Tobacco and Alcohol Use

Squamous cell carcinoma of the oropharynx most commonly affects patients older than 50 years, and men more than women. Despite this generalization, over the past 30 years oropharyngeal cancer rates have been on the rise in both men and women under the age of 45 years.⁷ Both alcohol and tobacco use are long-known, well-defined risk factors for squamous cell carcinomas of the head and neck, including those arising within the oropharynx. Again, separating data regarding oral cavity tumors and oropharyngeal tumors within published series can be challenging given reporting methods, and results may overstate the role of tobacco and alcohol use in oropharyngeal malignant diseases. The two substances individually and together contribute to a field cancerization effect within the upper aerodigestive tract. The effect of alcohol consumption and cigarette smoking on oropharyngeal cancer risk is reported to be dependent on both the intensity and duration of use and is responsible for approximately 80% of oropharyngeal cancers, with a higher proportion in men than in women in one series.⁹

A population-based study in Sweden compared 605 patients with head and neck cancer with 756 controls. A hazard ratio (HR) of 8.4 was seen with current smokers; this figure was increased by an earlier starting age, longer duration of smoking, greater lifetime total consumption, and increased intensity of daily tobacco use.¹⁰ Increasing alcohol intake, particularly more than 50 g per day, was also associated with an increased relative risk of head and neck cancer. A compilation of case-control studies places the tobacco-associated odds ratio at 2.13 for tobacco users when compared with never users, with the ratio doubling in persons who smoke more than 30 cigarettes per day or those who have smoked for more than 30 pack-years.¹¹ Involuntary or secondhand tobacco exposure may also be a risk factor, particularly when the person has been exposed for more than 15 years either at home or at work.¹² Alcohol use increases the rate of oropharyngeal carcinomas in never smokers, prior smokers, and current smokers, and the risk decreases with cessation of alcohol use.¹³ Although use of either alcohol or tobacco elevates the risk of oral cavity and oropharyngeal cancer, there is a synergistic effect from the use of both simultaneously. The risk is calculated to be thirteenfold the expected risk of each used independently, creating an approximately fiftyfold greater risk for oral cavity and oropharyngeal cancer compared with that of nonsmokers and nondrinkers.^13,14 Tobacco cessation decreased the risk of head and neck cancer by 40% in years 1 through 4, although the risk of head and neck cancers did not return to baseline until 20 years had elapsed after either tobacco or alcohol cessation.¹⁵

Human Papillomavirus Infection

Additional behavioral risk factors have been described besides the classic one of substance abuse, and they appear to be correlated with an elevated risk of oral human papillomavirus (HPV) infection. The role of HPV corresponds to an identified increase in head and neck cancer incidence seen in younger nonsmokers and nondrinkers. The increased incidence has been seen both in the United States and in European countries, despite the general trend of fewer head and neck cancers. This rise has been most marked among young patients in sites associated with HPV.⁷ HPV is a sexually transmitted disease recently recognized as a risk factor for squamous cell carcinoma of the head and neck, particularly in the oropharyngeal subsite, although the connection was initially suggested in 1983.¹⁶ HPV has been implicated in approximately 25% of head and neck cancers based on polymerase chain reaction (PCR) detection of HPV DNA. This prevalence seems to be site specific, with a significantly higher percentage of HPV-associated cancers in the oropharynx compared with the oral cavity or larynx.¹⁷ A prospective trial found the rate of HPV-positive tumors to be 60% in the oropharynx overall and even higher in the lingual or palatine tonsils.¹⁸ The increase in oropharyngeal cancers is not thought to be entirely attributable to the reduction in tonsillectomy frequency between the 1970s and the 1990s, because this trend would not be expected to alter the incidence of base of tongue primary tumors.¹⁹

The link between HPV and oropharyngeal cancers is severalfold and mimics the lines of evidence associating HPV and cervical cancer. First, HPV has been identified in tumor cells of head and neck squamous cell carcinomas.^16,20

The polymerase chain reaction has been frequently used for identification and subtyping of HPV, as has in situ hybridization via a signal amplification system. Identified prevalence rates have varied, depending on the tumor subsite, sensitivity of the HPV detection method, and geographic location, with associated ethnic variance.²

HPV-16 is the most common HPV subtype associated with oropharyngeal squamous cell carcinomas, seen in 85% to 90% of HPV-associated cancers.^17,20 The remainder are associated with HPV subtypes 18, 31, 33, and 35, which play a role in the development of cervical cancer. Second, HPV-positive squamous cell carcinomas of the head and neck have viral characteristics concordant with HPV-associated carcinogenesis, including a high viral load and viral oncoprotein expression.²¹ The oncogenic function of these HPV-associated oncoproteins ultimately accounts for the different molecular alterations found in HPV-positive tumors compared with HPV-negative tumors.

Additional evidence for an HPV association includes significant links in case-control studies between HPV seropositivity and squamous cell carcinomas of the head and neck. A case-control study comparing 100 patients diagnosed with oropharyngeal cancer and 200 controls found oropharyngeal cancer to be closely associated with oral HPV-16 infection (odds ratio, 14.6), oral infection with any of the HPV types (odds ratio, 12.3), and seropositivity for the HPV-16 L1 capsid protein (odds ratio, 32.2), strongly associating oral HPV with oropharyngeal cancer.²² Behavioral risk factors associated with oral HPV infection have also been correlated with an increased risk of oropharyngeal cancer. They include a high lifetime number of vaginal-sex partners and oral-sex partners.²² This correlation between HPV DNA in tumor specimens and lifetime sex partners has also been identified by others,²³ as has age at first intercourse and genital warts.²⁴

Patients with HPV-associated head and neck cancers also have an increased risk of anogenital cancers, of which cervical and anal cancers have been strongly associated with HPV infection, and vice versa.²⁵ Again, this supports the influence of sexual behavior and HPV infection on oropharyngeal cancer risk.

Patients with HPV-associated oropharyngeal cancers tend to have distinct clinical and pathologic features compared with those with HPV-negative cancers (Table 31-1). Besides the history of high-risk sexual behavior described above, patients with HPV-associated oropharyngeal cancers are more typically light users or nonusers of alcohol and tobacco,^26,27 although this lack of connection has not been universally identified.²⁴ Despite the apparent lack of association between HPV-associated oropharyngeal cancers and tobacco use, there is a correlation with marijuana use and its intensity and duration.²⁷ Individuals with HPV-positive squamous cell carcinoma of the head and neck tend to be younger by approximately 5 years compared with HPV-negative patients.²¹ Pathologically, HPV-positive cancers are more likely to be poorly differentiated with basaloid features.¹⁸

TABLE 31-1 Distinctive Clinicopathologic Characteristics for HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas

EGFR, endothelial growth factor receptor; HPV, human papillomavirus.

A meta-analysis of the prognostic impact of HPV in head and neck squamous cell carcinomas demonstrated that HPV-positive patients were likely to have improvements in rates of overall survival (OS) (HR, 0.85) and disease-free survival (DFS) (HR, 0.62). Similar improvements in OS and DFS were identified specifically within the oropharyngeal subsite.²⁸ Improved outcomes with HPV positivity were confirmed in an Eastern Cooperative Oncology Group (ECOG) phase II multicenter trial in which higher response rates were seen after induction chemotherapy and after chemoradiation treatment. This led to statistically improved OS and a lower risk of progression.¹⁸ See the Expert Consult website for more information on HPV subtyping, association with cancers, and cancer survival.

Analysis of the subset of patients with stage III or IV oropharyngeal cancer in Radiation Therapy Oncology Group (RTOG) study 0129 found HPV status to be the major determinant of overall survival (OS), followed by duration of tobacco use and tumor stage.²⁹ Locoregional recurrences were reduced at 3 years (13.6% vs. 35.1%) in HPV-positive tumors, and OS was 82.4% versus 57.1%. Although the bulk of the survival difference was attributable to HPV positivity, favorable prognostic features associated with the HPV-positive subgroup accounted for approximately 10% of the outcome difference.

HPV-positive patients also have a lower risk of second malignant tumors because such patients lack the field cancerization effect produced by alcohol and tobacco exposure.29,30 Given the different clinical, pathologic, and molecular characteristics, as well as the improved prognosis and treatment response, it has been proposed that HPV-positive squamous cell carcinomas of the oropharynx and elsewhere should be considered distinct disease entities from HPV-negative tumors.^21,29

Other Risk Factors

Numerous other potential risk factors have been described for oropharyngeal cancer and head and neck cancer in general. A family history of head and neck cancer produces an odds ratio risk increase of 1.7, although this is only seen in subjects exposed to tobacco, suggesting that this factor may represent an environmental as much as a genetic influence.³¹ Diets low in raw vegetables and citrus and noncitrus fruits have increased the oral cancer risk in a majority of studies.¹⁹ These results seem to hold true even when studies have been controlled for alcohol and tobacco usage, although the effect on diet and nutritional deficiencies from heavy alcohol and tobacco abuse is substantial and such factors can be difficult to account for in case-control studies.

Nutritional deficiencies, as signified by a body mass index decline before diagnosis, have also been associated with oral cancer risk. This was again seen primarily among individuals with active or prior alcohol and tobacco use. Poor oral hygiene, as measured by surrogates such as tooth loss and infrequent dental visits, also correlates with an elevated rate of oral and oropharyngeal carcinomas.³² In short, the family history, diet, nutritional status, and oral hygiene may all play a role in oropharyngeal carcinoma predisposition, but defining the impact of each of these in the setting of the more dominant risk factors of alcohol and tobacco use is challenging, particularly given the potential interplay between such factors.

Prevention and Early Detection

Classic prevention for squamous cell carcinoma of the oropharynx, and head and neck cancer in general, has revolved around tobacco cessation and bringing alcohol use to more moderate levels. With the impact of HPV now better understood, ongoing HPV vaccination campaigns to lower the incidence of cervical cancer may simultaneously reduce HPV-related head and neck cancers. Two vaccines are currently available for HPV: one against HPV types 16 and 18, Cervarix (GlaxoSmithKline), and a quadrivalent vaccine against HPV types 16, 18, 6, and 11, Gardasil (Merck). Both vaccines have been advised for women between the ages of 13 and 26 years because they lead to a reduction in precancerous cervical lesions and cancer incidence related to HPV.^33,34 Vaccine efficacy in nongynecologic cancers remains to be assessed, but there is optimism that a similar reduction in HPV-associated cancers will be seen in these sites, including the oropharynx.²⁷

Routine examinations of the oral cavity and proximal oropharynx should be part of a standard medical history and physical and dental examination. Routine oral examinations in high-risk patients have the potential to reduce cancer-related deaths through the discovery of premalignant and early-stage malignant changes. Unfortunately, the same substance abuse conditions that predispose individuals to head and neck cancer correlate with underuse of health and dental services,³² often leading to late detection and diagnosis of head and neck cancers. Radiation oncologists can play a role in the early detection of secondary oral cavity and oropharyngeal cancers attributable to field cancerization in patients who have been treated for primary head and neck cancers and are undergoing follow-up in the radiation oncology clinic.

Potentially malignant lesions include erythroplakia, leukoplakia, erythroleukoplakia, oral submucous fibrosis, and lichen planus. Leukoplakia and erythroplakia are Greek terms translated as “white plaque” and “red plaque,” respectively. Leukoplakia is an exclusionary diagnosis and is currently defined as “a white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer.”³⁵ The worldwide prevalence of leukoplakia is estimated at approximately 2% of the general population,³⁶ with the highest incidence in men from the fifth through the seventh decades; histologic findings show hyperplasia of the squamous epithelium. Most leukoplakia lesions do not progress to squamous cell carcinoma; the annual transformation rate is estimated at 1%.³⁷ This rate is strongly dependent on the presence and severity of dysplasia.³⁸ Dysplasia, carcinoma in situ, or carcinoma is frequently present within erythroplakia, which has only one-sixth of the prevalence of leukoplakia. Of the premalignant lesions, transformation to malignancy is highest in erythroplakia, particularly when dysplastic changes are present, with an annual transformation rate of at least 2.9%.³⁹ Others have predicted that the vast majority of erythroplakias will ultimately undergo malignant transformation.³⁷

Multiple chemopreventive regimens have been evaluated to prevent progression of dysplasia within the upper aerodigestive tract. At least one randomized study demonstrated a decreased rate of biopsy-proven dysplasia after the administration of isotretinoin.⁴⁰ However, the toxicity was significant, with almost half of patients requiring dose reduction. In addition, most responders relapsed within the first 3 months after treatment. Larger randomized trials found no reduction in the rate of second primary tumors with isotretinoin.^41–43

Currently, no chemopreventive strategies have been validated or are widely in use for high-risk patients, including those with known dysplasia. Clinical trials continue to search for effective treatment approaches. Close follow-up with biopsy and surgical excision or laser therapy as indicated remains mandatory for patients with premalignant lesions.

Pathologic Findings

Primary oropharyngeal tumors are almost exclusively squamous cell carcinomas (SCC) (≈95% of tumors). Alternative pathologic types include melanoma (web-only Fig. 31-1), primary lymphoid malignant tumors (web-only Fig. 31-2), minor salivary gland tumors, sarcomas, and other oddities. Given the preponderance of SCC in this site, this chapter will refer to the evaluation and treatment of SCC unless another type is specifically indicated.

Web-Only Figure 31-1 Hyperpigmented mass arising from the right tonsillar fossa pathologically confirmed as a mucosal melanoma.

Web-Only Figure 31-2 Large, protuberant, lobulated mass arising from the left tonsillar fossa displacing the uvula contralaterally and occupying the majority of the oropharyngeal lumen, identified as a diffuse large B-cell lymphoma. The tumor was treated with three cycles of CHOP followed by 36 Gy of involved-field radiation. The patient remains disease free 15 years from the time of treatment.

A substantial amount of literature has been generated evaluating the histologic subtypes of SCC of the head and neck, the appropriate nomenclature for these tumors, and their clinical impact. Specific subtypes include the spindle cell variant characterized by noncohesive spindle cells, which closely resembles sarcoma microscopically. The basaloid squamous variant is a distinct subtype traditionally correlated with aggressive behavior and poor patient outcomes.⁴⁸ However, the recent correlation of HPV-associated malignant disease with the basaloid subtype has shown that the basaloid group is a mixture of both HPV-16-positive and HPV-16-negative carcinomas. Because the HPV status imparts a substantially favorable influence on outcome, the implication is that the basaloid phenotype alone does not confer a worse clinical outcome.⁴⁹ Angiolymphatic invasion and perineural invasion are both associated with increased rates of cervical nodal metastases and a worse prognosis.⁵⁰

The prototypical SCC of the head and neck, including the oropharynx, is moderately differentiated, with approximately 60% moderately differentiated, 20% well differentiated, and 20% poorly differentiated. Some studies have found tumor grade to be predictive of regional nodal metastasis and, subsequently, clinical outcome. The determination of tumor grade based on traditional cytologic and histologic features of differentiation is challenging to reproduce because of interobserver variability. As a result, the tumor grade seems to have limited prognostic value, particularly when compared with the clinical staging parameters.⁵⁰ Undifferentiated carcinomas with a lymphoid stroma arising from the tonsil have biologic behavioral characteristics and an increased radiosensitivity that are more similar to undifferentiated nonkeratinizing nasopharyngeal carcinomas rather than conventional types of SCC.⁵¹

Pathways of Spread

The oropharynx makes up the central portion of the upper aerodigestive tract, encompassing the tongue base, palatine (faucial) tonsils, inferior aspect of the soft palate, and posterior and lateral oropharyngeal walls⁵² (see Fig. 31-1 and Figs. 31-2 and 31-3). The anterior margins are the anterior tonsillar pillars, the hard-soft palate junction, and the circumvallate papillae of the tongue, placing the posterior third of the tongue within the oropharynx. Superiorly, the oropharynx is bounded by the inferior aspect of the soft palate, posteroinferiorly by the pharyngoepiglottic folds that lie approximately at the level of the hyoid bone, and inferiorly by the glossoepiglottic fold and vallecula. The lateral and posterior borders of the oropharynx are defined by the pharyngeal constrictor muscles and their overlying mucosa. Understanding the anatomy of the oropharynx is necessary when identifying the typical pathways of spread by oropharyngeal neoplasms.^53–55

Figure 31-2 Normal CT scans of the oropharynx: sagittal (A) and axial (B and C) scans.

Figure 31-3 Normal MRI of the oropharynx: sagittal T1-weighted (A), axial T1-weighted (B), and axial T2-weighted (C) scans.

Soft Palate

The soft palate is a mobile flap of soft tissue with a central aponeurosis that serves as the attachment point for several palatine muscles. Five muscles form the bulk of the posterior and lateral portions of the soft palate. These muscles (levator veli palatini and tensor veli palatini muscles, muscle of the uvula, palatoglossus muscle, and palatopharyngeal muscle) insert on the palatine aponeurosis but have important attachments to the tongue base, posterolateral pharyngeal wall, and torus tubarius. The palatoglossus muscle and overlying mucosa form the anterior tonsillar pillar, which is the anteriormost part of the lateral oropharynx. The palatopharyngeal muscle, with its overlying mucosa, forms the posterior tonsillar pillar. The two pillars connect laterally and inferiorly with the lateral oropharyngeal wall.

The inferior aspect of the soft palate, which forms the upper portion of the oropharynx, is the site of the majority of soft palate tumors. The superior surface of the soft palate, part of the nasopharynx, is seldom a primary site of neoplasm. The soft palate also contains a substantial number of minor salivary glands. These glands are the site of origin for nonsquamous neoplasms of the soft palate (i.e., pleomorphic adenoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, acinic cell carcinoma, malignant mixed tumors, and adenocarcinoma).

A soft palate tumor can spread anteriorly to involve the hard palate. There is also potential for perineural spread along the greater and lesser palatine branches of the maxillary nerve superiorly into the pterygopalatine fossa^56,57 (Fig. 31-4). Further perineural spread from the pterygopalatine fossa can result in extension along branches of the maxillary division of the trigeminal nerve into the orbit via the inferior orbital fissure, into the central skull base via the foramen rotundum, and into the facial nerve and temporal bone via the nerve of the pterygoid canal (vidian nerve). This perineural spread can result in palsies of both the trigeminal and facial nerves. Patients with advanced disease and perineural spread may present with trismus resulting from involvement of the pterygoid muscles or branches of the trigeminal nerve.

Figure 31-4 T4bN2c soft palate squamous cell carcinoma: Axial (A and B) contrast-enhanced CT scans demonstrate a large enhancing mass of the soft palate (black arrows) with erosion of the hard palate. There is upward spread of mass along the lateral nasopharynx wall as well as upward perineural tumor spread via the greater palatine foramen into the pterygopalatine fossa (open arrows). The CT and PET/CT (C) images demonstrate N2c nodal metastasis involving levels Ia, Ib (curved black arrow), IIa (dashed black arrows), and IIb (dashed white arrow).

Tonsillar Region

The palatine (faucial) tonsils consist of lymphoid tissue constrained within a fibrous capsule that projects into the oropharynx between the triangle formed by the anterior and posterior tonsillar pillars. The tonsillar fossa is bounded laterally by the superior pharyngeal constrictor muscle. The anterior and posterior tonsillar pillars consist of the mucosa overlying the palatoglossus and palatopharyngeal muscles, respectively. Squamous cell carcinoma is the most frequent neoplasm of the palatine tonsils, followed distantly by non-Hodgkin’s lymphoma. Tumors within the tonsillar region can spread superiorly to the soft palate along the vertically oriented palatoglossus and palatopharyngeal muscles, as well as inferiorly to the tongue base and posterolaterally to the oropharyngeal wall⁵⁸ (Figs. 31-4 and 31-5).

Figure 31-5 T4aN2c squamous cell carcinoma of tonsil and soft palate: Sagittal (A), and axial (B and C) contrast-enhanced CT scans demonstrate a large enhancing mass of the palatine tonsil and soft palate (white arrows). There is invasion of the medial pterygoid muscle (MP) indicating a T4a lesion. There are bilateral enlarged and abnormally enhancing level Ib and IIa lymph nodes (black arrows) as well as an abnormal right level IIb node consistent with N2c nodal spread. An abnormal heterogeneously enhancing right lateral retropharyngeal lymph node is identified (dashed black arrow) with extracapsular spread into the parapharyngeal space (open arrows).

The superior pharyngeal constrictor muscle, in addition to forming the posterior and lateral borders of the oropharynx, courses deep to the palatine tonsils as it extends anteriorly to insert on the pterygomandibular raphe.⁵² This fibrous raphe is a shared insertion site with the buccinator muscle, with the raphe extending to the medial pterygoid plates superiorly and the lingual cortex of the mandible inferiorly just posterior to the mylohyoid line. Tonsillar neoplasms that invade the superior pharyngeal constrictor muscle and involve the pterygomandibular raphe, therefore, can spread anteriorly to the buccinator muscle and space, superiorly to the medial pterygoid plate and masticator space, and inferiorly to the lingual cortex of the mandible. Lateral extension of tumor allows its entry into the parapharyngeal space (Fig. 31-6). Involvement of the parapharyngeal space by tonsillar neoplasms may result in spread to and along the styloglossus and stylopharyngeal muscles, which extend superiorly toward the skull base and attach to the styloid process. Lateral extension into the medial pterygoid muscle is often associated with involvement of the mandibular division (V3) of the trigeminal nerve. Involvement of V3 can allow perineural tumor spread inferiorly into the mandible along the inferior alveolar nerve and superiorly along the main trunk of V3 to the foramen ovale and cavernous sinus.⁵⁷

Figure 31-6 T4bN2b tonsillar squamous cell carcinoma: Axial T1-weighted (A), coronal T1-weighted (B), and axial T2-weighted (C) non-contrast-enhanced MRI images demonstrate an extensive right tonsillar and posterior oropharyngeal wall neoplasm. The lesion extends across the glossotonsillar sulcus (dashed white arrow) into the oral tongue and sublingual space (SL). There is invasion of the intrinsic tongue musculature (I) as well as the hyoglossus (H) and genioglossus (G) muscles. The lesion infiltrates the superior pharyngeal constrictor muscle (dashed black arrows) to involve the parapharyngeal space (P) and medial pterygoid (MP) muscle. The lesion invades the prevertebral space (open white arrow). There is inferior spread into the supraglottic larynx (open black arrow). Several enlarged right level IIb lymph nodes are seen (black arrows). These findings are consistent with a stage of T4bN2b.

Tongue Base

The tongue base is separated from the oral tongue anteriorly by the circumvallate papillae. It extends posteriorly and inferiorly to terminate near the level of the hyoid bone (see Figs. 31-2 and 31-3). Laterally, it is separated from the palatine tonsils by the glossotonsillar sulcus. The lingual tonsils lie along the posterior surface of the tongue base. The lingual tonsils are variable in size and may be quite large in the first two decades of life and in patients with concurrent head and neck infections.

Neoplasms of the tongue base spread along several pathways as they increase in size. They may infiltrate along the intrinsic muscles of the tongue into the oral tongue and deep tongue musculature. It is especially important to identify involvement of the extrinsic muscles of the tongue (i.e., the hyoglossus, styloglossus, and genioglossus muscles) because this indicates a T4 lesion.⁶¹ Tumor may track superolaterally along the mylohyoid muscle to invade the lingual surface of the mandible.⁶² Deep anterior extension may also involve the hypoglossal or lingual neurovascular bundles. Tumor can track posteriorly along these nerves between the superior and middle pharyngeal constrictor muscles into the parapharyngeal and masticator spaces.

Base of tongue cancer can also spread superficially along the mucosa. Posteroinferior extension can involve the vallecula, lingual surface of the epiglottis, and pharyngoepiglottic folds (Fig. 31-7). There may be invasion of the pre-epiglottic space whenever the vallecula or glossoepiglottic folds are involved.

Figure 31-7 T2N2c base of tongue squamous cell carcinoma: Sagittal (A) and axial (B) views. A 2.2-cm enhancing neoplasm of the tongue base (open arrows) indicating a T2 primary. The lesion extends into the vallecula (dashed white arrow) but does not invade the adjacent genioglossus muscle (dashed black arrow). There are abnormal heterogeneously enhancing bilateral level IIa and right level IIb lymph nodes (black arrows) consistent with N2c nodal spread.

Nodal Involvement

Nodal metastasis has been reported in 40% to 66% of patients presenting with soft palate carcinoma.^63,64 Level II nodal involvement is most frequent, with extension into level III and IV nodes commonly seen. Level I, level V, and lateral retropharyngeal nodal involvement is uncommon.⁶⁵ Lymph node metastasis from squamous cell cancer of the palatine tonsils is very common (69% to 74%) at the time of presentation.^64,66 The incidence of nodal involvement at diagnosis in patients diagnosed with tongue base carcinoma has been reported to be between 64% and 78%.^63,64 Bilateral nodal disease is commonplace with base of tongue cancer, especially in patients with tumors near or crossing the midline. Both tonsillar and base of tongue primary tumors can drain to retropharyngeal nodes, with implications for radiation treatment design. The incidence of nodal involvement in patients with oropharyngeal wall squamous carcinomas has been reported to be between 57% and 60%^64,67 (see web-only Figs. 31-3 to 31-5).

Web-Only Figure 31-3 Distribution of positive nodes in patients with squamous cell carcinoma of the base of the tongue on presentation to the M.D. Anderson Cancer Center, 1948 to 1965.

Data from Lindberg RD: Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 29:1446, 1972, with permission.

Web-Only Figure 31-4 Distribution of positive nodes in patients with squamous cell carcinoma of the tonsil on presentation to the M.D. Anderson Cancer Center, 1968 to 1979.

Data from Remmler D, Medina JE, Byers RM, et al: Treatment of choice for squamous carcinoma of the tonsillar fossa. Head Neck Surg 7:206-211, 1985.

Web-Only Figure 31-5 Distribution of positive nodes in patients with squamous carcinoma of the soft palate on presentation to the M.D. Anderson Cancer Center, 1948 to 1965.

Data from Lindberg RD: Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 29:1446, 1972, with permission.

Patient Evaluation

A comprehensive history with an emphasis on head and neck–related symptoms should be taken for all patients, and a detailed physical examination of the head and neck region should be performed (Table 31-2). The examination should include a direct inspection of the oral cavity and proximal oropharynx; an indirect (mirror) examination of the distal oropharynx, hypopharynx, nasopharynx, and larynx; careful palpation of the oral cavity and proximal oropharynx; and inspection of the cervical lymph nodes (Fig. 31-8). Relaxing the sternocleidomastoid muscle by tilting the head slightly to the ipsilateral side allows easier palpation of the jugulodigastric nodes. Flexible fiberoptic nasopharyngoscopy is used as indicated by examination findings and the quality of the indirect examination.

TABLE 31-2 Diagnostic Evaluation for Oropharyngeal Cancer

Selection of Imaging Studies

Recommended radiographic studies include CT or MRI scanning of the neck with contrast enhancement, chest imaging, and panoramic studies as indicated.⁶⁹ CT is generally considered to be the examination of choice for the initial diagnostic evaluation of oropharyngeal neoplasms when compared with MRI and PET imaging.^70,71,72 The benefits of CT include lower cost, faster acquisition speed, less motion artifact, better detection of bone invasion, higher spatial resolution, greater reproducibility on sequential examinations, and wide availability. MRI is superior to CT in specific situations, including delineating orbital or skull base involvement and defining intracranial perineural tumor spread. MRI also has slightly superior multiplanar imaging capabilities and is better able to identify subtle soft tissue involvement by tumor, deep osseous invasion and marrow replacement, perineural spread of disease, and extent of anterior spread of tongue base tumors. MRI is also useful for patients in whom dental amalgam artifact renders the CT examination suboptimal. MRI and PET/CT are used in most institutions as ancillary diagnostic studies for oropharyngeal cancers when CT imaging inadequately addresses specific clinical questions. Imaging modalities are often complementary, however, and both CT and MRI are useful in some instances. PET/CT studies can provide additive information relative to the extent of the primary tumor, nodal involvement, and metastatic disease.

Imaging is indispensable for assessing regional lymphatic spread.⁷³ This is particularly true in patients in whom clinical assessment of nodal disease is difficult (because of a large or muscular neck), in whom there is occult involvement of normal-sized nodes, or in whom nodal chains are involved that cannot be palpated on physical examination (i.e., retropharyngeal nodes). Multiple criteria must be used to determine whether a specific lymph node is involved by tumor on CT or MRI studies. These criteria include the node’s size, homogeneity, distinctness of outer margin, focal areas of enhancement, location, loss of fatty hilum, and spherical shape and the presence of a clustering of lymph nodes. These criteria are best used as a whole and not considered in isolation. When imaging tests have been directly compared in the same patient population, PET and PET/CT studies have typically been found to be slightly more accurate in lymph node staging, followed by CT scanning and then by MRI.^74,75 See the Expert Consult website for further information on lymph node staging.

There is varied opinion regarding size criteria and how to best measure lymph nodes in order label them as radiographically involved. Measurements of 10 mm in the long axis and 8 mm in the short axis are often used as the upper limits of normal for nodes in most cervical levels. Upper level II nodes (jugulodigastric nodes) and level Ib nodes, however, may normally be slightly larger (12 to 15 mm). Lateral retropharyngeal nodes are considered abnormal if larger than 8 mm. Very young patients, those with severe dental disease, or those with concomitant head and neck infection may have reactive lymph nodes that are larger than the stated norm. Lymph node size should be considered as only one diagnostic criterion and must be modified in certain circumstances. One should specifically look for focal enhancement of a lymph node along its outer aspect where the afferent lymphatics enter the node. This is often the earliest evidence of lymphadenopathy and may even be seen in patients with normal-sized nodes. Assessment of lymphadenopathy on MRI scans can be more challenging than on CT scans.^70,72 In addition to the aforementioned criteria, one should look for areas of decreased signal intensity on T2-weighted images, which typically represent intranodal tumoral deposits. Meta-analysis suggests that the mean sensitivity of a neck CT scan for the detection of cervical lymph node metastasis is 81% (95% CI, 68% to 90%), of an MRI scan is 81% (95% CI, 65% to 91%), and of a PET scan is 79% (95% CI, 72% to 85%). The specificity of CT scanning has been found to be 76% (95% CI, 62% to 87%); of MRI scanning, 63% (95% CI, 43% to 80%); and of PET scanning, 86% (95% CI, 83% to 89%).^72,74 The quoted sensitivity and specificity for these studies depends greatly on the criteria that are used in declaring a lymph node positive. When imaging tests have been directly compared in the same patient population, PET and PET/CT studies have typically been found to be slightly more accurate in lymph node staging, followed by CT scanning and then by MRI.⁷⁴

PET/CT and PET can serve a complementary role in the imaging evaluation of oropharyngeal primary tumors. Besides the slightly improved accuracy for nodal disease, PET/CT is particularly useful in evaluating for a primary site in patients with cervical nodal disease but an unidentified primary site. An oropharyngeal origin remains the most likely source of an occult primary tumor in patients with level II or III lymph node involvement. PET/CT scanning can also identify synchronous second primary tumors in patients with oropharyngeal squamous cell carcinomas.⁷⁶ A PET/CT scan can also be used to screen for metastatic disease and excels at identifying atypical metastases outside of the standard metastatic search pattern, although metastatic spread at presentation is rare. The performance of PET/CT scanning can be improved with a dedicated head and neck protocol, which can also be incorporated into treatment planning. Although PET/CT in particular may have value in oropharyngeal cancer workup and staging, overuse of this expensive resource remains a persistent concern as more standard imaging modalities typically supply equivalent diagnostic information.

Limitations of imaging should also be acknowledged. CT and MRI have limited sensitivity for the detection of superficial mucosal disease, again emphasizing the necessity of a detailed head and neck examination. Also, dental amalgam artifact can limit visualization of the structures of interest, more so for CT than MRI. Motion artifact may degrade the image quality; this is particularly a problem with MRI, where images may be acquired over a several-minute time span. CT, MRI, and even physical examination are known to have limited sensitivity and specificity for the detection of small metastatic deposits within normal-sized lymph nodes. PET scans may be falsely negative in histologically low grade lesions and in lesions that are less than 5 mm in size and falsely positive when inflammatory changes are present, particularly postoperatively or in the setting of poor dentition.

The overall incidence of pulmonary metastases has traditionally been placed at 1% to 2% in newly diagnosed patients with cancers of the head and neck. The standard practice is to obtain a chest radiograph to evaluate for pulmonary disease, but chest CTs allow better definition of the thoracic cavity and have a higher sensitivity for detection of pulmonary parenchymal metastases or mediastinal or hilar nodal disease. A review of the literature found a pooled prevalence of 7.9% for abnormalities on chest CT scans in patients with head and neck squamous cell carcinoma.⁷⁷ Abnormal findings were more prevalent in patients with N2 or N3 nodal involvement or stage III or IV disease and less prevalent for oral cavity primary tumors. Not surprisingly, patients with recurrent disease had higher rates of positive chest CT scans (25.3%). These risk factors correlated closely with the clinical factors statistically associated with the development of distant metastases (T stage, N stage, gender, nodal level, and locoregional control).⁷⁸ Although there is significant institutional variation regarding chest imaging, a measured approach would include chest CT scans for patients with advanced nodal involvement (N2b, N2c, and N3), locally advanced primary disease (T3 and T4), low cervical nodes, and other risk factors, including recurrent disease. A CT scan of the chest can be performed at the same time as the neck CT scan, and modern multislice scanners can provide contrast-enhanced images with the same contrast bolus.

Imaging Technique

The Expert Consult website contains information on imaging technique.

The development of multiple detector-row CT (MDCT) scanning in conjunction with helical acquisition techniques over the last decade has revolutionized the cross-sectional imaging of patients with head and neck cancer. The ability to simultaneously obtain axial image information from 64 to 256 rows of detectors allows rapid scanning of patients with almost no motion artifact. The multiple rows of detectors can simultaneously produce 64 to 256 images, each with a slice thickness of 0.5 to 0.625 mm. This enables acquisition of a three-dimensional volume of image data that can be processed into images of varying slice thicknesses generated in sagittal, coronal, or oblique imaging planes. These two-dimensional re-formations offer improved visualization of the three-dimensional extent of the primary neoplasm and involved cervical lymph nodes.

Because of the possibility that lower cervical and upper mediastinal nodes may be involved by tumor, it is important to start the CT acquisition just below the aortic arch at the level of the aortopulmonary window. The scans should extend superiorly to the level of the cavernous sinus and skull base foramina in order to detect perineural tumor spread along cranial nerve branches, invasion of the masticator and parapharyngeal spaces, and skull base invasion. Non–contrast-enhanced scans are rarely beneficial and do not need to be routinely obtained. Sufficient time must be allowed for the injected contrast material to enhance the primary tumor and lymph nodes before scanning begins. As a result, a scanner-specific time delay must be inserted between the start of the contrast injection and the initiation of the CT scan in order to obtain maximal enhancement, with the goal of providing differentiating tissue enhancement rather than vascular opacification. Tight compact bolus injection of the contrast medium (3 to 4 mL per second) offers superior enhancement of lesions. Bone and soft tissue reconstruction algorithms should both be obtained for maximal diagnostic information.

MRI protocols should be constructed in a similar manner to cover the region from the skull base and cavernous sinuses to the aortic arch. It is particularly important to obtain both high-quality non–contrast-enhanced T1- and T2-weighted images because these are often more helpful than contrast-enhanced images at defining the extent of the primary neoplasm and assessing nodal disease.21,22,23–27 Post-contrast-enhanced T1-weighted images obtained with fat suppression are helpful for identifying perineural tumor spread, skull base invasion, and deep spread to the masticator and parapharyngeal spaces, as well as for detecting intranodal tumor deposits. Because of the extensive pterygoid plexus of veins in the masticator space and normal enhancement of mucosal areas of the head and neck, contrast-enhanced scans are often challenging to interpret. These images must be carefully compared with non–contrast-enhanced images in the same plane.

General Principles of Treatment

The primary goal of treatment is to maximize the chance for cancer cure while minimizing functional impairment and treatment-related morbidities. Selection of the treatment modality depends on the tumor stage, extent of nodal involvement, oropharyngeal subsite, and skill set of the healthcare team. As a whole, the effectiveness of irradiation and the potential functional compromise from large surgical resections has historically made the oropharynx the realm of the radiation oncologist. Given the dominant role of radiotherapy in the treatment of oropharyngeal tumors, a substantial body of work has accumulated in an effort to optimize local control through altered treatment schedules such as accelerated fractionation, hyperfractionation, and accelerated hyperfractionation. The addition of concurrent chemotherapy over the past 15 years has also improved rates of locoregional control and overall survival (OS), although at the expense of increased acute and late toxicities. Intensity-modulated radiation therapy (IMRT) provides local control rates similar to those of conventional irradiation while limiting potential acute and late toxicities through dosimetric avoidance of critical structures.

To date, only a single randomized trial evaluating primary surgery versus radiation therapy has been conducted for primary oropharyngeal squamous cell carcinomas (RTOG 73-03).⁷⁹ Seventy patients were randomized to definitive radiotherapy, preoperative radiotherapy followed by surgery, or surgery followed by radiotherapy. No significant difference was identified in rates of either OS or local control, although the study was grossly underpowered.

A similar study evaluating 119 patients with locally advanced head and neck cancers, including oropharyngeal cancers, demonstrated no difference in DFS or OS between surgery followed by adjuvant radiation versus adjuvant concurrent chemoradiation.⁸⁰ Improved organ preservation was observed in patients randomized to chemoradiation.

Because of the lack of large randomized studies, the bulk of the data guiding modality selection come from published retrospective single-institution experiences. The heterogeneity of tumors within the oropharynx given the multiple combinations of primary and nodal stages also makes broad treatment recommendations difficult.

Early-stage oropharyngeal carcinomas (T1 to T2, N0 to N1) can be treated with either irradiation or surgery, with the addition of adjuvant irradiation as indicated by surgical pathologic findings. Surgery and radiation therapy provide similar local and regional control rates.⁸¹ Treatment selection is consequently based on the anticipated modality-specific functional and cosmetic outcome as well as the most appropriate treatment for lymph nodes at risk. Well-lateralized tumors, particularly of the tonsillar complex, can be treated with unilateral irradiation and resultantly have a more favorable toxicity profile. Irradiation is typically used for early-stage oropharyngeal tumors based on excellent local control rates and acceptable morbidity; a higher rate of severe complications has been identified with surgery, particularly in older series. However, minimally invasive surgery with robotics or transoral laser microsurgery is being increasingly investigated at select institutions.

Intermediate-stage carcinomas (large T2 lesions, nonextensive T3 lesions, with or without advanced nodal disease) are preferentially treated by primary irradiation with or without chemotherapy because most patients undergoing surgical resection ultimately receive postoperative radiation therapy for the presence of multiple positive nodes, extranodal extension, or close resection margins. In this setting, definitive irradiation spares the combined toxicity of both surgery and adjuvant irradiation, particularly because resection of intermediate-stage carcinomas frequently leads to functional loss.

Locally advanced primary tumors (large, infiltrative T3 or T4 lesions) can be treated with irradiation, preferably with concurrent chemotherapy, or with primary resection, nodal dissection, and postoperative irradiation with or without concurrent chemotherapy. The large tissue defects typically required for such a resection can be reconstructed with microvascular free flaps, which decrease the degree of functional loss. Because this functional loss exceeds that expected by radiation therapy, primary irradiation plus concurrent chemotherapy is typically recommended. Surgical resection, however, is recommended for locally advanced cases with invasion of the mandible or other excisable osseous structures or if functional deficits such as gross aspiration or laryngeal impairment are present. Postoperative irradiation follows surgical resection in these cases.

Surgery

Definitive surgery followed by irradiation remains a viable treatment choice in oropharyngeal cancer, particularly with smaller primary tumors that are potentially amenable to resection without significant sequela. When surgery is used, several approaches may be applicable. Traditional surgical approaches include lateral pharyngotomy, a transhyoid approach, or an anterior approach with a midline or lateral mandibulotomy with a combined lip-splitting incision. Newer surgical approaches include transoral laser microsurgery (TLM), in which the tumor is excised with either a free-beam or fiber-delivered carbon dioxide laser with visualization through an operating microscope or rod telescope.⁸² The carbon dioxide laser allows precision with minimal cautery artifact or oozing, and the tumor is removed as a multibloc resection. Advocates of TLM state that this maximizes oncologic excision while minimizing the potential surgical side effects seen with older approaches. A transoral robotic approach for a radical tonsillectomy has also been described.⁸³

Primary surgery offers the possibility for improved local control with a negative margin excision followed by irradiation as needed. Primary surgery may also allow for lower radiation doses in the adjuvant setting and case-dependent omission of concurrent chemotherapy, diminishing potential treatment-related toxicities, although this remains to be rigorously studied.

The Washington University experience⁸² of 84 patients with stage III and IV oropharyngeal cancers treated with TLM followed by irradiation as indicated described rates of disease-specific survival (DSS) and OS of 92% and 88%, respectively, at 5 years, with only one local failure and four regional failures; only 3.4% of patients remained gastrostomy-tube dependent at 3 years. Only 26% of the patients had stage T3 and T4 disease, however, and these patients had a statistically worse OS. In addition, 95% of the patients were HPV-16-positive, and this may have contributed to the high rates of locoregional control. Again, such potential benefits are weighed against the hazards of surgery, which included a 6% reoperation rate, an 11% temporary tracheotomy rate, and an 11% rate of velopharyngeal incompetence (although oral intake and speech were not interrupted).

Although the Mayo Clinic experience^84,85 details a similarly high local control rate with transoral excision, others have found higher rates of local recurrence, particularly when lesions larger than stage T2 are resected. Pradier and colleagues⁸⁶ described lower rates of locoregional control, DSS, and OS of 61%, 48%, and 42%, respectively, in oropharyngeal cancers treated with TLM. As a whole, this study had higher percentages with locally advanced primary tumors (stage T3 and T4) and a worse outcome in patients in which adjuvant split-course irradiation was used. The worse outcome with split-course irradiation endorses the importance of radiotherapy in this patient cohort.

Treatment Recommendations by Subsite

Chemoradiation

Biologic Therapy

The Bonner study is a landmark study that compared EBRT alone (once-daily dose of 70 Gy in 35 fractions; twice-daily dose of 72 to 76.8 Gy in 60 to 64 fractions; concomitant boost of 72 Gy in 42 fractions) with EBRT plus the anti-EGFR monoclonal antibody cetuximab.¹²¹ This study proved a paradigm that the use of a biologic agent in combination with EBRT can improve survival rates for locoregionally advanced squamous cell carcinoma of the head and neck, and led to the approval of cetuximab by the U.S. Food and Drug Administration (FDA) in 2006 for this indication. The primary endpoint of the study was the duration of locoregional control, defined as the absence of progression of locoregional disease at the scheduled follow-up visits. The median duration of locoregional control was 24.4 months in the combined-therapy arm and 14.9 months in the radiotherapy alone arm (HR for locoregional progression or death, 0.68; 95% CI, 0.52 to 0.89; p = .005). The 2-year PFS, 5-year OS, and median survival durations were 46% versus 37%, 45.6% versus 36.4%, and 49 months versus 29.3 months (HR, 0.73; p = .018), respectively, favoring the combined-therapy arm.^121,122 With the exception of acneiform rash and infusion reactions, the incidence of grade III or greater toxic effects, including mucositis, did not differ significantly between the two groups. Rates of grade III or IV late toxicities were similar between the two groups.

In subgroup analyses, it would appear that patients who received EBRT with the concomitant boost regimen derived the most benefit when EBRT was used in combination with cetuximab. The hazard ratios were as follows: for the 26% of patients who received once-daily fractionation doses, 1.01; for the 18% of patients who received twice-daily fractionation doses, 0.74; for the 56% of patients who received concomitant boost EBRT, 0.64. Furthermore, when analyzed by disease site, patients with primary tumors in the oropharynx derived the most benefit from the combination of EBRT and cetuximab (HR, 0.62), compared with those with primary tumors in the larynx (HR, 0.87) and in the hypopharynx (HR, 0.94). There are several possible explanations for the results of this latter subgroup analysis. First, it is possible that the addition of an anti-EGFR antibody preferentially benefits locally advanced squamous cell carcinomas of the head and neck based on a tumor’s primary anatomic location, favoring oropharyngeal tumors. A second, and perhaps more plausible, explanation is that this finding is related to the fact that HPV is associated primarily with oropharyngeal squamous cell carcinoma. As such, it is possible that HPV-related squamous cell carcinoma derives a greater benefit from the addition of an anti-EGFR antibody compared with non-HPV-related disease, but this postulate must be verified by randomized data.

The RTOG is initiating a large phase III trial in 2011 to examine the role of cetuximab in HPV-associated cancers of the oropharynx. The two-arm study will randomize HPV-associated oropharyngeal cancer patients to 70 Gy of irradiation with concurrent cisplatin or cetuximab, with the primary objective being comparison of 5-year OS.

Management of the Neck

Locoregional Recurrent Disease

Locoregional recurrence after definitive treatment in the absence of distant metastases represents a challenging clinical scenario because patients are theoretically curable but the prognosis is grim. Curative treatment options include salvage surgery, frequently made more challenging by prior radiation treatment, or reirradiation. Patients treated previously with surgery alone may have the option of surgery followed by adjuvant irradiation or definitive irradiation with or without chemotherapy. Factors to be considered in aggressive retreatment include time elapsed from initial definitive treatment; site, stage, and resectability of the tumor; patient performance status; and comorbidities.

Salvage Surgery

In patients with locally recurrent, resectable oropharyngeal tumors, salvage surgery provides the best opportunity for long-term locoregional control and potential cure. This is weighed against the morbidity of surgical resections, which may include permanent loss of swallowing function, poor cosmesis, and significant medical cost. In addition, such surgical procedures in patients who have had irradiation carry higher complication rates than primary surgery alone. The introduction of free-flap reconstructions for large tissue defects has improved salvage surgery options and outcomes. This ability to transfer nonirradiated tissue with normal vasculature into the treatment field can decrease postsurgical complications.

A meta-analysis of 1080 patients treated with salvage surgery from 28 institutions showed a 5-year OS of 39%, with this better than expected outcome buoyed by the large number of recurrent early-stage laryngeal cancers.¹³⁵ Pharyngeal primaries in this meta-analysis had a 2-year DFS of 25% and a 5-year OS of 26%. The operative mortality rate was 5.2%, with a complication rate of 39% and a major complication rate of 27%. Surgical complication rates appear to be significantly increased following primary chemoradiation compared with irradiation alone.¹³⁶ A prospective trial that accompanied the meta-analysis found that OS declines progressively with a more advanced recurrent stage (24.3 months for stage I disease vs. 9.3 months for stage IV disease) and the prior use of chemotherapy (26.9 months vs. 8.8 months with prior chemotherapy).¹³⁵ The author concluded that stage I and II recurrent cancer patients had a 70% chance of being disease-free at 2 years and a 60% to 85% probability of a successful outcome relative to quality of life and a low surgical complication rate. On the other hand, recurrent cancer patients that initially had stage IV lesions had a less than 25% chance of being disease-free at 2 years, with disease recurring in half of these patients within 5 months. Significant complications were present in 30% of stage IV salvage surgeries, and 30% of patients had a good quality-of-life outcome.

Bachar and colleagues¹³⁷ reviewed the largest single-institution oropharynx salvage experience, in which 239 out of 640 patients treated definitively at the Princess Margaret Hospital with radiation for tonsillar carcinomas had subsequent recurrence. Of the 239, 175 (73.5%) were surgical salvage candidates. The median time to death was 1.3 years, and 5-year CSS and OS were 40% and 23%, respectively. The majority of patients died with disease. Both the T and N categories were predictors of time to death. Although the prognosis was poor overall for recurrent disease, the survivorship of 23% of patients at 5 years defines a finite group of patients cured by salvage surgery and argues in favor of a salvage surgical procedure when feasible.

Reirradiation

In attempting to determine which patients might benefit from repeating full-dose irradiation to the head and neck, some have warned that “experience has shown that indiscriminate use of high-dose reirradiation often makes a bad matter worse.”¹³⁸ Reirradiation has been pursued at some centers in the situation of a patient with good performance status, locoregional recurrence, and no other potentially curative treatment options. Appropriate patient selection is key, and patients should be fully informed of the increased complication rate incurred by cumulative radiation doses frequently topping 100 Gy.

Investigations at several academic centers have demonstrated that between 10% and 20% of selected patients who are reirradiated can be long-term survivors. The University of Chicago reported on 115 patients who underwent reirradiation with a median lifetime dose of 131 Gy, including 30 patients with oropharyngeal carcinoma.¹³⁹ Radiation was delivered with concurrent chemotherapy as part of seven consecutive phase I and II protocols in which radiation was given for five fractions every other week. Median OS and DFS were limited at 11 and 7 months, respectively. A subset of patients had long-term benefits from the repeat treatment, however, as 3-year OS, PFS, and locoregional control were 22%, 33%, and 51%, respectively. Improved outcomes were seen with higher doses of radiation (>58 Gy), multiagent chemotherapy, and surgery before repeat radiation. Conversely, only 11% of patients treated with repeat radiation alone were alive at 3 years. Side effects were substantial, with 19 patients (16.5%) dying of treatment-related complications and another 13 (11%) requiring surgery for osteoradionecrosis of the mandible.

The inability to undergo surgery as a negative prognostic indicator was reinforced by the RTOG 9610 clinical trial, which delivered 60 Gy at 1.5 Gy twice daily with concurrent chemotherapy. Patients were ineligible for surgical resection, and 2-year and 5-year OS were 15.2% and 3.8%, respectively. A follow-up study (RTOG 9911) with concurrent cisplatin and paclitaxel found 2-year OS of 25.9%, which exceeded the results generally seen with chemotherapy alone, although 8% of patients still died of treatment-related complications.¹⁴⁰

The side effects of reirradiation may be partially tempered by employing highly conformal treatment techniques. An M.D. Anderson Cancer Center 5-year experience of 74 patients reirradiated with IMRT reported a 20% rate of major toxic events, defined as hospitalization or corrective surgery, and one patient death.¹⁴¹ The median lifetime radiation dose was 116.1 Gy, and 41% of the lesions were oropharyngeal in origin. Two-year OS and locoregional control were encouraging at 58% and 64%, respectively. Salvage surgical resection had been previously performed in 27% of patients, and 81% of patients were treated for gross disease with margins only. Locoregional failure rates decreased with IMRT in the Memorial Sloan-Kettering Cancer Center experience, which described 2-year OS of 37% and a severe late complication rate of 11.4%.¹⁴²

Brachytherapy¹⁴³ and intraoperative irradiation (IORT)¹⁴⁴ can also be used in the setting of focal reirradiation with reasonable local control. IORT as a treatment option is discussed further in the Head and Neck Overview section of the textbook.

Janot and associates¹⁴⁵ reported on a randomized trial evaluating reirradiation in patients who had recurrent disease or a second primary tumor in a previously irradiated region, no major sequelae from the prior treatment, a good performance status, no distant metastases, and salvage surgery with macroscopic complete resection. The radiation dose was 60 Gy over 11 weeks (five fractions, followed by the next week off) with concurrent 5-FU and hydroxyurea. Repeat irradiation improved the DFS (HR, 1.68) but did not affect OS. Grade 3 or 4 late toxicities at 2 years were 39% in the radiation therapy arm and 10% in the observation arm (p = .06).

At many institutions, locoregional radiation failures undergo salvage surgery if feasible. Reirradiation following salvage surgery is not routinely added unless there is radiographic or clinical suspicion of residual gross disease or pathologic margins are diffusely positive. Reirradiation is performed in a highly selected group of patients who are either surgically unresectable, without marked sequelae from prior treatment, have a high performance status, are strongly motivated, and understand the high potential of significant treatment-related morbidity and the modest likelihood of long-term survival. Generally, these patients also have limited-volume, well-circumscribed recurrent disease and a prolonged time from initial definitive treatment. All attempts are made to limit the volume of full-dose retreatment with the usage of IMRT and daily image-guided radiation therapy (IGRT).

Recurrent or Metastatic Disease