with the oral administration of diphenoxylate hydrochloride, with loperamide, atropine sulfate, or opium preparations or emollients such as kaolin and pectin. Proctitis and rectal discomfort can be alleviated by small enemas with hydrocortisone and anti-inflammatory suppositories containing bismuth, benzyl benzoate, zinc oxide, or Peruvian balsam. Some suppositories contain cortisone. Small enemas with cod liver oil are also effective. A low-residue diet with no grease or spices and increased fiber in the stool (psyllium, polycarbophil) usually helps to decrease gastrointestinal symptoms.

Genitourinary symptoms secondary to cystourethritis are dysuria, frequency, and nocturia. The urine is usually clear, although there may be microscopic or even gross hematuria. Methenamine mandelate and antispasmodics such as phenazopyridine hydrochloride or a smooth muscle antispasmodic such as flavoxate hydrochloride, hyoscyamine sulfate, oxybutynin chloride, or tolterodine tartrate can relieve symptoms. Fluid intake should be at least 2,000 to 2,500 mL daily. Urinary tract infections may occur; diagnosis should be established with appropriate urine culture studies, including sensitivity to sulfonamides and antibiotics. Therapy should be promptly instituted.

Erythema and dry or moist desquamation may develop in the perineum or intergluteal fold. Proper skin hygiene and topical application of petroleum jelly, petrolatum, or lanolin should relieve these symptoms. U.S.P. zinc oxide ointment and intensive skin care may be needed for severe cases.

Management of acute radiation vaginitis includes douching every day or at least three times weekly with a 1:5 mixture of hydrogen peroxide and water. Douching should be continued on a weekly basis until the mucositis has resolved or for 2 or 3 months as necessary. Superficial ulceration of the vagina responds to topical (intravaginal) estrogen creams, which stimulate epithelial regeneration within 3 months after irradiation. Use of vaginal dilators several times daily, started during the course of treatment, prevents vaginal stenosis. Psychoeducational intervention and motivation improve the compliance in use of dilators.⁸⁵⁴ More-severe necrosis may require debridement on a weekly basis until healing takes place. Judicious use of biopsies is recommended to rule out persistent or recurrent cancer.

Petereit et al.⁸⁵⁵ reported 16 acute events (9.5%) in 169 patients treated with HDR brachytherapy (128 with cervical cancer also receiving external irradiation, and 41 medically inoperable endometrial carcinomas). The overall 30-day morbidity rate for the patients with cervical cancer was 5.5%, and the 30-day mortality rate was 1.6% (2 patients; 1 died of pulmonary edema 12 days after first HDR insertion and the other had enteritis and died in a nursing home).

The complication rates for HDR and LDR techniques are usually equivalent.⁶⁰⁸^,⁶¹⁰ Petereit et al.⁶⁰⁶ observed a 12% 3-year actuarial overall toxicity (2.6% genitourinary and 5.6% rectum) with LDR, compared to 15% overall (3% genitourinary and 4.6% rectum) with HDR brachytherapy. However, in the series by Cikaric,⁷¹¹ the rectal complication rate was significantly higher in the LDR group. Bladder complication rates reported, in general, are lower than rectal complication rates; again, except for the series by Cikaric⁷¹¹ showing a higher complication rate with the LDR technique, there were no significant differences with the two techniques.

Ogino et al.,⁸⁵⁶ in 253 patients with invasive carcinoma of the cervix treated with HDR brachytherapy, noted that grade 4 rectal complications were not observed in patients with a time–dose factor of <130 or biologic equivalent dose of <147, assuming an α/βratio of 3 Gy for late reactions.

Spontaneous intraperitoneal rupture of the urinary bladder, an extremely rare event, was reported by Fujikawa et al.⁸⁵⁷ after radiation therapy for cervical cancer in 6 of 148 patients treated with HDR intracavitary brachytherapy combined with EBRT. All 6 patients underwent laparotomy and repair of the perforation; however, rerupture of the bladder occurred in 3 of these patients.

Clark et al.⁸⁵⁸ reported on 43 patients treated with pelvic EBRT (46 Gy) and three HDR intracavitary treatments given weekly combined with concomitant chemotherapy (cisplatin, 30 mg/m² weekly) for advanced carcinoma of the cervix. At 40 months after treatment, 9 of 13 patients who received a dose to the rectal reference point greater than the prescribed point A dose had a 46% actuarial rate of serious (grade 3 and 4) rectal complications, compared with 14% in the remainder. A strong dose response was observed, with a threshold for complications at a brachytherapy dose of 8 Gy per fraction.

Hyperbaric Oxygen

In 13 patients with hemorrhagic cystitis treated with hyperbaric oxygen, all but 1 experienced durable cessation of hematuria.⁸⁵⁹ Lee et al.⁸⁶⁰ also noted that, in 16 of 20 patients (80%) with hemorrhagic radiation cystitis, significant improvement was observed after treatment with hyperbaric oxygen at 2.5 atm (44 sessions).

Several reports evaluated the efficacy of hyperbaric oxygen combined with irradiation in the treatment of a variety of human tumors, including carcinoma of the uterine cervix. Watson et al.,⁸⁶¹ in a randomized clinical trial of 320 patients (stages III to IVA), reported a 5-year survival rate of 33% in the oxygen-treated group in contrast to 27% in the control group treated in normal air (p = .08). The local recurrence rate was 33% in the 161 patients treated with oxygen and 53% in 159 patients treated in normal air (p< .001). Morbidity in the patients treated with oxygen was greater (20 severe and 13 moderate complications) than in those treated in normal air (6 severe and 8 moderate complications, respectively). The difference was particularly striking in the bowel (13 and 2 severe complications, respectively).

Dische et al.⁸⁶² reviewed the data in a randomized study of patients with advanced carcinoma of the cervix treated with radiation therapy and hyperbaric oxygen or air and noted that the patients treated with oxygen had improved survival at Mount Vernon and Glasgow but not at Cape Town. Data from the three centers were merged, and analysis showed that local tumor control was significantly worse in patients treated in normal air who had a prior blood transfusion, but in the oxygen group this effect was reversed. The same interaction was noted in the survival results (p = .042).

A trial reported by Fletcher¹⁶⁵ in which 233 patients with stages IIB, III, and IV carcinoma of the cervix were randomized to be treated with irradiation in normal air or with hyperbaric oxygen demonstrated no significant benefit in survival or tumor control (20 of 109 patients treated with oxygen failed in the pelvis, in contrast to 29 of 124 treated in normal air). Furthermore, morbidity was greater (26 complications) in patients treated with hyperbaric oxygen compared with the control group (15 complications).

Dische et al.⁸⁶² published results of a four-arm randomized trial of hyperbaric oxygen and radiation therapy of stages IIB and III carcinoma of the cervix in which 335 patients were randomized to treatment in 10 or 28 fractions in hyperbaric oxygen or in normal air. Data from 327 cases were analyzed. There was no advantage in tumor control with the use of hyperbaric oxygen. There was an increase in late radiation morbidity when treatment was given in hyperbaric oxygen rather than in normal air, and when using 10 fractions, a total dose of 45 Gy rather than 40 Gy was administered.

No definite conclusions can be drawn concerning the use of hyperbaric oxygen in carcinoma of the cervix. It is possible that hyperbaric oxygen administered with fewer high-dose fractions may be more efficacious than when combined with conventional dose and fractionation schemes. The trials reported have not shown an increased incidence of distant metastasis, which has been observed in a clinical study and in some animal experiments.⁸⁶³

Hormonal Replacement After Treatment of Cervical Cancer

After pelvic irradiation or bilateral salpingo-oophorectomy, usually carried out with a radical hysterectomy in patients treated for carcinoma of the uterine cervix, symptoms of menopause may occur. They can be treated with replacement hormones, although some gynecologists have expressed reservations. During the past 25 years, hormonal replacement therapy has been shown to reduce the risk of cardiovascular diseases, osteoporotic fractures, and colon carcinoma. On the other hand, there is a significant increase of the risk in breast cancer with prolonged use of estrogen plus progesterone for >5 years. Consideration may be given to progesterone alone, which does not increase the risk of endometrial cancer but has potential thromboembolic risks.⁸⁶⁴

Burger et al.⁸⁶⁵ concluded that squamous cell cancers of the cervix, vulva, and vagina are unlikely to be influenced by hormonal replacement therapy. In a study of women 50 years of age or younger with ovarian cancer, estrogen replacement therapy did not have a negative influence on disease-free survival. Long-term hormonal replacement therapy in women treated for a gynecologic cancer must be based on the medical history of and discussion of risk with the individual patient (and her family when warranted). Usually, 0.625 to 1.25 mg of coagulated estrogen daily is sufficient.⁸⁶⁶

Second Malignancy

The risk for induction of secondary primary cancers by pelvic irradiation is low, and many potential confounders are either unknown or may not be fully accounted for, given available information.⁸⁶⁷ Using the population-based cancer registries of Denmark, Finland, Norway, Sweden, and the United States, Chaturvedi et al.⁸⁶⁸ found a significantly increased cancer risk in both SCC and AC survivors, with standardized incidence ratio of 1.31 (95% CI = 1.29 to 1.34) and 1.29 (95% CI = 1.22 to 1.38), respectively. The risk of smoking-related lung cancer was higher in the SCC than in the AC population, whereas second malignancies of the colon, soft tissue, melanoma, and non-Hodgkin lymphoma were higher in the AC population. Similarly, 1-year survivors of cervical cancer had an increased risk of HPV-related cancers, including pharynx, genital, and anal cancers. Higher hazard ratios for second cancer of the rectum, anus, bladder, and genital sites was seen for younger patients, with a 40-year cumulative risk of any second cancer of 22% for women diagnosed with cervical cancer before age 50 years versus 16% for those diagnosed at age >50 years.⁸⁶⁹ In contrast, Lee et al.⁸⁷⁰ observed no significant increase in the incidence of second malignancies in patients irradiated for carcinoma of the cervix in comparison with the Connecticut Tumor Registry prevailing rates.

Boice et al.,³³⁹ in a review of 68,730 women with carcinoma of the cervix treated with radiation therapy, observed a second malignant tumor in 3,324, compared with 3,063 expected (4.8% increase; p < .001). The excess was concentrated in the lung, other genital organs, bladder, and rectum. In addition, in 10,817 women with invasive cervical cancer not treated with irradiation, 479 secondary malignant tumors were observed versus 435 expected (4.4%; p = .02). Thus, the incidence of secondary tumors in women treated for carcinoma of the cervix with or without irradiation is only slightly greater than in the general population. Pelvic organs receiving a high dose of irradiation appear to have a somewhat greater incidence of a second primary.

Storm,⁸⁷¹ in a comprehensive analysis of the Danish Cancer Registry data of 24,970 women with invasive cervical cancer and 19,470 with carcinoma in situ of the cervix treated between 1943 and 1982, noted a small overall excess of secondary primary cancers in the lung, stomach, pancreas, rectum, and bladder and connective tissue sarcomas, although there was a decreased incidence of breast cancer in the irradiated patients compared with nonirradiated patients (attributable to ovarian ablation by radiation therapy). In the patients irradiated for invasive carcinoma, there was an excess of 64 cases per 10,000 women per year of tumors in organs close to or at an intermediate distance from the cervix, reaching a maximum after 30 years or longer of follow-up. A high risk for development of acute nonlymphatic leukemia was observed in irradiated patients with carcinoma in situ but not in those with invasive lesions. This could be explained by the lower doses of irradiation delivered to the bone marrow in the in situ tumors treated with brachytherapy alone, with greater induction of mutations and less cell killing, which may be responsible for the leukemogenic effect. Decreased risk was noted for tumors of the brain, myeloma of the skin, and tumors of the colon other than rectal.

In a study of 117,830 women diagnosed with cervical carcinoma in situ and 17,556 with invasive cervical carcinoma in Sweden, treatment not specified and in situ lesions traditionally treated with surgery alone, there was an increased incidence (RR = 2.3 to 3) of second primary tumors in the anus, rectum, urinary bladder, pancreas, esophagus, and lung compared with the standardized incidence rate for all women.⁸⁷² The data showed consistent increases in suggested targets for HPV at tobacco-related sites. A contributing role for a depressed immune response was considered.

Werner-Wasik et al.,⁸⁷³ in an analysis of 125 women with stages I and II carcinoma of the cervix treated with radiation therapy, observed 11 secondary primary tumors in 10 patients (4 breast, 2 lung, and 1 each of myeloma, non-Hodgkin lymphoma, bladder, thyroid, and vulva). All secondary primary tumors were located outside the irradiation fields. The increased relative risk of breast cancer in these patients was 2.64, higher than reported by Boice et al.³³⁹

In an analysis of 199,268 individuals by Wright et al.,⁸⁷⁴ the risk of secondary leukemia increased 72% in patients who received pelvic radiotherapy, with a peak at 5 to 10 years after treatment; there was no increased risk of multiple myeloma. Mark et al.⁸⁷⁵ identified 13 of 114 patients diagnosed with uterine sarcoma who had a prior history of pelvic irradiation (doses of 40 to 80 Gy). Criteria for radiation-induced sarcomas included a prior history of pelvic irradiation, a latent period of several years, development of sarcoma within previously irradiated field, and histologic confirmation of malignancy. Histologic types of tumor were mixed Müllerian in 6, leiomyosarcoma in 4 patients, endometrial stroma sarcoma in 1, fibrosarcoma in 1, and angiosarcoma in 1. Sarcoma developed in the uterus in 12 patients and at the vaginal cuff in 1 patient. Ten patients were treated with surgery and 2 with radiation therapy. The 5-year disease-free survival rate after salvage therapy was 17%.

In a theoretical analysis of IMRT risk in postoperative cases relative to three-dimensional conformal radiotherapy, the estimated increase in second cancer risk was 6% for 6-MV IMRT and 26% for 18 MV IMRT, with large increases in organs away from the primary beam and skin because with IMRT a much larger volume of skin was exposed.⁸⁷⁶

Seidman et al.⁸⁷⁷ reviewed 15 cases of second malignancies after pelvic radiation; 5 were HPV-related vaginal primary tumors. The average latency period for development was approximately 20 years.

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