The Washington Manual of Oncology, 3 Ed.

Ovarian Cancer

Sara S. Lange • Matthew A. Powell

 I. EPITHELIAL OVARIAN CANCER

1. Epidemiology and etiology. Approximately 21,980 new cases of ovarian cancer are diagnosed each year in the United States and 14,270 deaths were estimated to occur in 2014, as a result of this disease. Ovarian cancer remains the fifth most common cause of cancer death in women and the leading cause of death from gynecologic cancer. It has been estimated that 1 woman in 70 in the United States will develop ovarian cancer in her lifetime and 1 in 100 will die from this disease. Most of the (85% to 90%) malignant ovarian tumors are epithelial in origin. The median age at diagnosis is 63 years and incidence is higher in women of white race. Risk factors include a strong family history, nulliparity, early menarche, late menopause, increasing age, white race, and residence in North America and Europe. Oral contraception usage and pregnancy are associated with a decreased risk, suggesting that continuous ovulation may lead to malignant changes. The etiology of malignant changes of the ovarian epithelium, which is contiguous with the peritoneal mesothelium, is unknown and likely a combination of genetic, environmental, and endocrine effects.
2. Genetics/familial syndromes. Familial ovarian cancer may be related to a breast–ovarian cancer syndrome caused by an inherited mutation in one of two genes, BRCA1 and BRCA2 on chromosome 17 and 13, respectively. Certain ethnic groups such as Ashkenazi Jewish women have an increased risk of a mutation in one of these two genes. Women with a BRCA1 mutation are reported to have a 16% to 44% lifetime risk of ovarian cancer, whereas those with BRCA2 mutations have a lower risk at 10%. Women with ovarian cancer due to these mutations tend to have a more indolent course than those with sporadic disease. Site-specific familial ovarian cancer and Lynch syndrome II in which multiple individuals within a family develop tumors in the colon, endometrium, and ovary are other types of familial ovarian cancers. Inheritance in familial ovarian cancer is in an autosomal dominant manner with multiple members in successive generations affected. There is sufficient evidence for prophylactic oophorectomy in women with a known mutation in BRCA1 or BRCA2 after completion of childbearing or 35 years of age so as to prevent the development of both ovarian and breast cancers. All patients with epithelial ovarian, tubal, and peritoneal cancer should be offered genetic counseling.
3. Clinical presentation. Women present with vague, nonspecific symptoms of abdominal bloating, distension, dyspepsia, early satiety, anorexia, weight loss, or constipation. Women are often treated for gastrointestinal problems such as gastritis, irritable bowel syndrome, and gall bladder disease. Physical examination findings may include ascites, pleural effusion, or an abdominal mass. Most patients with early-stage disease are asymptomatic and given the vague nature of the symptoms, approximately 80% present with advanced stage (metastatic) disease. The National Cancer Institute (NCI) does support annual screening through both CA-125 measurements and transvaginal ultrasonography for women at high genetic risk based on family history; however, in the general population no data exists that screening is effective in improving length and quality of life in women with ovarian cancer. Several biomarkers with potential application to ovarian cancer screening are under development but have not yet been validated or evaluated regarding their efficacy for early detection and mortality reduction.

Women found to have a mass or ascites on examination or by radiographic or ultrasonographic imaging should be evaluated to assess the possible risk of abnormality representing a malignancy. Appearance and size on ultrasonography or computed tomography (CT) scan combined with patient age and family history are factors that help determine the need for surgical evaluation. A complex mass with both solid and cystic components with septations and internal echoes is suggestive of cancer. Benign-appearing and indeterminate lesions can be followed for a brief period to evaluate for progression of disease. Serum CA-125 cancer antigen can occasionally be of aid in postmenopausal patients. CA-125 is elevated in more than 80% of patients with ovarian cancer but this test is neither sufficiently sensitive nor specific enough to be diagnostic as this may be elevated in a number of other benign and malignant conditions. CA-125 is most useful in following response to postoperative chemotherapy and detecting disease recurrence. No definitive tests are currently available and definitive diagnosis is often only possible with surgical evaluation.

1. Surgical treatment. Surgery is typically performed for histologic diagnosis, staging, and tumor cytoreduction. Exceptions to an immediate surgical approach are patients who are poor surgical candidates secondary to other comorbid diseases or performance status. In these patients, a confirmatory biopsy or cytology is obtained to establish a diagnosis followed by chemotherapeutic treatment. Preoperatively, patients should undergo all age-appropriate cancer screening (Pap smear, mammogram, and colorectal cancer screening) as well as additional tests depending on the clinical scenario (barium enema, colonoscopy, and/or cystoscopy). Laboratory assessment should include complete blood count, type and screen, electrolytes, renal and hepatic panel, electrocardiogram, and chest radiograph. Additional studies depend on the patient’s medical condition(s). Given the likelihood of large and small bowel involvement requiring resection, a thorough bowel preparation is recommended. Staging of ovarian cancer is surgical and proper staging procedures should typically consist of the following: (a) midline abdominal incision; (b) evacuation of ascites or peritoneal washings for cytologic analysis; (c) resection of the primary ovarian tumor, total abdominal hysterectomy, and bilateral salpingo-oophorectomy; (d) biopsies of omentum or omentectomy; (e) biopsies of the pelvic and abdominal peritoneum, including pericolic gutters; and (f) retroperitoneal nodal sampling (pelvic and para-aortic), if indicated by lack of abdominal disease greater than 2 cm or if grossly involved with tumor. The surgical staging system established by the International Federation of Gynecology and Obstetrics is depicted in Table 23-1 and was recently updated as of January 2014 to improve utility and reproducibility across all ovarian tumor types (Int J Gynaecol Obstet 2014;124:1). Tumor debulking is a critical component of initial surgical management as women with residual disease of less than 1 cm have survival rates higher than those with residual disease.

Five-year survival in patients with early-stage disease (stage I or II) is often as high as 80% to 95%; however, patients with advanced disease (stage III or IV) have much lower survival rates of 30% to 40%.

1. Postoperative treatment
2. Epithelial tumors of low malignant potential (LMP). Also called borderline tumors, this subgroup represents approximately 10% to 15% of all epithelial ovarian tumors. The tumors are usually stage I (80%) and are characterized pathologically by epithelial cell stratification, increased mitoses, nuclear abnormalities, and atypical cells without stromal invasion. Surgical staging is usually recommended, but given that these tumors tend to occur in younger patients, conservation of fertility is often possible. Treatment is simple surgical resection. Chemotherapy does not appear to have a role in treating most of these tumors. However, LMP tumors are on rare occasions found to have invasive implants (metastases) in which case the patient should be treated similar to frankly invasive disease with adjuvant chemotherapy. By convention, however, the tumor is still considered LMP as the diagnosis is based on the primary tumor only. Recurrent disease is usually treated with repeat surgical debulking. The prognosis for patients without invasive implants is excellent with very few patients dying of disease, with the average time to recurrence being 10 years. Patients are often followed with serum CA-125 determinations every 3 to 12 months, but it is unclear if this provides any survival benefit. Additionally, patients have been known to recur with invasive disease.
3. Early-stage disease. Patients with stage IA or IB with grade 1 or 2 disease are considered low risk, with excellent survival chances (90% to 95%). Treatment with full surgical staging followed by close follow-up is typically all the treatment that is required. For those patients who wish to preserve fertility, a unilateral salpingo-oophorectomy with adequate staging may be considered in some patients with stage IA grade 1 disease. Patients with stage IC disease, stage I grade 3 disease, stage I grade 2, or stage II disease are considered at high risk for recurrence and are treated with platinum-based adjuvant chemotherapy to reduce the risk of relapse. With chemotherapy, disease-free survival is approximately 80%.

 The number of chemotherapeutic cycles for treatment of early-stage disease is debatable and in 2006, the Gynecology Oncology Group GOG 157 showed that, compared to three cycles, six cycles of carboplatin and paclitaxel do not significantly alter the recurrence rate in high risk, early-stage ovarian cancer but are associated with more toxicity. However, some question the statistical power of this study as there was a strong trend toward decreased recurrence in stage I disease with six cycles (p = 0.073). Given these findings, in 2010, an exploratory analysis of the patients included in GOG 157 was undertaken to determine if there were subsets of patients with high risk early-stage ovarian cancers that may benefit from more cycles of chemotherapy (Gynecol Oncol 2010;116:301). The authors found that compared to three cycles, six cycles of adjuvant chemotherapy may decrease the recurrence of women with serous histologies, with a statistically significant difference at 2-year recurrence-free survivals (93% for 6 cycles vs. 80.8% for 3 cycles, p = 0.007). Unfortunately, this benefit did not extend to overall survival (OS). Additionally, the utility of subset analyses in shaping clinical treatments is debated, and a prospective randomized clinical trial would be necessary to confirm these findings.

7. Advanced disease. Most ovarian cancer patients present with advanced stage disease (stage III and IV). Maximal efforts for surgical cytoreduction of the tumor before chemotherapy should be made as studies have consistently demonstrated improved survival in those patients with an “optimal” cytoreduction. Optimal cytoreduction has been defined a variety of ways in the literature; currently, the GOG defines optimal cytoreduction as no residual tumor nodules with a diameter greater than or equal to 1 cm, but many are now using an international standard of no gross residual to be considered “optimal”. Optimally cytoreduced patients (<2 cm) have a median progression-free survival (PFS) and OS of 22 months and 50 months, respectively (GOG 158), versus suboptimally cytoreduced patients with an 18-month PFS and 38-month OS (GOG 111). A study assessing survival rates at specific residual disease diameters to determine the optimal goal of primary cytoreduction found that patients with no gross disease or less than 1 mm had significantly longer overall median survival compared with patients with macroscopic residual disease greater than 1 mm (Gynecol Oncol 2006; 103:559). Patients with advanced stage disease will require postoperative adjuvant chemotherapy to treat residual disease. Taxane and platinum-based chemotherapy is the current standard of postoperative care and has been shown to extend PFS as well as OS. This current standard of care is based on clinical trials demonstrating similar efficacy of carboplatin/paclitaxel to cisplatin/paclitaxel with less chemotherapy-related toxicity and a shorter administration time. The regimen consists of intravenous administration of paclitaxel (175 mg/m²) given over 3 hours and carboplatin dosed with an area under the curve (AUC) of 5 to 7.5, utilizing the Jeliffe formula to estimate creatinine clearance and the Calvert formula to determine AUC. This regimen is given every 3 weeks for a total of six cycles. Response rates (complete response [CR] + partial response [PR]) are approximately 80% with this combination, and more than 50% of patients will have a complete clinical response. Although most patients tolerate platinum- and taxane-based chemotherapy relatively well, some develop severe peripheral neuropathy and the use of docetaxel has been shown to result in less neuropathy with similar efficacy (J Natl Cancer Inst 2004;96:1682).

Recent clinical trials have investigated the success of maintenance chemotherapy in improving both PFS and OS. A Cochrane review from 2013 looked at eight trials including 1,644 women total, and determined that there was no significant difference in 3-, 5-, and 10-year PFS and OS between women who received maintenance chemotherapy and those that did not. The trials included regimens with platinum agents, doxorubicin, and paclitaxel. However, two well-designed phase III clinical trials (ICON7 and GOG218) investigated the use of bevacizumab, a VEGF monoclonal antibody, alongside standard chemotherapy in women with newly diagnosed advanced ovarian, primary peritoneal, and fallopian tube cancer. GOG 218 included a maintenance bevacizumab arm as well, and a significant improvement in PFS of 3.8 months was noted in the maintenance bevacizumab arm when compared to both the standard paclitaxel and carboplatin and the paclitaxel, carboplatin, and bevacizumab arm (N Engl J Med 2011;365:2473). ICON7 compared two arms, a standard carboplatin and paclitaxel arm with 6 cycles of therapy and the experimental carboplatin, paclitaxel, and bevacizumab arm, which included 5 to 6 cycles plus up to an additional 12 cycles of maintenance therapy (N Engl J Med2011;365:2484). Bevacizumab did improve PFS; however, final analysis of OS revealed no clinically important improvement in the randomized population, with a 4.8-month improvement in mean survival time in a subgroup of women at high risk of progression. However, the use of bevacizumab did expand the number of toxic effects in both studies, including hypertension and bowel perforation. Currently, the NCCN considers the administration of chemotherapy plus bevacizumab in the first-line setting a reasonable option, but does not routinely recommend the drug at this time given the clear lack of OS benefit.

In 2013, the Japanese Gynecologic Oncology Group (JGOG) published its results of a prospective randomized clinical trial (JGOG 3016) comparing standard treatment with carboplatin and paclitaxel every 3 weeks to the experimental arm of carboplatin every 3 weeks concurrently with weekly paclitaxel. In both arms, the regimen was repeated every 3 weeks for up to nine cycles. The dose-dense therapy arm resulted in a significant improvement in PFS (28 months vs. 17.5 months) and OS (100.6 months vs. 62 months), with women who had >1cm of residual disease following surgical treatment showing the greatest benefit in PFS (17.6 months vs. 12 months) and OS (51 months vs. 33 months). However, this benefit did not extend to patients with mucinous or clear cell histologies. Also, there was a higher rate of treatment discontinuation and delay secondary to toxicity in the dose-dense arm. It should be noted that better survival outcomes with standard chemotherapy have been noted in other trials, as well as a potential difference in outcomes based on race, with Asian patients appearing to fare better in this trial than in other trials with a predominately Caucasian enrollment (Lancet Oncol 2013;14:1020).

Intravenous chemotherapy has been the standard treatment in the past; however, intraperitoneal chemotherapy (IP) has also been investigated over the last several decades. Three recent large prospective trials have shown survival improvements for those patients treated with IP (N Engl J Med 2006;354:34; N Engl J Med 1996;335:1950; J Clin Oncol 2001;19:1001). More recently, GOG 172 reported a PFS of 23.8 months for combination IP and intravenous chemotherapy versus 18.3 months for intravenous (IV) alone (N Engl J Med 2006;354:34). Similarly, OS was longer with the combined IP/IV therapy (65.6 months vs. 49.7 months). Patients who receive IP therapy do experience greater toxicity and even report worse quality of life in some studies; therefore, many oncologists are still slow to use this method of treatment. A small study recently published investigated the use of IP chemotherapy in the community-based practice setting. They identified 288 women with FIGO stage 2 or greater ovarian cancer diagnosed between 2003 and 2008 at three integrated delivery systems in the United States. They noted that 12.5% (n=36) of women received IP chemotherapy between 2003 and 2008, with a height of use at 26.9% of patients in 2006. These results demonstrate that the use of IP chemotherapy for newly diagnosed advanced ovarian cancer patients in the community setting was uncommon (Front Oncol 2014;4:43).

Second-look laparotomies are not recommended unless the patient is enrolled in a protocol as these studies have shown no impact on survival. Less commonly, radiation of the abdomen and pelvis is employed as treatment for advanced stage and/or recurrent disease. Following adjuvant chemotherapy, patients are monitored with physical examination, CA-125 measurements, and imaging studies (CT, magnetic resonance imaging [MRI], and positron emission tomography [PET]) as clinically indicated for recurrent disease.

1. Recurrent disease. Despite standard treatment with cytoreductive surgery and chemotherapy, up to 75% of patients experience recurrence and will eventually succumb to disease. Median survival following relapse from initial therapy is approximately 2 years. Patients found to progress with upfront therapy or with a recurrence should be offered additional treatments that will hopefully allow for control of their disease and maintain the best quality of life possible. One must realize that very few of these patients are ultimately cured of their disease, and enrollment in clinical trials at this point is strongly encouraged. The usual first sign of recurrence is a rising CA-125, which is usually followed by evidence of recurrence on examination or by a CT scan of the abdomen and pelvis. It is not clear if early retreatment (before the onset of symptoms or radiographic evidence of disease) of a patient with an elevating CA-125 has any effect on disease control or OS.

Treatment of recurrent or persistent disease is based on the timing and location of the recurrence. “Platinum-sensitive” patients are defined as experiencing a recurrence more than 6 months from the time of their initial CR. These patients can be successfully retreated with platinum-based regimens with reasonable responses (20% to 40%). ICON IV showed that in patients with platinum-sensitive disease, combination chemotherapy (platinum plus paclitaxel) led to higher CRs or PRs (66% vs. 54%) as well as PFS (13 months vs. 10 months) compared to platinum therapy alone for recurrent disease. Patients with a treatment-free interval of greater than 12 months received the greatest benefit from retreatment with combination platinum, paclitaxel therapy.

Patients having a recurrence before 6 months (“platinum-resistant”) can be treated with a variety of agents. Many authorities recommend that single-agent therapy be used in this setting to minimize toxicity and to more easily identify non-responding agents. Given that there is no ideal second-line salvage agent(s), patients should be encouraged to participate in available study protocols. Second-line agents have an approximate response rate of 15% to 40%, depending on agent and amount of previous chemotherapeutic treatments. Treatment is usually continued until the CA-125 normalizes, toxicity precludes further therapy, or disease progression. Patients with progressive disease are then offered a different regimen usually with a differing side effect profile to minimize toxicity.

Generally speaking, because recurrent disease is typically not curable, symptom palliation and prevention of complications such as bowel obstruction remain the goals of management. Radiation and/or surgical resection have been used to successfully treat localized disease. Indications for repeat surgery (secondary debulking) are highly controversial and decisions must be individualized. In general, if the progression-free interval is greater than 1 year and the mass appears isolated, or if it is symptomatic (obstruction of bowel or kidney), surgical resection can result in prolonged survival.

Complications of therapy are primarily related to continued growth of the tumor (bowel obstruction) and toxicities of the chemotherapy. Bowel obstructions should initially be managed conservatively with intravenous fluids and gastric decompression. Studies such as abdominal plain films, small bowel follow-through, contrast enemas, and abdominal/pelvic CT may be necessary to further evaluate cause of obstruction. Persistent obstructions can be managed with chronic decompression (G-tube) or surgical exploration in cases where the imaging studies suggest a limited focus of obstruction. Toxicities of chemotherapy are related to the specific agents and are covered elsewhere in this text.

1. Future directions. A great deal of attention has been focused on identification of the genetic factors involved with ovarian cancer tumorigenesis with identification of potentially useful biomarkers. Inhibition of epidermal growth factor receptor (EGFR) and vascular epithelial growth factor (VEGF) has been studied both alone and in combination with chemotherapy. Treatment with VEGF inhibitors such as bevacizumab needs to be optimized in terms of length of maintenance treatment and identification of additional active drugs. Poly (ADP-ribose) polymerase (PARP) inhibitors, namely olaparib, have shown promise in phase I trials and randomized trials comparing the drug to liposomal doxorubicin. PARP inhibitors are thought to cause significant tumor lethality secondary to the cell’s inability to repair spontaneous DNA damage without the PARP repair pathway. Identification of more specific tumor markers could potentially be used to identify disease at earlier, more treatable stages. Microarray gene expression profiles hold promise as prognostic tools for identification of gene targets and may shed light on mechanisms of drug resistance. Current clinical studies are examining new chemotherapeutic agents and novel combinations of known agents in efforts to improve survival of this devastating disease.
2. FALLOPIAN TUBE CARCINOMA. Fallopian tube carcinoma is a rare gynecologic malignancy that behaves biologically like serous epithelial ovarian carcinoma. Fallopian tube carcinoma is staged and treated in a manner similar to ovarian carcinoma. The classic presentation is intermittent, profuse, watery vaginal discharge (hydrops tubae profluens). The diagnosis is seldom made preoperatively but has been detected by Pap smear. Prognosis is related to stage of disease with long-term survival of approximately 50% for stages I and II. As with ovarian carcinoma, long-term survival is rare with advanced disease.

 III. GERM CELL OVARIAN CANCERS. These cancers typically occur in young women, are highly curable, and account for approximately 3% of ovarian cancers. The majority present as early-stage lesions confined to one ovary except for dysgerminomas, which are bilateral in 15% of cases. Dysgerminoma, endodermal sinus tumor (yolk sac tumor), embryonal carcinoma, choriocarcinoma, immature (embryonal) teratoma, and malignant mixed germ cell tumors are the cell types seen. Fertility-sparing surgery is nearly always possible. Surgical cytoreduction appears to be important and is likely associated with increased survival. Most of these tumors will have a tumor marker available to follow (human chorionic gonadotropin [HCG], α-fetoprotein [AFP], lactate dehydrogenase [LDH], CA-125, or neuron-specific enolase [NSE]). Following surgery, most tumors are treated with chemotherapy except some well-staged IA/IB cancers. The BEP regimen is the most commonly used and consists of a 5-day regimen, although a 3-day regimen has also been studied (cisplatin 20 mg/m² IV days 1 to 5, bleomycin 30 units IV weekly, etoposide 100 mg/m² IV days 1 to 5—cycle repeated every 3 weeks). Some support observation only for localized, completely resected malignant germ cell tumors based on French survival data and pediatric oncology group trials.

 IV. STROMAL TUMORS OF THE OVARY. Stromal tumors are classified by the World Health Organization (WHO) into five main classes: (a) granulosa-stromal cell tumors (adult and juvenile granulosa cell tumor and tumors in the thecoma/fibroma group); (b) Sertoli-stromal cell tumors (Sertoli, Leydig, or Sertoli–Leydig cell tumor); (c) gynandroblastoma; (d) sex cord tumor with annular tubules; and (e) unclassified. These tumors are rare and are usually of early stage and low grade, which make them readily curable with simple surgical resection. Primary metastatic or recurrent disease is usually treated with surgical cytoreduction followed by combination chemotherapy. The BEP regimen is most often used; however, recent data from Brown et al. suggest that taxanes demonstrate activity against ovarian stromal tumors and have less toxicity than BEP regimens.

SUGGESTED READINGS

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Bowles EJ, Wernli KJ, Gray HJ, et al. Diffusion of intraperitoneal chemotherapy in women with advanced ovarian cancer in community settings 2003-2008: The effect of the NCI clinical recommendation. Front Oncol 2014;34:43.

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