Joseph K. Salama, Maura L. Gillison, and David M. Brizel
The incidence of oropharyngeal carcinoma is increasing. This is in contrast to the decreasing incidence of head and neck cancer arising in other anatomic sites. The classic etiologic factors of tobacco abuse and alcohol use continue to play a significant role. However, a significant increase in rates of oropharyngeal cancers in nonsmokers and nondrinkers caused by oncogenic human papillomaviruses (HPVs) is occurring, predominantly among men. Although both HPV–associated and HPV-unassociated malignancies are classified as squamous cell carcinomas, the behavior of these cancers markedly differs as HPV-associated cancers have a significantly more favorable prognosis after the delivery of standard treatments. The recognition that HPV-associated oropharyngeal cancer is a distinct clinical entity, as well as the impact of standard therapies on speech, swallowing, degustation, and psychological well-being, has led to significant multidisciplinary interest in defining different treatment paradigms for HPV-associated and HPV-unassociated oropharyngeal cancers. Treatment recommendations for these two clinical entities remain the same, however, until ongoing investigations are completed.
Based on the critical function of the oropharynx in speech and swallowing, the treatment of oropharyngeal carcinomas can significantly impact patient quality of life. Appropriate treatment strategies should focus on maintaining high cure rates while minimizing long-term, treatment-induced functional morbidity. Early-stage oropharyngeal cancers are managed with single modality therapy (radiation or surgery), with the choice based on anticipated posttherapy consequences. Treatment of locoregionally advanced tumors involves multiple modalities with the use of either concomitant chemotherapy and radiotherapy or surgery followed by adjuvant radiotherapy with or without chemotherapy based on pathologic risk factors.
Novel surgical and radiation delivery modalities, as well as molecularly targeted chemotherapeutics, are the current focus of clinical investigation, with an intent to maximize the therapeutic index for HPV-associated oropharyngeal cancers. Transoral surgical advances including laser and robotic interventions have the potential to reduce morbidity. Advances in radiotherapy allow for improved dosing to the primary tumor and involved nodes while reducing radiation exposure of normal tissues, particularly the parotids and pharyngeal constrictors. Further studies are needed to more completely integrate molecularly targeted agents into the treatment of oropharyngeal cancers.
EPIDEMIOLOGY
Oropharyngeal cancers account for approximately 10% of the annual worldwide incidence of head and neck squamous cell carcinomas. The incidence of oropharyngeal cancer differs significantly by geography.1 In the United States, the annual incidence of oropharyngeal squamous cell carcinoma is 4.8 in 100,000,2 which is similar to other developed countries. This rate increased by 28% from 1988 to 2004, largely because of the 225% increase in HPV-associated oropharyngeal cancer, whereas HPV-unassociated oropharyngeal cancer declined by 50% over the same time period.3 The incidence of oropharyngeal cancer in developing countries is lower at approximately 3 in 100,000.1 This rise in developed countries is unique because other mucosal head and neck cancer incidences have decreased over this same time period. The putative cause is the increasing incidence of HPV-associated cancers, which is discussed in detail later. Worldwide, the majority of oropharyngeal cancers remain attributable to tobacco smoking and/or the ingestion of excessive amounts of alcoholic beverages. For these cases, incidence rates are generally higher for men than women (4:1), who are diagnosed more commonly in the sixth and seventh decades of life.
HUMAN PAPILLOMAVIRUS–ASSOCIATED OROPHARYNGEAL CANCER
Human Papillomavirus
HPV is a circular, double-stranded DNA virus, first determined to be oncogenic when it was found to be the associated with cervical cancer in 19834 and subsequently established as a significant human carcinogen in 1996.5 To date, approximately 150 HPV types have been identified. HPV subtypes are classified as high or low risk based on epidemiologic associations with cervical cancer in case-control studies.6 HPV 16 is the most common HPV type identified in human tumors and is associated with more than 90% of all HPV-associated related oropharyngeal cancers.7 Infection with HPV 16 confers an approximate 14-fold increase in risk for oropharyngeal cancer.8
The HPV genome encodes three oncoproteins (E5, E6, and E7), in addition to regulatory genes (E1 and E2) as well as capsid protein genes (L1 and L2). Oncogenesis is primarily mediated via the E6 and E7 proteins. HPV E6 complexes with E3 ubiquitin ligase and E6-associated protein, promoting ubiquitin-mediated destruction of p53. Loss of cellular p53 function results in dysregulation of the G1/S and G2/M checkpoints. An E7/cullin 2 complex ubiquitinates the Rb protein, resulting in loss of G1/S checkpoint control.9 E7 is believed to be the major transforming oncogene during early carcinogenesis, with E6 functioning later.10 A diagram of the pathways affecting the malignant transformation of keratinocytes by HPV is shown in Figure 45.1. Although E6 and E7 oncoprotein function is necessary for development of an HPV-associated malignancy, it is not sufficient. It is believed that as yet undefined genetic events are required for HPV malignant transformation.11
Several different techniques are used to detect HPV in oropharyngeal cancer biopsy specimens. The gold standard is demonstration of HPV E6/E7 in clinical specimens. However, this approach is clinically impractical because it is very difficult to detect viral RNA from cytologic fluid and paraffin embedded tissues. Polymerase chain reaction (PCR) of HPV DNA is a technique with high sensitivity but low specificity, as cross contamination or transcriptionally inactive DNA can be detected. In situ hybridization (ISH) uses oligonucleotide probes designed to anneal to complementary HPV DNA in the tumor specimen. Advantages of this technique include localization of DNA within the tumor specimen and allow for identification of a single viral copy.12 A consequence of HPV E7-mediated Rb inhibition is induction of demethylases resulting in expression of p16INK4A, an upstream tumor suppressor cyclin-dependent kinase inhibitor.13 Immunohistochemistry staining for p16INK4A is frequently used as a surrogate for HPV status. There is a small (7%) discordance between HPV ISH and p16INK4A IHC (approximately 7%), which is likely related to a combination of infection with non-HPV-16 subtypes or low viral copy numbers not detectable by IHC and true p16-positive/HPV-negative cases.
FIGURE 45.1. Diagram of malignant transformation in keratinocytes caused by the HPV oncoproteins E6 and E7. Clockwise from A, ubiquitination by E7 and the cullin 2 ubiquitin ligase complex leading to pRb degradation (23, 25, 56, 57); B, interaction between E7 and p27Kip1 resulting in inhibition of cell cycle arrest contributing to carcinogenesis (58); C, interaction between E7 and p21Cip1 resulting in inhibition of cell cycle arrest contributing to carcinogenesis (31, 59); D, ubiquitination by E6 and ubiquitin ligase E6AP leading to p53 degradation (19–21); E, increased expression of p16INK4A by a consequent of feedback loops from the absence of pRb function (42); and F, degradation of NFX1, a transcriptional repressor of hTERT, by association with E6/E6AP resulting in hTERT activation and cellular immortalization (60). (From Chung CH, Gillison ML. Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications. Clin Cancer Res 2009;15(22):6758–6762, with permission.)
TABLE 45.1 HUMAN PAPILLOMAVIRUS STATUS AND SURVIVAL OUTCOMES IN PROSPECTIVE TRIALS
Clinical Characteristics of Human Papillomavirus–Associated Oropharyngeal Cancer
HPV-associated oropharyngeal cancers are more likely to occur among men and than women (3:1), most of whom (80%) will not have a smoking history. These cancers are more common among white individuals than other races, are diagnosed in individuals who are 5 to 10 years younger than HPV-unassociated oropharyngeal cancers, and are associated with higher socioeconomic status. Furthermore, when compared to patients with HPV-unassociated cancers, these patients are more likely to be married, college educated, and have a median income of more than $55,000. The use of marijuana also elevates odds of HPV-associated oropharyngeal cancer.14 Analogous to cervical cancers, patients with HPV-associated oropharyngeal cancer have been associated with certain sexual behaviors. These include high number of vaginal or oral sex partners, infrequent condom use, engagement in casual sex, and early age of first intercourse.15 Whether or not HPV acts in a synergistic manner with tobacco or alcohol exposure in patients to increase the risk of HPV-associated oropharyngeal cancer is a matter of ongoing controversy.
HPV-associated oropharyngeal cancers are characterized frequently as poorly differentiated, nonkeratinizing, or basaloid in histopathology.16 HPV-associated and HPV-unassociated carcinomas are also different with regard to molecular alterations. HPV-associated oropharyngeal cancers demonstrate wild-type p53, p16 expression, and infrequent amplification of cyclin D, whereas the converse is true for HPV-unassociated cancers. A subset of HPV-associated oropharyngeal cancer patients with more extensive smoking histories will have tumors exhibiting TP53 mutations, higher epidermal growth factor receptor (EGFR), and Bcl-xL expression and have outcomes similar to those of HPV-unassociated patients.9
Response of Human Papillomavirus–Associated Oropharyngeal Cancer to Standard Therapy
Patients with HPV-associated oropharyngeal cancers have significantly better outcomes compared to HPV-unassociated oropharyngeal tumors.17,18 In a reanalysis of Radiation Therapy Oncology Group (RTOG) 0129, a randomized study comparing cisplatin administered with either accelerated concomitant boost radiotherapy or conventionally fractionated radiotherapy, HPV status was independently associated with improved outcomes. Three-year overall survival was 82% in HPV-positive patients compared with 54% in HPV-negative patients. Even after adjustment for age, tumor stage, nodal stage, treatment assignment, and tobacco use, HPV status independently predicted for improved survival (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.27 to 0.66). Additionally, locoregional progression (13.6% vs. 24.8%) and progression-free survival (71.8% vs. 50.4%) were significantly improved in HPV-positive cases. Other large cooperative group studies have demonstrated similar findings.18,19 It is important to realize that the prognostic significance of HPV was independent of the chemoradiotherapy platform and applies to treatment with radiotherapy alone,20 as shown in Table 45.1. In fact HPV-related tumors have a better prognosis regardless of the treatment modality (surgery, radiotherapy, or chemoradiotherapy) used.
TABLE 45.2 ANATOMIC BOUNDARIES OF NECK NODE LEVELS
TABLE 45.3 RADIOGRAPHIC BOUNDARIES OF NECK NODE LEVELS
ANATOMY
The oropharynx is contiguous with the oral cavity anteriorly, the larynx and hypopharynx posterior-inferiorly, and superiorly with the nasopharynx. Three main subregions compose the oropharynx including the tonsil, base of tongue, and soft palate. Normal function of the oropharynx is critical for speech and swallowing.
The tonsillar region contains the anterior and posterior tonsillar pillars as well as the palatine tonsil. The palatine tonsils are lymphoid aggregates incompletely encapsulated with a keratinized stratified squamous epithelial mucosal lining positioned in the tonsillar bed, which is a part of the tonsillar cleft between the anterior (palatoglossal) and posterior (palatopharyngeal) tonsillar pillars.
The base of tongue comprises the posterior third of the tongue and is bounded anteriorly by the circumvallate papillae, sitting in front of the sulcus terminalis. The base of tongue is bounded posterior-inferiorly by the hyoid and epiglottis and laterally by the glossopharyngeal sulci. Underlying the mucosa of the base of tongue are lymphatic nodules collectively known as the lingual tonsil. The vallecula is a 1-cm mucosal strip that serves as a transition between the base of tongue and epiglottis and is considered a part of the base of tongue. The sensory innervation of the base of tongue is via the glossopharyngeal nerve (cranial nerve [CN] IX) with a small aspect of the base of tongue supplied by the internal laryngeal nerve (CN X).
The soft palate is a fibromuscular structure bounded anteriorly by the hard palate, laterally coursing into the anterior tonsillar pillars and posterior-inferiorly forming a free edge, and the midline uvula. The soft palate is composed of five muscles (levator veli palatini, tensor veli palatini, palatoglossus, palatopharyngeus, and musculus uvulae) posteriorly and the palatine aponeurosis an expanded tendon of the tensor veli palatini anteriorly. The muscles of the soft palate are supplied through the pharyngeal plexus (which is composed of the pharyngeal branches of CNs IX and X, as well as sympathetic branches from the superior cervical ganglion, except for the tensor veli palatini, which is supplied by CN V2). The sensory supply is from CN IX.
The oropharynx serves many functions, including that of degustation, respiration, and speech. Advanced tumors arising in the oropharynx can infiltrate muscles and nerves, thus significantly impeding these functions. A major goal of successful therapy is to limit the impact of the treatment on long-term function.
ROUTES OF SPREAD
Primary routes of spread for oropharyngeal cancers include direct extension and lymphatic spread, with hematogenous metastases being less common. Oropharyngeal cancers have a predilection for submucosal extension, often visualized as raised erythematous regions without distinct borders or ulceration. This can best be appreciated by direct visualization rather than on radiographic imaging.
Lymphatic Spread of Oropharyngeal Cancer
The lymphatic drainage of the oropharynx and the neck was first described by Rouviere21 in 1938 and has since been refined by others.22 Originally grouped by lymph node chains located in particular anatomic regions, nodal groups are now classified by the level system23 with the location of lymph nodes in the neck being defined by surgical-anatomic landmarks (Table 45.2). Recently, this system (levels I to VI) was refined with the addition of sublevels (Ia/Ib, IIa/IIb, and Va/Vb) (as shown in Table 45.2), also incorporating radiologically defined landmarks24 (as shown in Table 45.3 and Fig. 45.2).
The most common location for lymph node metastases from oropharyngeal cancers is the ipsilateral level II. The probability of lymphatic (regional) metastasis is related to the size and location of the primary tumor within the oropharynx. The typical order of metastatic progression is systematic, from the upper jugular chain nodes superiorly (level I/II; first echelon), to mid-cervical (level III), and to lower cervical nodes (level IV), inferiorly. In large series of oropharyngeal cancer patients, isolated skip metastases are rare (0.3%), and level I or V involvement is usually associated with the involvement of other levels. Additionally, tumors encroaching or crossing midline or involving the posterior pharyngeal wall exhibited a higher propensity for bilateral lymphadenopathy.
Knowledge of the probability of occult pathologic lymphadenopathy for each involved oropharynx anatomic subsite and extent of disease is critical to modern radiotherapy and surgery planning, as selective neck dissections and limited radiotherapy volumes are the norm. Standardized contouring atlases have been published to aid clinicians in development of appropriate radiotherapy volumes to cover potential occult microscopic lymphatic spread in the N0 neck.25–27 Additionally, information about probabilities of occult pathologic lymphatic involvement has been compounded from series of patients undergoing elective neck dissection.28 The use of this knowledge to develop appropriate radiotherapy volumes will be discussed in more detail in the radiotherapy volumes section. The rate of pathologic lymphadenopathy for the pathologically involved neck is outlined in Table 45.4.
FIGURE 45.2. Schematic diagram indicating the location of the lymph node levels in the neck based on anatomic boundaries. (Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition [2010] published by Springer Science and Business Media LLC, www.springerlink.com.)
TABLE 45.4 DISTRIBUTION OF CLINICAL METASTATIC NECK NODES FROM HEAD AND NECK SQUAMOUS CELL CARCINOMAS
Distant Metastatic Spread of Oropharyngeal Cancer
Distant metastatic spread in oropharyngeal cancer is relatively uncommon, affecting approximately 15% of all patients during the course of their disease.29 The most common locations for distant metastatic spread of oropharyngeal cancers are the lung parenchyma,29 followed by osseous and hepatic metastases. Metastases are more common in patients presenting with locoregionally advanced or recurrent tumors, with the risk increasing with primary tumor stage as well as the burden of pathologic lymphadenopathy (N2-N3 disease).29,30 Extranodal extension, lower cervical pathologic lymphadenopathy (level IV), and lymphovascular invasion have also been associated with increased rates of distant metastases.31
Metastatic deposits within the lung parenchyma typically appear radiographically as well-circumscribed, peripherally located nodules. Care should be taken to differentiate between pulmonary metastases and primary pulmonary malignancies, characterized as spiculated irregularly shaped masses commonly associated with hilar and mediastinal lymphadenopathy, given their differing prognostic implications. This distinction often is impossible, even after biopsy, as both can be of squamous cell histology. In such instances, physically fit patients should be given the benefit of the doubt and treated as if they have two separate primary tumors. In patients with limited pulmonary metastases, who are technically resectable and fit for surgery, resection of pulmonary oropharyngeal cancer metastases may improve survival.32–34 For nonsurgical candidates, hypofractionated image-guided radiotherapy to all known metastatic sites can result in long-term disease control and should be considered for patients with limited metastatic disease.35
CLINICAL PRESENTATION
Oropharyngeal cancers present with a constellation of symptoms that depend on the location of the primary tumor, invasion of nearby organs, and extent of nodal disease. Often, patients will present with a painless neck mass, which is usually mobile, firm, and nontender but can be fixed, indicating extranodal extension and invasion into surrounding structures. Such masses are frequently treated with an initial course of antibiotics; however, persistence or growth in this context mandates further evaluation. Some patients complain of a deep-seated otalgia located within the auditory canal. This is mediated via irritation of the glossopharyngeal nerve (CN IX) with referral via the petrosal ganglion to the tympanic nerve of Jacobson. Regurgitation of foods can occur with invasion of the soft palate, inhibiting its ability to elevate during swallowing. Trismus is seen with more advanced tumors and reflects invasion of the pterygoid fossa and/or musculature. Odynophagia and dysphagia are other common presenting symptoms that occur with invasion into the pharyngeal musculature or obstruction by pathologic lymphadenopathy.
FIGURE 45.3. Diagnostic computed tomography image demonstrating locoregionally advanced oropharyngeal cancer with extensive ipsilateral cervical lymphadenopathy.
DIAGNOSTIC EVALUATION
Physical Examination
A complete examination of all mucosal head and neck sites should be performed in any patient with a known or suspected diagnosis of oropharyngeal cancer. This process not only characterizes the primary tumor but also evaluates for other malignancies given the high propensity for second primary upper aerodigestive tract tumors. A thorough physical examination is essential for diagnosis and understanding of the complete extent of disease, and it helps to guide the surgeon on the choice of optimal biopsy site. Inspection of the oropharynx should be performed under adequate illumination and be well practiced, systematic, and reproducible. Following examination of the oral cavity, where attention should be directed to the number and health of the patient’s teeth and to the mucosal sites, one should closely examine the anterior tonsillar pillars, the tonsillar fossae, and posterior tonsillar pillars followed by the soft palate. Proper exposure can be achieved either with gloved index fingers or with two disposable tongue depressors used in unison. Palpation of the tonsillar fossa and the base of tongue should be performed because these locations can harbor occult primary tumors, with the base of tongue performed at the completion of the examination owing to its propensity to trigger the gag reflex. Direct visualization should be followed by fiberoptic examination whenever possible, because this allows optimal inspection of the base of tongue, posterior-inferior tonsil vallecula, as well as documenting spread to laryngeal and pharyngeal subsites. Fiberoptic examinations should be recorded and compared to assess response during the course of therapy. Indirect mirror examination is less informative than fiberoptic evaluation; however, it should be performed if fiberoptic capabilities are not available.
Oropharyngeal tumors often appear as ulcerated masses, with surrounding erythema, neovascularization, and mucositis. Tenderness, evidence of recent bleeding, obstruction of the airway, skin invasion, alteration of gag reflex, and extent of trismus (measured from upper to lower incisors) should be documented. Bulging of the parapharyngeal space should also be noted because this could represent retropharyngeal lymphadenopathy.
Careful examination of the neck is also important for staging and management. Palpation of the neck should focus on neck levels defined by standard anatomic relationships. The neck should gently be turned to the side while being examined to relax the sternocleidomastoid muscle, which facilitates the detection of smaller involved lymph nodes. Care should be taken not to palpate too firmly in older patients or those with known vascular disease, as aggressive carotid massage can be associated with syncope. Lymph nodes should be recorded in terms of the level in which they arise, their size, and the character of their firmness, as well if they are fixed and whether or not they penetrate and involve the skin.
Confirmatory biopsy of the primary site should be performed. Adequate exposure is usually possible for in-office biopsies of the proximal oropharynx. Posterior oropharyngeal tumors are often biopsied under general anesthesia in the operating room, often as part of a comprehensive examination under anesthesia as well as comprehensive endoscopic evaluation (laryngoscopy, bronchoscopy, and esophagoscopy).
Computed Tomography
Computed tomography (CT) imaging of the head and neck with intravenous contrast should be performed for all newly diagnosed oropharyngeal cancer patients to assess the extent of primary tumors and to determine the presence or absence of cervical lymph node metastases. Scan slice thickness <5 mm is desirable to optimize the detection of smaller pathologically involved lymph nodes and to provide the best anatomic delineation of both primary and nodal disease. Pathologically involved lymph nodes are characterized on CT imaging as those that are enlarged, enhance with contrast, and have a necrotic center. Primary tumors appear as contrast-enhancing masses, distorting normal anatomic relationships. Whereas ulceration and invasion into surrounding organs are readily assessed, submucosal spread is often difficult to characterize with CT. As multiplanar image reconstruction is routinely available, lymph node and primary tumor size should be measured in both longitudinal and cross-sectional dimensions to more accurately stage patients. Unfortunately, dental artifact on CT imaging may often obscure complete visualization with neutral head position, requiring further scanning with an adjusted head position. Thoracic CT should be performed routinely to assess for pulmonary spread of oropharyngeal cancer patients with N2 or greater nodal disease, as well as those with advanced primary tumors, given the risks of pulmonary metastases described previously. A diagnostic CT image of a patient with locoregionally advanced head and neck cancer is shown in Figure 45.3.
Positron Emission Tomography
Positron emission tomography (PET) and/or PET/CT imaging incorporating tumor physiology in conjunction with anatomic information are now routinely recommended for the initial staging of oropharyngeal cancer patients. From a practical standpoint, PET-based imaging can assess not only the locoregional burden of disease but also detect and quantify distant metastases. For oropharyngeal cancer patients specifically, the ability to detect clinically and radiographically occult pathologic cervical lymphadenopathy renders PET a powerful clinical tool, as ipsilateral radiotherapy volumes are used in specific circumstances.36 Although commonly reported as the maximum standard uptake value (SUVmax), alternative measurements such as SUVmean may have greater prognostic value.37 The utility of PET/CT for oropharyngeal cancer patients demonstrates high sensitivity approaching 100%, although only about 60% specificity for pathologically proven tumor. Clinical status and knowledge of prior procedures is critical to PET interpretation, because recent biopsies and infections can cause artificially elevated metabolic activity.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) can be a useful imaging tool for oropharyngeal tumors. Squamous cell carcinoma appears as low signal in T1 MRI and corresponding high signal in T2 sequences. The ability of MRI to differentiate tumor from soft tissues is particularly useful when determination of the extent of base of tongue or oral tongue invasion is needed. Additionally, MRI is useful in patients with compromised renal function who are not able to receive iodine-based CT contrast agents.
TABLE 45.5 TNM STAGING SYSTEM FOR OROPHARYNGEAL CANCER
TABLE 45.6 STAGE GROUPING FOR OROPHARYNGEAL CANCER
PATHOLOGIC CLASSIFICATION
Squamous cell carcinomas are the most common histologic subtype comprising more than 95% of all oropharyngeal cancers. Uncommonly, minor salivary gland and mesenchymal tumors can affect this region. Given the proportionally high content of lymphoid tissue in the region within Waldeyer’s ring, malignant Hodgkin and non-Hodgkin lymphomas also arise in this region. This chapter will discuss only squamous cell and related (poorly differentiated and lymphoepithelioma) histologic subtypes. Malignant lymphomas are discussed in Chapters 77–78. Minor salivary gland tumors are discussed in Chapter 43, and sarcomas are discussed in Chapters 48 & 83.
STAGING
Staging for oropharyngeal cancer is based on the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) system, shown in Table 45.5. Clinical staging is based on all available history, physical examination, endoscopic, radiographic, metabolic, and scintigraphic data. For all subsites, the size of the primary tumor contributes to the T-stage, with T1 being <2 cm, T2 >2 cm but <4 cm, and T3 >4 cm. T4a describes tumors invading the larynx, extrinsic muscles of the tongue, medial pterygoid, hard palate, or mandible. T4b disease describes oropharyngeal tumors invading the lateral pterygoid, pterygoid plates, lateral nasopharynx, skull base, or surrounding the carotid artery. Nodal staging for each of the subsites is the same: N0 indicates no clinical or radiographic evidence of pathologic lymphadenopathy; N1 indicates a single lymph node <3 cm in the ipsilateral cervical chains; N2a indicates a single lymph node >3 cm and <6 cm in the ipsilateral cervical chain; N2b indicates multiple ipsilateral cervical lymph nodes all <6 cm in size; N2c indicates bilateral pathologically involved cervical lymph nodes with the largest node <6 cm; and N3 indicates the presence of at least one lymph node >6 cm. Distant metastatic disease is classified as M1.
Stage grouping is shown in Table 45.6. Stage I comprises T1N0 tumors, and stage II is made up of T2N0 tumors. Stage III includes patients with T3N0–1 or T1-T2N1. Stage IV is divided into three subgroups: stage IVa is made up of patients with T4aN0–2a-c, T1–3N2a-c tumors; stage IVb disease basically describes patients who are technically unresectable, including patients with an extensive primary tumor (T4b) or those with any primary stage who have extensive lymphadenopathy (T any N3); stage IVc disease is reserved for patients with distant metastases.
MANAGEMENT STRATEGIES
Functional organ preservation with minimal toxicity is the management goal for all oropharyngeal cancer patients. Based on AJCC stage, patients are usually grouped into two different treatment groups to help guide therapy decisions. Those with locally confined disease (stage I and stage II tumors) are considered as early stage, whereas those with stages III and IV (nonmetastatic) disease are considered as having locoregionally advanced disease. For all subsites, early-stage tumors are usually well controlled with a single local modality, either radiotherapy or surgery. Selection of local modality should be based on the primary tumor size, extent of local spread, and subsite involved. Small tumors of the tonsil and small exophytic tumors of the base of tongue can be well managed surgically, whereas the morbidity of surgery on the soft palate favors radiotherapy. For locoregionally advanced disease, two appropriate treatment strategies are used: (a) either surgery followed by radiation therapy with or without chemotherapy based on pathologic risk factors or (b) radiotherapy usually given with chemotherapy.
SURGICAL TECHNIQUES, APPROACHES, AND RESULTS
Base of Tongue
Surgery plays a limited role in the management of base of tongue tumors given the inherent morbidity of a near-total or total glossectomy, which is required for large and/or midline tumors. For select, well-lateralized base of tongue tumors with minimal cervical lymphadenopathy, a partial glossectomy can be performed. Given the high propensity for occult microscopic nodal involvement, bilateral cervical lymph node dissection is often performed. Base of tongue tumors in close proximity to the laryngeal apparatus, such as those arising in the vallecula, often require a supraglottic or total laryngectomy to achieve adequate margins of resection.
Traditional surgical approaches for base of tongue tumors include the midline mandibulotomy (splitting the lip, mandible, and oral tongue midline), the lateral mandibulotomy (dividing the mandible near the angle and approaching the base of tongue from the side), and the floor drop procedure (elevating the inner periosteum from the mandible from angle to angle, which releases the entire floor of mouth and oral tongue into the neck, exposing the base of tongue).
Tonsil Cancers
For small (<1 cm) early-stage tonsil cancers confined to the anterior pillar, a wide local excision can achieve adequate tumor-free margins, whereas tumors involving the palatine tonsil often require a radical tonsillectomy. For both of these situations, the tonsil is approached transorally, with primary closure. Larger tumors with extension onto the tongue, onto the mandible or into surrounding tissue often require a composite resection, usually including resection of the tonsil, tonsillar fossa, pillars, a portion of the soft palate, tongue, and mandible. For tumors not adjacent or adherent to the mandible, a midline mandibulotomy approach is used. For tumors adherent to the mandible, a partial mandibulectomy is used. Defects are often closed with a myocutaneous flap. Complications from surgery depend on the extent of resection, with impairment in swallowing possible by removal of part of the tongue or soft palate.
Soft Palate Cancers
Surgical resection is rarely recommended as initial therapy for soft palate tumors. Resection of the soft palate is often associated with significant reflux into the nasopharynx during swallowing, even with the use of custom prostheses. Additionally, because of the midline location, primary disease spreads bilaterally to the neck with frequency high enough to require elective treatment. However, when surgery is performed, the tumors are approached transorally and a full-thickness wide local resection is performed for tumors limited to the soft palate. A more extensive composite resection is required if disease extends to surrounding structures. Flaps or prostheses are used to preserve velopharyngeal competence. Nasal speech is also often a consequence.
Transoral Surgical Approaches
Transoral surgical approaches, routinely used for limited tonsillar resections, are increasingly being used for other oropharyngeal cancer operations as an alternative to open surgical procedures. By limiting the need for open surgical exposure, these operations can have a quicker recovery time and less morbidity. More recently, endoscopic approaches have been adopted to enhance the utility of transoral surgery. However, limited prospective data support the benefit of transoral operations over traditional approaches. Prospective data are needed to further elucidate the benefits of these surgical advances and better integrate them with the other standard oncologic therapies.
Transoral Laser Surgery
Small series report favorable outcomes for selected patients with stage I through stage IV oropharyngeal tumors treated with transoral laser microsurgery with or without neck dissection, followed by adjuvant radiotherapy or chemoradiotherapy.38–40 Positive margin rates are variable (3% to 24%) and appear to vary based on primary site, being more common in base of tongue tumors. Complications include postoperative hemorrhage (5% to 10%). Temporary tracheostomy placement is relatively common (17% to 30%) and needed for exposure, airway control, or aspiration following extensive resection. High rates of locoregional control following this procedure have been reported, primarily for stage I/II patients (87% to 100%), although for stage III/IV patients, local recurrence is more common (20% to 30%). Swallowing outcomes are favorable with series reporting most patients tolerating a normal diet.40
Transoral Robotic Surgery
The use of a computer-aided interaction between the surgeon and the patient is commonly referred to as robotic surgery. The most common robotic surgical system, the da Vinci Surgical System, is comprised of three surgical instruments and a binocular endoscope controlled by robotic arms and inserted under direct or endoscopic guidance by the surgeon from a patient-side apparatus. The surgeon controls the instruments from a console separated from the patient. The operative environment is visualized virtually, in a three-dimensional (3D) environment created via a computer that links the environment provided by the binocular endoscope to the position of the instruments. The surgeon’s movements are translated into the micromovements of the instruments. The advantages of this system include motion scaling, which can increase precision as well as reduce hand tremor and fatigue. When the system is used for transoral surgeries, an assistant is often positioned by the patient’s head.
There are no prospective randomized studies supporting the use of transoral robotic surgery (TORS) for oropharyngeal tumor resection over conventional surgery. All studies to date are small single-institution series. Proponents of TORS highlight an enhanced visualization of the surgical field over traditional transoral techniques. Some have hypothesized that perhaps local control could be enhanced via TORS debulking with minimal acute sequelae. However, this claim has yet to be tested prospectively. Prospective studies have shown that TORS can be used safely with a low risk of laceration or fracture to a patient.41 In a series of 27 patients with tonsillar cancer who underwent TORS tonsillectomy, morbidity was “acceptable,” including one case of musical bleeding and two cases of moderate trismus; one patient required a tracheostomy, and negative margins were obtained in 25 of 27 patients.42
Until mature prospective multi-institutional series and randomized data are available, the true utility of transoral laser microsurgery and TORS remains unknown. Although early results are favorable and associated with shorter hospital stays, long-term data are needed. Additionally, standard oncologic principles limiting the number of modalities used to minimize treatment related side effects should be carefully considered prior to widespread adoption of the surgical techniques.
ADJUVANT THERAPY FOLLOWING DEFINITIVE SURGICAL RESECTION
Following surgical resection of oropharyngeal cancers, pathologic features including advanced primary T-stage (T3 or T4), lymphovascular space invasion, perineural invasion, positive margins, multiple pathologically involved cervical lymph nodes, and extranodal extension place patients at high risk for locoregional recurrence.43 In these cases, postoperative radiotherapy (PORT), often in conjunction with chemotherapy, has been shown to reduce the risk of locoregional relapse.44,45,46 PORT was shown in RTOG 73–03 to results in superior locoregional control (70% vs. 58%) when compared to preoperative radiotherapy but did not affect survival.47
Adjuvant Chemoradiotherapy for Oropharyngeal Cancer
The addition of cisplatin-based chemotherapy to PORT has been compared to PORT alone for medically fit head and neck cancer patients of any site in several randomized studies.48–51 All of these studies have demonstrated statistically significant48–50 or strong statistical trends51 for improved locoregional control and disease-free survival with the addition of chemotherapy to PORT. Additionally, two of these studies have demonstrated statistically significant improvements in overall survival,48,49 whereas the other two have shown numerically improved but not statistically significant survival improvements.50,51 A significant portion of patients in these studies had oropharyngeal cancer (European Organisation for Research and Treatment of Cancer [EORTC] 30% and RTOG 43%) generalizing these results to oropharyngeal patients with high-risk pathologic features.
Concurrent Chemotherapy Regimens for Adjuvant Chemoradiotherapy
The optimal chemotherapy regimen delivered with PORT is currently unknown. Schedules of bolus cisplatin 100 mg/m2 were tested in two48,51 randomized studies mentioned earlier, one tested 50-mg weekly cisplatin49 and the other tested cisplatin 20 mg/m2 and 5-fluorouracil (5-FU) 600 mg/m2 days 1 through 5 and days 29 through 33.50 There have been no randomized comparisons of these cisplatin-based schedules. Randomized studies have been attempted to identify the role of carboplatin-based chemotherapy concurrently with PORT compared to PORT alone.52 Unfortunately, these studies closed before accrual goals were met, and no significant benefit was found with the addition of carboplatin to PORT. RTOG 0234 randomized high-risk postoperative patients (positive margin, extranodal extension, and/or ≥2 pathologically involved cervical nodes) to PORT in combination with cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly) and weekly docetaxel 15 mg/m2 or to PORT with cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly) and 30 mg/m2 cisplatin weekly. Results of this randomized phase II study are maturing. Currently, no randomized data support the use of taxanes or cetuximab in the postoperative setting.53 Based on the available data, many consider cisplatin 100 mg/m2 every 3 weeks as the standard.
Adjuvant Radiotherapy Dose
The optimal radiation therapy dose for PORT is also not well defined. Most of the randomized studies demonstrating the benefit of concurrent chemotherapy with PORT used radiotherapy doses of 60 to 66 Gy in 2-Gy daily fractions to high-risk areas (primary tumor bed with positive margin or nodal regions with extracapsular spread). Doses of 50 to 54 Gy in 2-Gy fractions were usually given to areas at risk for microscopic involvement. There is little evidence supporting the higher PORT doses used in these randomized trials over those recommended from the PORT-alone dose-finding studies of 63 Gy for extranodal extension and 57.6 Gy for all others. In three of four randomized studies testing the utility of chemotherapy concurrently with PORT, doses of more than 65 Gy were delivered to high-risk areas.48–51 The fourth study, RTOG 95–01, allowed a dose of 60 Gy with or without an optional 6-Gy boost. As these studies were associated with significant benefits for patients with extracapsular extension and positive margins, we recommend similar dosing schedules.
Postoperative Radiotherapy Treatment Volume
The typical treatment volume used in PORT for head and neck cancer includes the bilateral neck and the primary tumor site. However, it is unclear whether both the neck and primary always need to be within the PORT volume. In those with completely resected primary tumors with negative margins whose sole indication for PORT is pathologic cervical adenopathy, some would direct therapy only to the neck. Additionally, for patients with a positive margin as the sole indication for treatment in the setting of a comprehensive neck surgery without pathologically involved cervical lymph nodes, some would direct treatment to the primary resection bed only. For well-lateralized primary tumors, patterns of progression would suggest that PORT to the ipsilateral neck only may be appropriate.53
DEFINITIVE RADIOTHERAPY
For early-stage oropharyngeal cancers, the use of radiation therapy as a single modality is associated with good outcomes and functional preservation.54 Although there is not consensus on the optimal dose fractionation schedule for oropharyngeal cancer patients receiving radiotherapy alone, randomized data55–57 and meta-analyses58,59 support an overall survival benefit with the use of accelerated fractionation or hyperfractionated radiotherapy. Therefore, for oropharyngeal cancer treated with radiotherapy alone, strong consideration should be given to altered fractionation of some sort.
Hyperfractionated Radiotherapy
The benefit of hyperfractionated radiotherapy for oropharyngeal cancer was clearly demonstrated in EORTC 22791, in which patients with T2-3N0-1 non–base of tongue oropharyngeal cancers were randomized to conventionally fractionated radiotherapy at 70 Gy (2 Gy per day) or to 80.5 Gy hyperfractionated at 1.15 Gy twice daily. Hyperfractionated radiotherapy was associated with statistically significant improvements in locoregional control (5-year, 59% vs. 40%). Additionally, there was a trend toward improved overall survival (p = 0.08) particularly in stage III patients.57
Accelerated Radiotherapy
Accelerated radiotherapy has also been shown to benefit oropharyngeal cancer patients; however, this may depend on the exact regimen used. For example, a randomized study comparing an accelerated regimen of 66 to 70 Gy delivered in 2-Gy daily fractions 6 days a week to the same dose delivered 5 days a week with oropharyngeal cancer affecting the majority of patients demonstrated improved locoregional control (42% vs. 30%, p = 0.004), disease-free survival (50% vs. 40%, p = 0.03), and a trend toward improved overall survival (35% vs. 28%, p = 0.07).60 When analyzed as a separate subgroup, pharyngeal primary sites had improved locoregional control (HR 0.6, 95% CI 0.41–0.86).56 Of note, accelerated fractionation improved local control for both p16-positive (HR 0.56, CI 0.33–0.96) as well as p16-negative tumors (HR 0.77, CI 0.60–0.99).61 However, when a more intensive accelerated regimen of 1.8 Gy twice daily to 59.4 Gy was compared to 70 Gy in 2-Gy fractions in stage III/IV head and neck cancer patients, no statistical benefits were seen in terms of locoregional control or overall survival.62 It is unknown if the lack of benefit seen was due to the regimen used or to inclusion criteria because the benefit for acceleration in some randomized studies was less significant for those with stage IV disease as well as those with a larger nodal disease burden.60
Accelerated Versus Hyperfractionated Radiotherapy
For oropharyngeal cancer patients in particular, and head and neck cancer patients in general, it is not known if hyperfractionated or accelerated radiotherapy is superior. The meta-analysis of radiotherapy in carcinoma of the head and neck collaborative group pooled 15 randomized studies (including 6,515 patients) comparing conventionally fractionated radiotherapy to either accelerated radiotherapy or hyperfractionated radiotherapy. Oropharyngeal cancer patients were the largest subsite, representing 44% of all patients (1,585 patients). Altered fractionation radiotherapy regimens were associated with a 3.4% absolute improvement in 5-year overall survival. Heterogeneity in patients included on accelerated and hyperfractionated trials obscure direct comparison, although hyperfractionated patients had an absolute 8.2% improvement in overall survival at 5 years compared to a 2% absolute benefit with accelerated radiotherapy.59
One of the studies included in the meta-analysis, RTOG 90-03, compared conventional fractionation (70 Gy in 2-Gy daily fractions) to hyperfractionation (81.6 Gy in 1.2 Gy twice daily) to accelerated fractionation with a split course (67.2 Gy in 1.6 Gy twice daily with a 2-week rest after 38.4 Gy) to accelerated fractionation with concomitant boost regimen (72 Gy in 1.8-Gy fractions for 14 fractions followed by a 1.8-Gy morning and a 1.5-Gy afternoon boost to gross disease). Although all primary sites other than the nasopharynx were included, 60% of patients included had oropharyngeal primary tumors. Improved locoregional control was seen in both the hyperfractionated and accelerated concomitant boost arms.63 These improvements resulted in trend toward improved disease-free survival for patients treated with hyperfractionation (37.6% vs. 31.7%, p = 0.067) and accelerated concomitant boost (39.3% vs. 31.7%, p = 0.054), which almost reached statistical significance at the p = 0.05 level. These improvements were associated with an increase in both acute and late toxicity in all three accelerated treatment arms. No significant difference in overall survival was seen.
Simultaneous Integrated Boost Radiotherapy
With the increasing use of intensity-modulated radiotherapy (IMRT), simultaneous integrated boost radiotherapy has been investigated for oropharyngeal cancer patients. The RTOG completed a study (00-22) in early-stage (T1-2, N0-2) oropharyngeal cancer patients treated with bilateral neck radiotherapy54 using doses of 2.2 Gy, 2 Gy, and 1.8 Gy to gross tumor, intermediate-risk, and low-risk planning target volumes (PTVs), respectively. The 2-year risk of local progression was 9% and was higher in patients who had significant underdosing of known tumor. Additionally, no local recurrences, distant metastases, or second cancers were seen in never smokers, possibly representing a surrogate for HPV-related disease, compared to seven locoregional recurrences, five second cancers, and one case of distant metastases in smokers. Two-year overall survival was 95%, and disease-free survival was 82%. Therefore, it appears that for patients with early-stage oropharyngeal cancer treated with radiotherapy alone, simultaneous integrated boost radiotherapy is a viable treatment option.
FIGURE 45.4. Overall survival among patients with oropharyngeal cancer treated with radiotherapy alone (RT) or with radiotherapy with concomitant chemotherapy (RT/CT) as analyzed by the Kaplan-Meier method on GORTEC 94-01. (From Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22[1]:69–76. Reprinted with permission. © 2004 American Society of Clinical Oncology.)
CONCURRENT CHEMORADIOTHERAPY FOR LOCOREGIONALLY ADVANCED OROPHARYNGEAL CANCER
For patients with locoregionally advanced oropharyngeal cancer, concurrent chemoradiotherapy is the standard treatment. Resection is generally not recommended given the associated surgical morbidity. Additionally, adjuvant chemoradiotherapy is frequently necessary and has similar morbidity to definitive intent chemoradiotherapy. Comparisons of outcomes with radiotherapy with or without neck dissection or surgery with or without adjuvant radiotherapy resulted in similar outcomes with higher complication rates with surgery.64
Evidence for Concurrent Chemoradiotherapy
The use of concurrent chemoradiotherapy for most stage III and IV (nonmetastatic) oropharyngeal cancer patients is based on the results of the meta-analysis of chemotherapy in head and neck cancer (MACH-NC), which demonstrated a 6.2% absolute improvement in overall survival at 5 years from the use of concurrent chemoradiotherapy compared to radiotherapy alone. This benefit was also observed in the oropharyngeal cancer subgroup.65Additionally, level I evidence from multiple randomized studies restricted to oropharyngeal cancer patients supports the use of concurrent chemoradiotherapy for stage III/IV oropharyngeal cancer.66,67 The Groupe d’Oncologie Radiothérapie Tête Et Cou (GORTEC) compared 2-Gy daily conventional radiotherapy to 70 Gy concomitantly administered with daily bolus carboplatin and continuous infusion 5-fluorouracil 600 mg/m2/day on days 1 through 4 every 3 weeks for three cycles. A total of 222 patients (113 assigned to radiotherapy alone and 109 assigned to combined treatment) were eligible for analysis. With a median follow-up of 5.5 years, absolute 5-year overall survival was significantly higher in the combined modality arm (15.8% with radiotherapy alone to 22.4% with chemoradiotherapy), as shown in Figure 45.4. Five-year locoregional control was also significantly improved with concomitant therapy (from 24.7% vs. 47.6% for the combined-treatment group, p = 0.002).68 Combined modality therapy was associated with increased hematologic toxicity, increased mucositis, and weight loss. Severe late toxicity was also increased with combined modality therapy (14% vs. 9% radiotherapy alone), including increased mandibular toxicity and cervical fibrosis. These patients were treated with two-dimensional (2D) treatment planning, typically including parallel-opposed fields with dosimetric hotspots located in the mandible and neck soft tissues. The extent to which concurrent chemotherapy contributes to these specific late toxicities in the setting of IMRT is not clearly understood.
Outcomes of locoregionally advanced oropharyngeal cancer have improved in the era of concurrent chemoradiotherapy and modern radiotherapy planning and delivery techniques. This improvement is likely influenced by newer imaging techniques leading to more informed patient selection and radiotherapy planning and the influence of a rise in HPV-related oropharyngeal cancer cases. A recent analysis of more than 300 locoregionally advanced oropharyngeal cancer patients treated with primary chemoradiotherapy with a median follow-up of 34 months reported low 2-year rates of local progression (6.1%), regional progression (5.2%), and distant progression (12.2%).69Base of tongue cancers have historically been associated with poor outcomes when treated with surgery or radiotherapy alone or in combination (5-year disease-specific and overall survival of 27.8% and 40.3%, respectively).70However, recent single-institution series using chemoradiotherapy highlight high rates of locoregional control for BOT cancers with the use of either 3D conformal radiotherapy (5-year, 82%) or IMRT (5-year, 97.4%),71 which could represent the influence of HPV-related oropharyngeal cancer.
Acute Toxicity of Chemoradiotherapy
For oropharyngeal cancer patients, a course of concurrent chemoradiotherapy is a life-changing event given the associated toxicities, including fatigue, nausea, emesis, thickened secretions, xerostomia, mucositis, dysphagia, odynophagia, alopecia, dermatitis, anemia, neutropenia, hoarseness, Lhermitte’s syndrome, and infection. Dysphagia is perhaps the most difficult acute complication of chemoradiotherapy for oropharyngeal cancer. Oropharyngeal patients are less likely to be affected than those with laryngeal or hypopharyngeal tumors.72 Older patients and those with worse performance status are more likely to have worsening of their swallowing following chemoradiotherapy. Those with more advanced tumors are more likely to have swallowing improvement likely owing to reduction of tumor bulk.73 Given the adverse effect of dysphagia on nutritional status, management recommendations include early therapeutic intervention with swallowing exercises designed to strengthen the pharyngeal musculature. Patients should be instructed to swallow as large a volume as possible during and after treatment and to perform exercises shown to improve swallowing ability.74 Dysphagia has been associated retrospectively, with the exceeding of specific dosimetric thresholds to the pharyngeal constrictors or laryngeal apparatus, which should be incorporated into radiotherapy planning as discussed later.
Late Toxicity of Chemoradiotherapy
Late toxicities of chemoradiotherapy for oropharyngeal cancer patients can be quite significant and may include fibrosis, osteoradionecrosis, trismus, xerostomia, dental caries, feeding tube dependence, and neuritis. Late toxicities of chemoradiotherapy have been catalogued by the RTOG in a pooled analysis of 230 patients treated on three prospective chemoradiotherapy trials with a median follow-up of 3 years. Oropharyngeal primaries affected 34% of all patients. Older patients and those with larger (T3, T4) tumors were more likely to experience late toxicity, as were those who underwent a posttreatment neck dissection.75 When late toxicity was analyzed by primary tumor site, patients with oropharyngeal and oral cavity primary tumors were statistically less likely to experience late toxicity. Long-term analysis of the aforementioned GORTEC randomized trial demonstrated that 56% of patients treated with chemoradiotherapy had at least one grade 3 to 4 late toxicity compared to 30% treated with radiotherapy alone (p = 0.12). The small number of long-term survivors probably reduced the power to detect statistically significantly differences between these groups.68
Alternative Concurrent Chemoradiotherapy Regimens
The toxicities of concurrent chemoradiotherapy have stimulated the search for improvements in this platform. Some questions still remain unanswered, including what constitutes the optimal chemotherapy regimen. Cisplatin at 100 mg/m2 every 3 weeks for 2–3 cycles is often cited as a standard regimen. The aforementioned GORTEC randomized study demonstrated an overall survival advantage using a carboplatin/5-FU regimen specifically chosen to avoid cisplatin-related tinnitus, renal dysfunction, and emesis. There are no randomized studies comparing alternative cisplatin dosing schedules (such as 30 to 40 mg/m2 weekly, 20 mg/m2/day, days 1 through 5 and days 22 through 26) to bolus cisplatin or to other chemoradiotherapy platforms. However, multiple randomized studies that compared radiotherapy alone to concurrent chemoradiotherapy using nonbolus cisplatin schedules including daily cisplatin (6 mg/m2/day),76 weekly cisplatin 40 mg/m2 weekly,77 or cisplatin 20 mg/m2/day, days 1 through 5 repeated every 3 weeks,78 had comparable outcomes to bolus cisplatin. The relative merits of various chemoradiotherapy platforms will be discussed in more detail in Chapter 40.
Induction Chemotherapy Prior to Definitive Local Therapy
The use of neoadjuvant chemotherapy prior to surgical resection or radiotherapy for oropharyngeal cancer patients has been tested in randomized studies. In particular, a phase III study restricted to oropharyngeal cancer patients compared cisplatin 100 mg/m2 on day 1 and 5-fluorouracil 1,000 mg/m2/day, days 1 through 5, repeated every 3 weeks for three cycles followed by definitive local therapy to definitive local therapy alone. At the time of the study, standard local therapies included either radiotherapy alone (70 Gy to the primary, 50 Gy to the neck) or composite surgery with PORT (50 to 65 Gy based on pathologic findings). Although only 318 of a planned 760 patients were enrolled, a statistically significant improvement in overall survival was seen in the induction chemotherapy arm at 5 years (5.1 years vs. 3.3 years) with a median follow-up of 5 years.79 This study suggests a benefit to neoadjuvant chemotherapy. The applicability of this trial in the chemoradiotherapy era is questionable, however, because the patients in the control arm of the study received surgery or 70 Gy of daily radiotherapy, which is known to be inferior to accelerated or hyperfractionated radiotherapy. The value of this treatment compared to concurrent chemoradiation is also unknown.
Whether or not induction chemotherapy prior to concurrent chemoradiotherapy improves survival when compared to chemoradiotherapy is currently unknown and waiting maturation of data from completed randomized studies. Induction chemotherapy has been advocated by some given that distant metastases is frequently a site of first failure for patients with locoregionally advanced head and neck cancer in general.80 This is particularly true for patients with oropharyngeal cancer because local regional therapy (chemoradiotherapy) has become so much more effective.69 Induction chemotherapy has resulted in low rates of distant metastases in single-arm phase II studies,81,82suggesting a role for some oropharyngeal patients at increased risk for distant metastases. Randomized studies assessing the role of induction chemotherapy were initiated prior to robust knowledge of the behavior of HPV-associated oropharyngeal cancers. Therefore, inclusion of these patients with their favorable outcomes were not accounted for in the study design and may complicate interpretation of these studies.
Targeted Agents and Radiotherapy
A randomized study compared radiotherapy, 70 to 76.8 Gy with or without weekly cetuximab, (loading dose of 400 mg/m2 followed by 250 mg/m2) for locoregionally advanced head and neck cancer patients. The combination therapy was found to improve locoregional control, disease-free survival, and overall survival.83 The majority of patients had oropharyngeal primary tumors (60%). When analyzed alone, patients with oropharyngeal cancer treated with cetuximab had demonstrated improved 2-year locoregional control (50% vs. 41%) and median locoregional disease-free duration: 49 months versus 23 months (HR 0.61) with the use of cetuximab. Furthermore, the median overall survival for oropharyngeal cancer patients treated with cetuximab and radiotherapy was >66 months compared to 30.3 months in those treated with radiotherapy alone (HR 0.62), a larger difference than those with laryngeal (32.8 months vs. 31.6 months) or hypopharyngeal (13.7 months vs. 13.5 months) primary sites. Therefore, for oropharyngeal cancer patients meeting the inclusion criteria for this study, stage III/IV, nonmetastatic, Karnofsky performance status score >60, and normal hematopoietic, hepatic, and renal function, cetuximab and radiotherapy is an alternative treatment platform. Consideration should be given to the use of altered radiation fractionation with cetuximab because improved overall survival was seen in patients who were treated with accelerated concomitant boost and hyperfractionated radiotherapy.
Cetuximab should be avoided in specific regions (particularly the southeastern United States) where severe anaphylactic reactions mediated by an immunoglobulin E response to the galactose-alpha-1,3-galactose oligosaccharide found on the Fab portion of the cetuximab heavy chain are seen.84 A fully humanized monoclonal antibody to the EGFR, panitumumab, has a much lower rate of severe allergic reactions; however, there is no level-1 evidence to support its equivalent efficacy in this clinical setting. Aside from these geographic limitations, it is unclear which patient populations should receive concurrent chemotherapy and which should receive cetuximab plus radiotherapy. Some physicians use cetuximab plus radiotherapy preferentially over cisplatin plus radiotherapy in patients with renal dysfunction or overall poor functional status, although there is no level-1 evidence to support this indication. In fact, these same medical conditions constituted exclusion criteria for the randomized trial proving its benefit.
Given the improved outcomes of HPV-associated oropharyngeal cancer with standard treatments, deintensification of therapy is being considered in this patient population. Randomized studies comparing standard chemoradiotherapy to combined EGFR inhibition and radiotherapy are ongoing in the cooperative group setting. RTOG 1016 is comparing bolus cisplatin 100 mg/m2 days 1 and 23 with accelerated radiotherapy (70 Gy, 2 Gy/day, 6 days per week) to the same radiotherapy and cetuximab 400 mg/m2 loading dose and 250 mg/m2 weekly with radiotherapy. This noninferiority study has a primary end point of comparable 5-year survival. The National Cancer Institute of Canada (NCIC) is conducting a similar study, although with the use of panitumumab with radiotherapy given the lower rates of dermatologic and anaphylactic reactions. Other investigations are attempting radiation dose reduction by aiming to keep locoregional control high while reducing acute toxicity, with some using induction chemotherapy before chemoradiotherapy. Mature reports from these studies will help to determine how to optimally treat this unique patient population.
Targeted Agents in Combination with Cytotoxins and Radiotherapy
To date, there are no comparisons of cytotoxic agents and radiation with and without cetuximab for oropharyngeal cancer patients. Oropharyngeal cancer patients comprised 70% of RTOG 0522, which compared two concurrent cycles of 100 mg/m2 cisplatin and accelerated concomitant boost to 72-Gy radiotherapy with or without the addition of a loading dose of 400 mg/m2 followed by weekly 250 mg/m2 cetuximab. The combination of cisplatin, cetuximab, and radiotherapy did not improve locoregional control, disease-free survival, or overall survival. However, this triplet therapy was associated with increased grade 3/4 mucositis (45% vs. 35%, P = 0.003) and skin reactions (40% vs. 17%, P <0.0001) without increasing grade 3/4 dysphagia rates (62% vs. 66%, P = 0.27).85 Fifty-one percent of oropharyngeal tumor specimens were evaluated for p16 expression, and 73% of these specimens were positive. No differences in outcome were seen as a function of differences in HPV status.
Oropharyngeal cancer patients have also been included in studies evaluating the addition of bevacizumab to chemoradiotherapy. The addition of bevacizumab to 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy (FHX) did not confer any benefit in a study of locoregionally advanced head and neck cancer patients. The study was terminated early because of toxicity and because only 5 of 26 participants had oropharyngeal primary tumors.86 Bevacizumab has also been integrated with erlotinib (synchronous dual inhibition of vascular endothelial growth factor [VEGF] and EGFR) and cisplatin (33 mg/m2 cisplatin days 1 through 3, weeks 1 and 5) together with 1.25-Gy twice-daily radiotherapy to 70 Gy. Seventy-one percent of patients had oropharyngeal primary tumors. At a median follow-up of 46 months, 3-year locoregional control and overall survival were promising at 86% and 85%, respectively, compared to historical series.87 Soft tissue and osteoradionecrosis occurred in both series, and careful attention should be paid to the results of ongoing studies integrating bevacizumab to multiple chemoradiotherapy platforms for locoregionally advanced head and neck cancer patients, including those with oropharyngeal tumors.
EXTERNAL-BEAM RADIOTHERAPY SIMULATION AND TREATMENT PLANNING
Radiotherapy Simulation
Prior to a course of radiotherapy or chemoradiotherapy, patients should undergo simulation, preferably CT based, to allow for optimal radiotherapy planning. A peripheral IV should be placed prior to simulation for the delivery of low osmolar iodinated contrast to optimize the distinction between vascular structures and lymph nodes. Patients are positioned supine, with a rigid head holder cradling the posterior calvarium. Generally, an extended head position is preferable. The shoulders should be positioned as caudally as possible to allow adequate exposure of the neck. This can be achieved either with shoulder pulls or with commercially available devices. Tongue immobilization can be useful for oropharyngeal cancer patients with oral tongue involvement. Bite blocks are also useful because they often elevate the hard palate with its minor salivary glands. The head should be immobilized with a thermoplastic mask. Care should be taken to ensure that the mask is tight and should not allow movement of the nose, chin or, forehead. Images should be taken from above the calvarium to the carina to ensure that appropriate volumes can be drawn. The addition of metabolic imaging and MRI has been found to be complementary for gross tumor volume (GTV) delineation.88
Radiotherapy Volumes
Radiotherapy volumes for oropharyngeal cancer patients are based on the International Commission on Radiation Units and Measurements (ICRU) 50. The GTV includes all known primary and cervical lymph node tumor extension based on clinical, endoscopic, and imaging findings. Care should be taken to look for fat stranding, which could be indicative of extranodal extension. This is usually expanded to include a margin for microscopic extension forming the high-dose clinical target volume (CTV). The true CTV indicating the margin needed to cover microscopic extension not visible on clinical and imaging modalities is not known. Current RTOG guidelines specify an extension of 0.5 to 1 cm from the GTV to form the high-dose CTV. Nodal regions at risk for occult microscopic spread are usually included in a low-risk CTV. Many studies using clinical presentation data as well as elective surgical series have attempted to define the risk based on primary tumor site and extent of involvement as shown in Table 45.7. In general, this includes at least bilateral level II to IV. Typically, one nodal region beyond those pathologically involved is included—that is, for a patient with level II pathologic lymphadenopathy, level IB should be included. The inclusion of the retropharyngeal nodes routinely in the low-risk PTV is controversial as it often increases radiation dose to the pharyngeal constrictors, which has been associated with dysphagia89 and should depend on the extent of the primary tumor and cervical lymphadenopathy. The incidence of retropharyngeal lymphadenopathy is demonstrated in Tables 45.8 and 45.9. Coverage of the retropharyngeal nodes up to the base of skull is associated with a low risk of progression;90 however, absence of coverage is not necessarily associated with an increased risk of recurrence. Certainly, retropharyngeal coverage (i.e., extending the superior border of level II to include the retrostyloid space) should be considered for oropharyngeal tumors extending into the nasopharynx or pterygoid region, those with gross retropharyngeal nodal involvement, and those with high level II lymphadenopathy.26
Consensus guidelines for contouring the clinically node-negative neck have been published and endorsed by international head and neck cancer cooperative groups, including the RTOG, EORTC, Danish Head and Neck Cancer Group (DAHANCA), GORTEC, and NCIC.27 These guidelines are clinically useful aids for delineating specific nodal treatment volumes. Similar guidelines have been proposed for the node-positive neck and postoperative patients.26 Specific recommendations for node-positive patients include coverage of the supraclavicular fossa for patients with level IV or Vb lymphadenopathy and inclusion of the entire thickness of muscles invaded by pathologic lymphadenopathy in the CTV. Additionally, pathologic lymphadenopathy spanning adjacent levels should trigger inclusion of the full extent of both levels in the CTV. For postoperative patients, coverage of the entire operative bed in the neck is recommended to account for potential tumor spillage. Coverage of the retrostyloid space was recommended for all patients with pathologic level II lymphadenopathy. Similar to the nondissected node-positive neck, inclusion of muscles invaded by tumor is recommended, as is coverage of all levels spanned by pathologic lymphadenopathy.
CTVs are expanded to account for organ motion and setup uncertainty ideally based on institution-specific data to form the PTV. For oropharyngeal cancer patients, movement of the base of tongue should be considered (particularly with swallowing) when designing an appropriate PTV margin. The expansion from CTV to PTV should account for imaging methods used to assess daily setup. In general, if more frequent image guidance is performed, the margin needed for setup uncertainty should be less. The RTOG currently recommends 5 to 10 mm for patients treated with standard weekly megavoltage port films and 0.25 to 5 mm if more frequent kV image or cone-beam CT guidance is used. Representative contours for a patient with locoregionally advanced oropharyngeal cancer are shown in Figures 45.5, 45.6, and 45.7.
TABLE 45.7 INCIDENCE (%) OF PATHOLOGIC LYMPH NODE METASTASIS IN SQUAMOUS CELL CARCINOMAS OF THE OROPHARYNX
TABLE 45.8 INCIDENCE OF RETROPHARYNGEAL LYMPH NODES IN HEAD AND NECK PRIMARY TUMORS
TABLE 45.9 INCIDENCE OF PATHOLOGIC RETROPHARYNGEAL LYMPH NODE METASTASES IN HEAD AND NECK PRIMARY TUMORS
Indications for Ipsilateral Radiotherapy
For well-lateralized tonsillar cancer cases not involving the base of tongue and with minimal involvement of the soft palate (>1-cm margin between medial extent of tumor and midline), the CTV can be limited to the ipsilateral neck, which will significantly limit the exposure of the contralateral parotid, submandibular gland, and pharyngeal musculature.91 The ability to forgo treatment to the contralateral neck is based on the extremely low risk of occult contralateral neck lymph node involvement. Surgical series demonstrate that the risk of contralateral cervical lymph node involvement is owing to primary tumor size (more common in T3 and T4 tumors).92,93 Additionally, an analysis of tonsillar cancer patients, mostly T1-2 (79%) and N0-1 (88%), who underwent resection of the primary tumor often with ipsilateral lymph node dissection showed that only 5% of patients progressed in the contralateral neck.94 The low incidence of progression seen in early-stage tonsil cancers is likely owing to a lack of invasion of the soft palate and base of tongue, which have a richer lymphatic network and access to the contralateral nodes. Patients with contralateral cervical lymph node involvement usually have extensive involvement of ipsilateral cervical lymph nodes95 or tumors approaching or crossing the midline.
In properly selected tonsil cancer patients, ipsilateral-only radiotherapy results in low rates of contralateral neck progression. Large series of patients undergoing ipsilateral radiotherapy only demonstrated no contralateral neck progression in patients with T1 tumors and only 1% to 2% in those with T2 tumors. In the few patients with T3 tumors, contralateral nodal progression was 3% to 10%.96,97 Further analysis of these series shows that contralateral nodal progression was associated with both base of tongue and soft palate involvement (13%), T3 stage (10%), and involvement of the midline of the soft palate (16.5%). No contralateral nodal progression was seen in patients with N2b or higher neck disease, although there were not many patients with this presentation.
Studies evaluating the role of ipsilateral treatment in the context of concurrent chemoradiation are sparse. An analysis of tonsil cancer patients treated at MD Anderson Cancer Center from 1970 to 2007 included only three patients who received concurrent systemic therapy for N2b disease. In these patients, there was no contralateral neck progression.98 An analysis of 20 locoregionally advanced tonsillar cancer patients with N2b nodal disease, 18 of whom received concurrent chemoradiotherapy, demonstrated high rates of primary and nodal disease control along with a low risk of contralateral nodal progression. A caveat to this study is that all of these patients were staged with a PET scan, and most of these patients underwent surgery at the primary (80%) and/or at the neck (70%).99 There appears to be little progression in properly selected patients treated with ipsilateral-only radiotherapy; however, care should be taken to ensure that patients with more advanced tumors are not treated in this fashion.
FIGURE 45.5. Axial image of a patient with locoregionally advanced oropharyngeal cancer with gross tumor volume and planning treatment volumes.
FIGURE 45.6. Coronal image of a patient with locoregionally advanced oropharyngeal cancer with gross tumor volume and planning treatment volumes.
FIGURE 45.7. Sagittal image of a patient with locoregionally advanced oropharyngeal cancer with gross tumor volume and planning treatment volumes.
Ipsilateral External-Beam Radiotherapy Planning Techniques
Techniques for ipsilateral radiotherapy traditionally include a wedge pair or mixed photon electron field arrangement. The wedge pair technique includes ipsilateral anterior and posterior oblique fields with the head hyperextended to move the orbits out of the treatment field. Adequate sparing of normal tissue with this technique is achieved as the anterior beam spares the oral cavity and the contralateral parotid gland, although this usually contributes dose to the spinal cord. The posterior field aperture also spares the contralateral parotid, although this contributes dose to the spinal cord and oral cavity. With the wedge pair technique, hot spots are typically located peripherally near the surface and are between 110% and 115%. These hot spots can be reduced or eliminated if necessary with the addition of a lightly weighted (10%) third lateral field. The contralateral parotid dose is usually negligible at zero to 10%.
Alternatively, a combination of photons and electrons can be delivered through two ipsilateral fields. Traditional energies used 14 to 16 MeV electrons and 4 to 6 MV photons but should now be based on optimal 3D planning dosimetry. Bolus is often used to reduce dose to the temporal lobe. Often an off-cord reduction is used to limit the spinal cord to 45 Gy with low-energy electrons supplementing the region over the spinal cord. Recently, the use of IMRT for ipsilateral-only treatment has been increasing.
Bilateral External-Beam Radiotherapy Planning Techniques
Radiotherapy planning should be performed with 3D conformal radiotherapy or IMRT as available. Standard beam arrangements for 3D conformal radiotherapy are opposed lateral upper fields that are exactly matched to a low neck/supraclavicular field treated with either a single anterior or anterior-posterior–posterior-anterior (AP-PA) fields. Once spinal cord tolerance is reached, electron fields can be used to increase dose to gross disease as needed. Caution must be exercised to ensure that AP-PA and lateral fields do not overlap, causing an overdose to the spinal cord. Multiple techniques can be employed to prevent this complication.
Intensity-Modulated Radiotherapy
IMRT has been widely adopted for the treatment of head and neck cancers.100 Although hypothetical consideration of second cancers exists with IMRT,101 this technology has the ability to minimize normal organ exposure to radiation. This is particularly important for oropharyngeal cancer patients because pharyngeal constrictor dose and parotid dose are associated with dysphagia and xerostomia, respectively.102 In addition, IMRT has the potential to decrease acute dermatitis.103
Care should be taken during IMRT to minimize dose to the uninvolved larynx to limit radiation-related speech disorders. Different techniques are available to achieve this objective. The two most commonly used techniques are (a) using IMRT to cover the entire head and neck volume or (b) using an upper IMRT field matched to a low anterior neck field. Comparisons of these two techniques have demonstrated significantly reduced mean dose to the larynx and inferior pharyngeal constrictor with the use of a low anterior neck field matched to the IMRT field.104 Whole-field IMRT is preferable when gross disease is present, close to, or below the level of the larynx because coverage is better with this technique.105
Impact of Intensity-Modulated Radiotherapy on Xerostomia
The impact of IMRT on reduction of xerostomia in pharyngeal cancer patients (oropharynx or hypopharynx) was prospectively tested in a randomized trial.103 Patients with pharyngeal squamous cell carcinoma (either oropharynx or hypopharynx) not involving the parotid glands, with good performance status and without distant metastatic spread (T1-4 N0-3), were recommended to receive either definitive or adjuvant radiotherapy without concurrent chemotherapy and were randomized 1:1 to either conventional radiotherapy or IMRT. The primary end point was the proportion of patients with grade 2 or worse xerostomia at 12 months, assessed via the late effects of normal tissues (LENT SOMA) scale.103 Additionally, salivary flow was assessed prior to radiotherapy, during week 4 of radiotherapy, then 2, 3, 6, 12, 18, and 24 weeks after radiotherapy. Unstimulated and sodium citrate–stimulated parotid saliva from each parotid orifice and floor of mouth were also collected. Patient-reported quality of life was collected via the EORTC QLQC30 instrument and with the head and neck–specific instrument HN35. Patients could not receive prophylactic pilocarpine or amifostine. Radiotherapy dose was 65 Gy in 30 fractions for definitively treated patients or postoperative patients with macroscopic residual disease (2.17/fraction) or 60 Gy in 30 fractions (2 Gy/fraction) for postoperatively treated patients without macroscopic residual disease. Uninvolved nodal regions at risk for microscopic spread were treated to 50 Gy (2 Gy/fraction) in the conventional arm and 54 Gy (1.8 Gy/fraction) in the IMRT arm.
Six centers in the United Kingdom participated and recruited 94 patients (47 to each arm). Eighty-five percent of participants had oropharyngeal primary tumors. Eighty-one percent of patients in the IMRT arm were N0–1 compared to 53% in the conventional arm. This correlated with the statistical difference in stage with 83% of the conventional arm being stage 3 to 4 compared to 68% of the IMRT group. In addition, there were numerically more patients who received PORT in the conventional group (32% vs. 17%).
IMRT significantly reduced mean radiotherapy dose to the ipsilateral (47.6 Gy vs. 61 Gy) and contralateral (25.4 Gy vs. 61 Gy) parotid glands (p <0.0001). Median follow-up was 44 months. At each planned observation time point, a smaller proportion of IMRT patients reported grade 2 or worse LENT SOMA subjective xerostomia compared to conventional radiotherapy. At 12 months, only 38% of patients treated with IMRT had grade 2 or higher xerostomia compared to 74% in the conventional arm. These were independent of tumor site, radiotherapy indication, stage, and use of neoadjuvant chemotherapy. Additionally, both unstimulated (47% vs. 0%) and stimulated contralateral parotid saliva flow were increased in the IMRT group. Interestingly, grade 2 and higher fatigue was increased in the IMRT group (74% vs. 41%). Locoregional progression (IMRT 78%, conventional 80%, p = 0.34) and overall survival (IMRT 78%, conventional 76%) were similar between the two arms.
These findings in primarily oropharyngeal patients are consistent with those found in studies of nasopharyngeal patients. It is unclear if the benefit of salivary reduction seen with IMRT continues when pharmacologic agents to reduce xerostomia such as pilocarpine and amifostine are employed. Ongoing cooperative group trials recommend limiting the mean dose to the parotids as low as possible and be at least <26 Gy. Furthermore, the mean dose to the submandibular gland is recommended to be limited to 36 Gy (RTOG 1016).
Impact of Intensity-Modulated Radiation Therapy on Dysphagia
IMRT planning should take into consideration the risk of dysphagia. Many studies have attempted to correlate dosimetric parameters with functional swallowing consequences following radiotherapy or chemoradiotherapy. As highlighted in the studies that follow, radiation dose to the larynx and pharyngeal constrictors should be limited as reasonably as possible to reduce the risks of aspiration, feeding tube dependence, and stricture. Consensus on dosimetric parameters does not exist because the studies to date have all been retrospective, and their findings are not completely concordant.
Careful correlation of videofluoroscopic findings to radiotherapy dose to normal tissues has been performed in oropharyngeal cancer patients treated with chemoradiotherapy. Based on this analysis, the dose with a 25% or 50% risk (TD25 or TD50) of dysphagia to the pharyngeal constrictors was 56 and 63 Gy, respectively. Similarly, TD25 and TD50 were 39 Gy and 56 Gy for the glottis and supraglottic larynx.106 Mean dose to the esophagus was associated with the development of strictures. There were no threshold doses found in this analysis, thus it is reasonable to use the TD25 as a planning goal, and if not achieved, then trying to keep the dose to these structures as low as possible.
Others have analyzed radiotherapy doses to normal tissues and correlated to clinical outcomes the persistent use of percutaneous endoscopic gastrostomy (PEG) tubes, aspiration rates, and stricture rates.107 In this analysis, mean dose to the larynx and mean dose to the inferior pharyngeal constrictor predicted for persistent use of PEG tubes and aspiration. Additionally, the volume of larynx receiving 35 to 70 Gy (V35 to V70) and inferior pharyngeal constrictor V40 through V65 was associated with PEG tube dependence, and larynx V55 through V70 and inferior pharyngeal constrictor V60 and V65 were significantly associated with aspiration. Patients with a mean dose of approximately 50 Gy to the larynx and inferior constrictor all had PEG tubes removed by 12 months.
Concurrent Chemotherapy and Accelerated Radiotherapy
Two recently reported randomized studies showed that there was no benefit to accelerated radiotherapy over conventionally fractionated radiotherapy when delivered with concurrent platinum based chemotherapy.108 GORTEC 99–02 randomized locoregionally advanced head and neck cancer patients to either very accelerated radiotherapy at 64.8 Gy (1.8 Gy twice daily), 70 Gy (2 Gy daily over 7 weeks) with concurrent carboplatin 70 mg/m2 and 5-FU 600 mg/m2/day on days 1 through 4, days 22 through 25, and days 43 through 46, or 70 Gy (2 Gy daily to 40 Gy, then 1.5 Gy twice daily) with carboplatin 70 mg/m2 and 5-FU 600 mg/m2/day on days 1 through 4 and days 29 through 33. Outcome in both chemoradiotherapy arms was similar, and both were superior to very accelerated radiotherapy with lower rates of acute toxicity and percutaneous gastrostomy tube placement during therapy and at 5 years. Similarly, RTOG 0129 randomized patients to 72-Gy accelerated concomitant boost radiotherapy with two cycles of cisplatin 100 mg/m2 or to 70 Gy daily radiotherapy with three cycles of cisplatin 100 mg/m2. Again, there was no benefit to accelerated chemoradiotherapy seen in 3-year overall survival (accelerated 59% vs. conventional 56%), locoregional progression (31% vs. 29%), or worst grade 3 to 4 toxicity (26% vs. 21%). The value of acceleration via the use of a simultaneous integrated boost, a commonly used approach for IMRT delivery, must therefore be questioned when concurrent chemotherapy is being used as part of the treatment program.
Brachytherapy
Brachytherapy, the application of radioactive materials in close proximity to tumors, was developed in the pre-IMRT, preconcurrent chemoradiotherapy era as a means to deliver a tumoricidal dose to gross tumors while minimizing dose to the mandible. The advent of improved radiotherapy planning and delivery techniques, in addition to a recognition that osteoradionecrosis secondary to brachytherapy is significantly underreported, has corresponded to a major decrease in the utilization of brachytherapy for oropharyngeal tumors.
For oropharyngeal tumors, brachytherapy has historically played a role in boosting gross disease following external-beam therapy, as oropharyngeal tumors have a high propensity for occult nodal spread. Typically, catheters are implanted under general anesthesia in the operating room, with two capable physicians present to handle unexpected events, highlighting the fact that brachytherapy is an operator-dependent procedure. Although low dose rate brachytherapy has previously been the most common type of brachytherapy used, high dose rate (HDR) and pulsed dose rate (PDR) techniques are becoming much more common and sometimes preferred given the ability to control dwell times and develop more customized dose distributions. Given the historically poor locoregional control rates for tumors of the base of tongue, intensifying the treatment with brachytherapy makes logical sense. High rates of locoregional control have been achieved using an integrated treatment approach of external-beam radiotherapy directed at the primary and bilateral neck, followed by a brachytherapy boost.109 Complications of brachytherapy for base of tongue tumors include osteoradionecrosis of the mandible. The risk of complication appears to be related to the technique of implantation but may approach 30%. There is limited information regarding the use of brachytherapy and chemotherapy concurrently, which should be avoided.
When brachytherapy is planned following external-beam radiotherapy, care should be taken to delineate the pretreatment tumor extent because regression is not always uniform. Tattoos and gold seeds have been used to accomplish this. The CTV used is recommended by the European Society for Radiotherapy and Oncology (ESTRO) to be 5 mm at minimum and more commonly 1 to 1.5 cm for base of tongue tumors. The PTV is usually equal to the CTV as the implanted catheters move with the tumor. Catheters are typically positioned parallel and equidistant at 1 to 1.5 cm apart. Whereas traditional methods of calculating dose have been used in the past based on the Paris, Manchester, or New York systems, computer-derived brachytherapy plans are now routine.
Brachytherapy Guidelines
The American Brachytherapy Society (ABS) has published guidelines for the use of HDR brachytherapy for head and neck tumors and oropharyngeal tumors in particular. Prophylactic tracheostomy is recommended because posterior and large tumors are at risk to cause airway obstruction. Expert panel evidence, as well as single-institution series, recommend external-beam radiotherapy doses of 45 to 60 Gy followed by an HDR brachytherapy boost of 3 to 4 Gy per fraction for 6 to 10 doses with locoregional control of implanted tumors reaching 82% to 94%.110
The European Brachytherapy Group (GEC) and ESTRO have also published joint guidelines for the use of brachytherapy for head and neck malignancies. Similar to the ABS, these were based on consensus recommendations reflecting limited data.111 For oropharyngeal tumors, these guidelines recommend 45 to 50 Gy external-beam radiotherapy followed by 25 to 30 Gy boost for tonsillar tumors, and 30 to 35 Gy boost to base of tongue tumors. The total brachytherapy boost dose is fraction-size dependent: 21 to 30 Gy in 3-Gy fractions and 16 to 24 Gy in 4-Gy fractions. Quality of life analyses comparing a combined regimen of brachytherapy and external-beam radiotherapy to surgery and PORT favored a primary radiotherapy-only approach,112 suggesting that in experienced hands, this is a reasonable treatment method.
Hypofractionated Image-Guided Radiotherapy for Oropharyngeal Cancer
Hypofractionated image-guided radiotherapy techniques, commonly referred to has stereotactic body radiotherapy (SBRT), have resulted in promising outcomes for the treatment of early-stage lung cancers113 and limited metastases.35 Consequently, investigators are attempting to incorporate these techniques into the treatment of oropharyngeal cancer. To date, data are limited,114,115 and further investigations are needed to determine what role, if any, exists for this approach.
POSTTREATMENT MANAGEMENT AND SURVEILLANCE
Following definitive therapy for oropharyngeal cancer, patients should be seen regularly for clinical evaluation. Current guidelines suggest examination every 1 to 3 months for the first year posttherapy, every 2 to 4 months in the second year posttherapy, and every 4 to 6 months in the third through fifth years. The intensity of the examinations within the first 2 years coincides with the likelihood of recurrence in the interval. Given that radiation to the neck commonly causes hypothyroidism, thyroid-stimulating hormone levels should be evaluated every 6 months.
Following definitive radiotherapy or chemoradiotherapy, follow-up imaging should be performed within the first 3 months of treatment completion for patients with node-positive presentations. A radiographic complete response on CT imaging of the neck, defined as nonenhancing, nonnecrotic nodal tissue <1.5 cm, is associated with 100% long-term disease control in the neck, and no further therapy is needed.116 Surveillance CT imaging of the primary site does not add additional information to physical/fiberoptic examination and should not be routinely performed.117
PET/CT is more widely available and is often used as the sole imaging modality following the completion of radiotherapy. An analysis of 121 node-positive predominately oropharyngeal (74%) head and neck cancer patients, prospectively followed with PET/CT at around 12 weeks posttherapy and again 4 weeks later if there was residual activity, helped to clarify the role of PET/CT scan following chemoradiotherapy. With or without residual CT abnormalities in the neck, a negative PET scan at 12 weeks, defined as the absence of metabolic activity, was associated with no isolated nodal progression.118 Additionally, the negative predictive value of PET was 98.1% (95% CI 93.2% to 99.8%) compared to 96.8% in CT (95% CI 88.8% to 99.6%). However, more importantly, false-positive readings were seen in only 1.8% of PET scans compared to 38% of CT scans, resulting in a positive predictive value of 77.8% for PET/CT scan and 14% for CT. When the analysis was restricted to p16 positive patients, the results were similar with a negative predictive value of 98.2% (95% CI 90.4% to 100%) and 66.7% (95% CI 9.4% to 99.2%) for PET.
TREATMENT OF RECURRENT AND METASTATIC OROPHARYNGEAL CANCER
Systemic Therapy for Recurrent and Metastatic Oropharyngeal Cancer
The standard therapy for patients with recurrent or metastatic oropharyngeal cancer is systemic therapy with platinum-based chemotherapy. In phase II studies, many drugs in addition to platinum agents and methotrexate have shown single-agent activity, including paclitaxel,119 docetaxel,120 gemcitabine,121 ifosphamide,122 vinorelbine,123 pemetrexed,124 capecitabine,125 and irinotecan.126 Single-agent cisplatin (100 mg/m2) has been shown to improve overall survival compared to best supportive care.127 Cisplatin was also shown to be superior to single-agent methotrexate.128 Multiple randomized studies have attempted to improve survival with combination cisplatin-based regimens. The combination of cisplatin (100 mg/m2) with 5-FU (1,000 mg/m2/day) demonstrated improved response rates (32% vs. 17%) but not improved median survival (5.7 months) over cisplatin alone.129 Similar results were seen when the combination of cisplatin/5-FU, carboplatin/5-FU, and methotrexate alone were randomly compared. The combination of cisplatin and 5-FU was shown to have increased response rates compared to methotrexate (32% vs. 10%) as was carboplatin and 5-FU compared to methotrexate (21% vs. 10%); however, neither had improved median survival (6.6 and 5.6 months, respectively compared to 5.0 months) to methotrexate.130 Response rates and survival are similar with cisplatin and paclitaxel versus cisplatin/5-FU, which provides a regimen that is easier to administer.131 For oropharyngeal cancer specifically, a planned subset analysis of a phase III trial comparing cisplatin and pemetrexed to cisplatin and placebo demonstrated that oropharyngeal cancer patients receiving the combination regimen had improved survival (9.9 months vs. 6.1 months, p = 0.002) and improved progression-free survival (4 vs. 3.4 months, p = 0.047).132
The addition of agents targeted to the EGFR to platinum-based systemic therapy has been shown to improve overall survival compared to platinum agents alone in a phase III study with a large proportion of oropharyngeal cancer patients. The EXTREME study randomized recurrent and metastatic head and neck cancer patients to either cisplatin 100 mg/m2 day 1 or carboplatin area under the curve (AUC) = 5 day 1 combined with 5-FU 1,000 mg/m2/day 5-FU days 1 through 4 every 3 weeks, with or without cetuximab 250 mg/m2 following a loading dose of 400 mg/m2. Cetuximab was continued until disease progression or patient intolerance.133 Median overall survival was improved from 7.4 months with chemotherapy alone to 10.1 months with the combination of systemic therapy and cetuximab, as was median progression-free survival (3.3 months to 5.6 months). No phase III data have suggested a benefit for the addition of tyrosine kinase inhibitors including gefitinib or erlotinib to platinum-based therapy. Ongoing investigations are determining the role of bevacizumab and other targeted agents.
Reirradiation for Locoregionally Confined Recurrent or Second Primary Disease
For the subgroup of recurrent oropharyngeal cancer patients with locoregionally confined disease, surgical resection is recommended, although this is possible only in a small proportion of patients.134 Following surgery135 in those with high-risk pathologic features or in those who are not surgical candidates,136 a second course of full-dose radiotherapy with chemotherapy has been shown to result in long-term survival in approximately 20% of patients.136Patients who are able to undergo surgery prior to reirradiation as well as those who have not been exposed to prior chemotherapy and are treated to higher doses have improved outcomes. Because of the high risk of normal tissue toxicity including up to a 20% carotid rupture rate and 15% fatal toxicity, patients undergoing a second course of chemotherapy and radiation therapy should be managed at experienced centers. It is unknown if systemic therapy alone or chemotherapy and reirradiation is a better therapy for these patients, because a phase III comparison of these modalities failed to accrue. Therefore, treatment decisions will have to be individualized based on extent of disease, performance status, and preference.
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