Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

8. Oropharynx

Alexander M. Stessin • Gokhan Ozyigit • K. S. Clifford Chao

Oropharynx Cancer – Highlights

Key Recent Clinical Studies

Ang et al. (NEJM 2010) reported the analysis of RTOG 0129 and found that patients with HPV-positive oropharyngeal cancers had a 58% reduction in risk of death as compared with the HPV-negative cohort. (PMID 20530316)

Nutting et al. (Lancet Oncol 2011) reported in the PARSPORT trial, a phase III randomized trial comparing IMRT with conventional radiotherapy for head and neck cancer of which 85% had oropharyngeal carcinoma, that after 2 years 29% of IMRT patients had grade 2 or worse xerostomia as compared to 83% in the conventional group. (PMID 21236730)

New Target Delineation Contours

FIGURE 8-6. CTV1, CTV2, and CTV3 delineation in a patient with clinically T2N2bM0 squamous cell carcinoma of the tonsil who received definitive IMRT. For clarity, the parotid glands are marked with lower case p.

1. ANATOMY

• The oropharynx is the posterior continuation of the oral cavity; it communicates with the nasopharynx superiorly and the laryngopharynx inferiorly. It can be subdivided into the palatine (faucial) arch and oropharynx proper. Its subsites include the base of tongue (BOT), palatine tonsils, tonsillar pillars, soft palate, and the pharyngeal wall.

1.1. Tonsillar Fossa and Faucial Arc

• The palatine arch, a junctional area between the oral cavity and the laryngopharynx, is formed by the soft palate and the uvula superiorly, the anterior tonsillar pillar and glossopalatine sulcus laterally, and the glossopharyngeal sulcus and the BOT inferiorly.

• Figure 8-1 shows a coronal section of the oropharynx with relationships in the parapharyngeal regions.

• The retromolar trigone has been included in the structures of the faucial arch, although it is actually located within the oral cavity. Its apex is in line with the tuberosity of the maxilla (behind the last upper molar); the lateral border extends superiorly into the buccal mucosa; medially, it blends with the anterior tonsillar pillar; and its base is formed by the distal surface of the last lower molar and the adjacent gingivolingual sulcus.

• The lateral walls of the oropharynx are limited posteriorly by the tonsillar fossa and posterior tonsillar pillar (pharyngopalatine folds). These pillars are folds of mucous membrane that cover the underlying glossopalatine and pharyngopalatine muscles. Deep into the lateral wall of the tonsillar fossa are the superior constrictor muscles of the pharynx, upper fibers of the middle constrictor, pharyngeus and stylopharyngeus muscles, and glossopalatine and pharyngopalatine muscles. The tonsillar fossa continues into the lateral and posterior pharyngeal walls.

• The tonsillar fossa and faucial arch have a rich submucosal lymphatic network, laterally grouped into four to six lymphatic ducts that drain into the subdigastric, upper cervical, and parapharyngeal lymph nodes. Submaxillary lymph nodes may be affected in lesions involving the retromolar trigone, the buccal mucosa, or even the BOT.

1.2. Base of Tongue

• The BOT is bounded anteriorly by the circumvallate papillae, laterally by the glossopharyngeal sulci and oropharyngeal walls, and inferiorly by the glossoepiglottic fossae or valleculae and the pharyngoepiglottic fold.

• The vallecula is the transition zone between the BOT and the epiglottis and is considered a part of the BOT.

• The surface of the tongue is irregular because of the submucosal lymphoid follicles, but the mucous membrane is smooth when compared with the dorsum of the oral tongue. The lymphoid tissue at the BOT does not penetrate the intrinsic tongue muscles.

• The BOT is almost parallel to the posterior pharyngeal wall. Its musculature is continuous with that of the oral tongue and the floor of the mouth anteriorly. The genioglossus fibers fan out in the tongue to interdigitate with the intrinsic tongue musculature (Fig. 8-2). The tongue base also is continuous with the pre-epiglottic space.

2. NATURAL HISTORY

2.1. Tonsil

• Many tonsillar tumors are keratinizing squamous cell carcinomas, which can be graded I to IV, depending on the degree of differentiation.

FIGURE 8-1. Coronal section of the oropharynx showing relationships in the parapharyngeal regions.

FIGURE 8-2. (A) Sagittal section of the upper aerodigestive tract. (From Respiratory System. Anesthesia Technician & Technologist’s Manual, Lippincott Williams & Wilkins, 2008.) (B) Sagittal magnetic resonance imaging (MRI). Lymphoid tissue (LT) at the tongue base does not penetrate the intrinsic tongue muscles (IM); it is limited to the surface. Genioglossus fibers fan out in the tongue (arrowheads) to finally interdigitate with the intrinsic tongue musculature. The tongue base is continuous with the pre-epiglottic space (arrow). Areas of high signal intensity within soft palate (SP) are the result of its fatty content. (From Million RR, Cassisi NJ, Mancuso AA. Oropharynx. In: Million RR, Cassisi NJ, eds. Management of Head and Neck Cancer: A Multidisciplinary Approach, 2nd ed. Philadelphia, PA: JB Lippincott, 1994:402, with permission.)

• Carcinomas arising in the faucial arch tend to be keratinizing and more differentiated than those of the tonsillar fossa.

• Tonsillar fossa lesions tend to be infiltrative, often involving the adjacent retromolar trigone, soft palate, and BOT. Perez1 reported that the primary tumor was confined to the tonsillar fossa in only 5.4% of 384 patients; 65% had involvement of the soft palate, and 41% had extension into the BOT.

• Tumors of the faucial arch can be superficially spreading, exophytic, ulcerative, or infiltrative; the last two types are frequently combined. They become extensive and involve the adjacent hard palate or buccal mucosa in <20% of patients.1

• Tumors of the tonsillar fossa have a high incidence of lymph node metastases (60% to 70%); most are in the subdigastric lymph nodes, midjugular chain, and submaxillary lymph nodes (in lesions extending anteriorly); 5% to 10% involve the posterior cervical lymph nodes (Table 8-1).1

• Metastases in the low cervical chain occur in approximately 5% to 15% of patients with upper cervical lymph node involvement.1

• The incidence of metastatic lymph nodes in the neck increases with tumor stage. Less than 10% of T1 lesions, 30% of T2 lesions, and 65% to 70% of T3 and T4 lesions have metastatic cervical lymph nodes at presentation.1

• Contralateral lymphadenopathy in tonsillar tumors is noted in 10% to 15% of patients with positive ipsilateral lymph nodes, more frequently if the primary tumor extends to or beyond the midline (Table 8-2).1

• Tonsillar pillar and soft palate lesions have an overall metastatic rate of approximately 45%. Initially, the most frequent site of nodal involvement is the jugulodigastric lymph nodes. Approximately 10% of patients have submaxillary lymph node involvement. Tumors of the retromolar trigone, anterior faucial pillar, and soft palate rarely metastasize to the posterior cervical lymph nodes. Contralateral spread is infrequent (10%).1

2.2. Base of Tongue

• Squamous cell carcinoma of the BOT tends to have early, silent, and deep infiltration; therefore, it is difficult to estimate tumor extension by clinical examination. However, tumors originating from the peripheral regions usually remain there.24

• BOT cancers have little tendency to spread to the palatine tonsils, whereas tonsillar cancers tend to invade the BOT.

• Vallecular lesions are often exophytic and invade along the mucosa to the lingual surface of the epiglottis, laterally along the pharyngoepiglottic fold, and then to the lateral pharyngeal wall and anterior wall of the pyriform sinus.

• The first echelon nodes are the subdigastric (level II) nodes; lymphatic drainage then continues along the jugular chain to the mid- and lower jugular nodes. If anterior extension into the oral tongue or massive upper neck disease is present, then the submandibular lymph nodes may be involved. The posterior cervical lymph nodes are often involved, but submental spread is rare.

• Bilateral and contralateral lymphatic spread is common (Fig. 8-3A,B). Retrograde spread to retropharyngeal lymph nodes has been reported particularly in advanced lesions. Typical spread of disease by T stage is illustrated in Figure 8-3C.

• The deeply infiltrating nature of BOT cancers correlates with the high frequency of lymphatic metastases at presentation (80% of patients overall, with bilateral spread in 37% to 55%).26

• The incidence of clinically positive neck node at presentation is approximately 50% to 83% (Table 8-3).

• The incidence of pathologically positive neck node in clinically N0 neck is approximately 22% to 33%. Contralateral lymphatic metastasis at presentation is 37% (Table 8-2).24 Table 8-1 shows the percentage of the incidence and distribution of metastatic disease in clinically negative and positive neck nodes in BOT cancers.

FIGURE 8-3. (A) Lymphatics of head and neck. The red node highlights the sentinel node, which is the jugulodigastric node. Left: anterior view; right: lateral view. (From Rubin P, Hansen JT. TNM Staging Atlas with Oncoanatomy, 2nd ed. Philadelphia, PA: Lipppincott Williams & Wilkins, 2012:78. Modified from Agur AMR, Dalley AF, eds. Grant’s Atlas of Anatomy, 12th edition. Philadelphia: Lippincott, Williams & Wilkins, 2009.) (B) Distribution of nodal involvement at presentation of squamous cell carcinoma of base of the tongue (BOT). (Redrawn from figure in Lindberg RD. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tract. Cancer 1972;29:1446–1449, with permission.)

FIGURE 8-3. (C) Typical patterns of spread in oropharyngeal cancer. Left: Sagittal view: highlights cancer spread from oropharynx into nasopharynx and hypopharynx. Right: Coronal view: indicates the sphincter musculature of the pharynx: middle constrictor between superior constrictor of the nasopharynx and inferior constrictor of the hypopharynx as to invasive pathways of pharyngeal tube. The primary cancer (oropharynx) invades in various directions, which are shown as color-coded vectors (arrows) representing stages of progression: Tis, yellow; T1, green; T2, blue; T3, purple; T4a, red; and T4b, black. (From Rubin P, Hansen JT. TNM Staging Atlas with Oncoanatomy, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012:73. Modified from Agur AMR, Dalley AF, eds. Grant's Atlas of Anatomy, 12th edition. Philadelphia: Lippincott, Williams & Wilkins, 2009.)

3. DIAGNOSIS AND STAGING SYSTEM

3.1. Signs and Symptoms

3.1.1. Tonsil

• Sore throat is the most frequent symptom. Asymptomatic lesions are frequently found on routine examination.

• Dysphagia or otalgia is related to the anastomotic-tympanic nerve of Jacobson.

• Trismus may be a late manifestation if the masseter or pterygoid muscle is involved.

• Invasion of the tongue will eventually limit tongue mobility. Ulceration at the junction of the anterior tonsillar pillar and oral tongue can cause a great deal of pain.

• Tumors of the tonsillar fossa have similar signs and symptoms, except that the lesions tend to be larger before symptoms develop. Ipsilateral sore throat and otalgia are the hallmarks of these lesions.

• Lymphomas of the tonsil tend to be large submucosal masses but may ulcerate and appear similar to carcinomas.

3.1.2. Base of Tongue

• The BOT is visualized only by indirect mirror examination, so earlier diagnosis is rare. The earliest symptom is mild sore throat. Many of the early lesions are asymptomatic and relatively silent, and a subdigastric neck mass is frequently the first sign.

• Necrosis and internal bleeding may cause sudden enlargement and mild tenderness.

• Dysphagia, a nasal quality to the voice, and deep-seated otalgia occur with enlargement of the mass. Otalgia is associated with tumor involvement of the retropharyngeal space.

• Hypoglossal nerve invasion is rare but can cause unilateral paralysis and atrophy of the tongue when it does occur.

3.2. Physical Examination

3.2.1. Tonsil

• Indirect mirror examination and digital palpation are required for diagnosis.

• In addition to a complete history and physical examination, a complete examination of the head and neck is mandatory. Fiberoptic nasopharyngolaryngoscopy is routinely used to examine the upper aerodigestive tract. Speech and swallow evaluation may be indicated prior to treatment.

3.2.2. Base of Tongue

• Early lesions are usually submucosal and relatively soft. Because the surface of the BOT is irregular, it is difficult to palpate the mass. Rigid or flexible endoscopes permit examination in some patients.

• Palpation through the lateral floor of the mouth can be helpful to detect anterior extension.

• Fullness in the soft tissue around the hyoid bone may be a sign of inferior penetration through the valleculae.

• Fixation of the tongue causes incomplete protrusion of the fused site.

3.3. Imaging

• The main imaging tools of the oropharyngeal region are computed tomography (CT) and magnetic resonance imaging (MRI).

• CT is better for the lymph nodes and bone detail, so it is the preferred initial study. MRI is used adjunctively.

• Positron emission tomography (PET) may be used as a complementary imaging modality for determination of target volumes that appear equivocal on CT or MRI. However, potential drawbacks of PET, including poor spatial resolution (~6 to 8 mm), partial volume effects causing blurring of the edges, and reported sensitivity of only 50% to 70% in the clinically negative neck,7 have put into question its reliability as a primary imaging tool for target delineation.

• Lee and co-workers105 used F-18-Misonidazole for PET imaging of hypoxia and found that the presence of PET-avid tissues did not correlate with clinical outcome for patients treated with platinum-based chemotherapy and IMRT.

• A recent study by Shukla-Dave et al.9 in 74 squamous cell carcinoma patients using dynamic contrast-enhanced MRI indicated that the parameter Ktrans (volume transfer constant) was a strong predictor of outcome for those with stage IV disease.

• Evaluation of the BOT should include slices from the nasopharynx to the lower neck. Axial sections are often sufficient; however, coronal sections may be required when lesions invade the base of the skull. Sagittal MRI is necessary for detection of early pre-epiglottic space invasion.

• CT and MRI sections of this region require injection of contrast media. Contiguous 3- to 4-mm slices should be used through the primary tumor and neck. It is important to keep the field of view small so that the pictures are magnified and spatial resolution is optimized. Evaluation of the BOT must include a complete CT study of the cervical and retropharyngeal nodes (Fig. 8-4).

• CT and MRI are excellent for showing the deep structures surrounding the pharynx. The deep tissue planes are generally symmetric, and obliteration of the deep fat spaces, such as the parapharyngeal space, or invasion of deep musculature is a sign of spread. Such spread is frequently not expressed as signs and symptoms nor detected by physical examination. The pharyngeal wall becomes tightly surrounded by musculature, and the intervening fat planes are less visible lower in the oropharynx, making diagnosis of invasion more difficult.

• Lymphoid tissue is present throughout the oropharynx and is responsible for most of the variation seen in the surface contours on CT and MRI. Inexperienced interpreters may frequently mistake the various bumps and bulges on the mucosal surfaces for tumors. These regions should either be ignored or be used as prompts to look for adjacent deep infiltration as a sign of pathology. These surfaces are best evaluated by physical examination, not by CT or MRI. There are no findings that can distinguish lymphoid tissue and other benign mucosal lesions from cancer other than infiltration of the deeper structures.

• Any tumor that is suspicious for deep infiltration should be studied primarily with CT. A significant portion of MRI studies in this area will be of low quality because of motion artifacts. In general, MRI is preferred for the evaluation of the parapharyngeal space.

FIGURE 8-4. Computed tomography (CT) study shows an enlarged retropharyngeal lymph node (N). The node lies medial to the carotid artery (A), parotid gland (PG), and jugular vein (JV). A more normal-sized retropharyngeal node (arrow) is present on the opposite side. M, mandible.

• The relationship of tumor margins to both the lingual neurovascular bundles can be anticipated to be visualized on imaging with far greater precision than on physical examination. Occasionally, retrograde spread of tumor out of the tongue along the lingular neurovascular bundles to the external carotid artery will be visible.

• Tumors in the region may also grow onto the styloid musculature. Inferior growth along the mylohyoid and hyoglossus muscles may bring the tumor to the insertion of these muscles on the hyoid bone, and there may be direct extension into the soft tissues of the suprahyoid and infrahyoid neck at that point. Occult spread from the BOT to the pre-epiglottic space may also be visualized.

3.4. Staging

• In 2010, the American Joint Committee on Cancer (AJCC) issued a new (seventh) edition of its Cancer Staging Manual10; the readers are referred to this new edition for more details on staging. The most significant change from the sixth edition was that T4 lesions have been split into two subgroups, one for moderately advanced local disease (T4a) and the second for very advanced local disease (T4b).

4. PROGNOSTIC FACTORS

4.1. Tonsil

• Stage: The stage of primary tumor and presence of involved cervical lymph nodes have a significant correlation with local control and survival.1116

• Treatment-Related Factors: External-beam dose and fractionation schedule also significantly influence local control.14 Cause-specific survival rate is influenced by planned neck dissection.14

• Histologic Differentiation: Multivariate analysis revealed that survival was significantly influenced by histologic differentiation.14

• HPV Status: Infection with human papilloma virus (HPV) has been identified as a prognostic factor associated with favorable outcomes in patients with cancers of the oropharynx. The highest prevalence of HPV is found in tonsillar carcinomas.16 In a retrospective analysis of RTOG 0129, patients with HPV-positive tumors, treated with chemoradiotherapy, had a 58% reduction in risk of death, as compared with the HPV-negative cohort.17 A review of SEER data by Nguyen et al.18 showed that younger patients had a better prognosis, and this could be due to higher HPV infection rates.19,20

4.2. Base of Tongue

• Tumor Size and Extent: BOT cancers have a worse prognosis than those observed in oral tongue cancers because of larger sizes at diagnosis, more frequent spread to adjacent structures, and higher rate of lymphatic spread. However, stage for stage, they may have a prognosis similar to that of oral tongue cancers.21

• Stage: One of the most dominant prognostic factors is tumor stage.21

• Overall Treatment Time: Survival and locoregional control become worse when overall treatment time increases.21

• Histopathologic Grade: Poorly differentiated or undifferentiated carcinomas are shown to have better survival and local control rates.

• HPV Status and Tobacco Use: The presence of HPV infection has been identified as a favorable prognostic factor; however, the risk of death in HPV-positive patients increases with each additional pack-year of tobacco smoking.17

• Molecular Markers: Increased expression levels of HPV p16 protein correlate with better disease-free survival and overall survival outcomes, while increased expression of epidermal growth factor receptor (EGFR) is associated with poorer prognosis.22,23

• Other: Other prognostic factors include age and extension to both epilarynx and endolarynx (associated with poor survival).5,24

4.3. Oropharynx General

• Kong et al.19 reported on correlations between HPV status and other molecular markers: it was prognostic for survival and correlated inversely with EGFR expression but directly with T-cell infiltration. Moeller et al.25 used FDG-PET/CT and plain CT to assess post-RT mortality risk in 98 patients, 79% of whom had oropharyngeal cancer. Both imaging modalities had high specificity and negative predictive value to separate patients into high- and low-risk groups. Notably HPV-negative status and disease outside the oropharynx correlated with poorer outcome. Moeller et al.20 later reported that Ku80 overexpression was an independent predictor of locoregional failure and mortality. HPV-negative patients with Ku80 overexpression had 9 times higher mortality at 2 years.

• Calvin et al.26 examined tissue from 450 patients previously enrolled in RTOG 90–03 for RT in locally advanced head and neck cancers, 60% of which were in the oropharynx. Somewhat counterintuitively they found that high microvessel density did not correlate with outcome.

• Chen et al.27 examined 101 matched pairs of head and neck cancer patients, about half of whom had their lesions located in the tonsil or BOT. One of the pair continued using tobacco during radiation therapy and the other had ceased tobacco use. As might be expected, both 5-year overall survival and locoregional control rates were significantly lower in the patients who continued to smoke (23% vs 55% and 58% vs 69%, respectively).

• Overexpression of EGFR was a significant predictor for lowered overall survival and higher locoregional relapse in data from 533 head and neck cancer patients (60% oropharynx). Chung et al.28 concluded that pretreatment EGFR expression data could be useful in patient stratification.

5. GENERAL MANAGEMENT

• Surgery and radiation are equally successful in controlling early stage oropharyngeal cancer. Radiation may be the preferred modality where the functional deficit will be high, such as the tongue base or tonsil. A total of 175 patients with AJCC stages I and II oropharyngeal carcinoma were treated with external-beam radiotherapy at M.D. Anderson Cancer Center.29 The actuarial 5-year locoregional control and disease-free survival rates were 81% and 77%, respectively.

• The management of advanced-stage carcinomas of the oropharynx requires a multidisciplinary approach to establish optimal treatment. In general, the preferred treatment has been to combine surgery with postoperative radiation therapy. Recent studies have explored concurrent chemoradiotherapy as an alternative approach for treatment of advanced-stage disease with a view to organ preservation.30 Aggressive radiation therapy alone will give control rates equivalent to those of surgery for cancers originating in the tonsil.

• A recent study by Soltys et al.31 including 60 patients with locally advanced N2 or N3 oropharyngeal disease using induction and concurrent chemoradiation showed that partial neck dissection (PND) offered no significant benefit to those achieving clinically complete response. Prognosis for partial responders was worse, and PND was indicated.

5.1. Tonsillar Fossa and Faucial Arc

5.1.1. Tumors of Tonsillar Fossa

• Tables 8-4 and 8-5 show the initial local control rates for carcinoma of the tonsil according to T stages with different treatment strategies.

• Table 8-6 summarizes the disease-specific survival of patients with carcinoma of the tonsil.

• T1 or T2 lesions can be treated with irradiation or surgery alone.

• T1, T2, and T3 tumors are treated with irradiation alone (66 to 75 Gy in 6 to 7 weeks, depending on stage; conventional prescription to primary tumor and gross adenopathy is 70 Gy in 2 Gy/fraction). Regional lymph nodes are treated with 44 to 75 Gy, depending on nodal involvement. Uninvolved nodal stations are considered as either low- or intermediate-risk, depending on proximity to gross disease areas, and are treated to 44 to 64 Gy in 1.6 to 2 Gy/fraction. Interstitial brachytherapy has been used to deliver an additional dose (25 to 30 Gy) to the primary tumor.32

• In T3 and T4 tumors, a combination of irradiation and surgery has been advocated because of the higher incidence of recurrences with either modality alone.12,13,33 These lesions are treated with radical tonsillectomy with ipsilateral neck dissection followed by irradiation. Areas of primary tumor and gross adenopathy are treated to 60 to 66 Gy at 2 Gy/fraction, depending on the status of the surgical margins, while uninvolved nodal regions are treated to 44 to 64 Gy at 1.6 to 2.0 Gy/fraction, following the same rationale as for definitive cases.34

5.1.2. Tumors of Faucial Arch

• T1 lesions <1 cm in diameter are treated with wide surgical resection or irradiation alone (60 to 66 Gy in 6 to 7 weeks).51,52

• T2 tumors require more extensive surgical procedures, including partial resection of the mandible if there is bone involvement.53 Because of the tendency of these tumors to extend to the midline, the site of lymph node metastasis is less predictable; therefore, neck dissection should be performed only in patients with palpable cervical lymph nodes.

• T2 tumors can also be treated with irradiation alone (66 to 74 Gy). Irradiation has the advantage of treating subclinical disease in the neck (50 Gy or higher total dose).51,54

• Interstitial brachytherapy (20 to 30 Gy) in the primary tumor has been combined with external irradiation (50 Gy).

• In more extensive lesions, preoperative or postoperative irradiation can be used in doses similar to those used in the tonsil.

5.2. Base of Tongue

• Exophytic or surface tumors respond well to irradiation alone. Ulcerative, endophytic cancers that are partly or completely fixed require surgery.55,56

• When all stages are considered, overall treatment results for BOT cancer seem to be most optimal for combinations of surgery and irradiation when compared with conventional irradiation alone.

5.2.1. Surgical Management

• Radical neck dissection yields information to determine whether postoperative irradiation is required, which is recommended for patients with disease more extensive than stage N1 or with extracapsular extension.

• Thawley et al.57 reported that 47% of patients treated with combined surgery and preoperative irradiation had the mandible preserved.

• Tumors of the lower BOT that involve the valleculae and extend inferiorly to the supraglottic larynx and pyriform sinus may be controlled by partial glossectomy and subtotal supraglottic laryngectomy or partial laryngopharyngectomy with preservation of voice.57,58

• Prerequisites for a subtotal supraglottic laryngectomy include no gross involvement of pharyngoepiglottic fold, preservation of one lingual artery, resection of <80% of the BOT, pulmonary function suitable for supraglottic laryngectomy, and medical condition suitable for a major operation.

• Locoregional control is approximately 48% with surgery alone.59

5.2.2. Irradiation Alone

• Doses to the primary tumor and palpable lymph nodes range from 66 to 74 Gy delivered in 6 to 7 weeks. Doses for elective irradiation of subclinical, microscopic lymphatic metastases should be at least 50 Gy.

• Small T1 and T2 BOT tumors without significant infiltration and surface or exophytic T2 and T3 lesions of the glossopharyngeal sulcus (glossopalatine sulcus) are controlled by high-dose radiation, with locoregional control of 70%.55

• Large, unresectable BOT cancers that cross the midline, infiltrate, and fix the tongue are often irradiated palliatively to achieve as much tumor regression as possible.

• Local control results correlated with T and N stages, and disease-specific survival rates according to T and N stages in the literature are summarized in Tables 8-78-8, and 8-9, respectively.

• Radiotherapy, either alone or combined with neck surgery, has been used successfully for some patients with early T stage, N+ oropharyngeal cancer. In a large retrospective series from M.D. Anderson Cancer Center, 299 patients with T1–T2 (94%) and N1–N3 (95%) disease were treated with radiotherapy alone or in combination with neck dissection (64%) and primary tumor resection (13%). The actuarial 5-year rates of locoregional control, distant metastasis-free survival, and overall survival were 85%, 81%, and 64%, respectively.60

5.2.3. Combined Surgery and Irradiation

• Surgery combined with irradiation is best suited for larger tumors that extend beyond the BOT or infiltrate and partially fix the tongue.

• Adjuvant irradiation should be routinely used for resectable T3 and T4 BOT cancers to reduce the likelihood of recurrence.57

• Bilateral fields covering the primary site and upper neck are necessary because of the significant primary tumor burden and high rate of contralateral and bilateral lymphatic spread.

• To eradicate residual microscopic disease, doses of 56 to 60 Gy (66 Gy for positive margins or extracapsular extension) may be delivered to the primary tumor bed and neck beginning 4 to 6 weeks after surgery.

• Locoregional control ranges from 57% to 84% with the combined approach (Table 8-10).

• Transoral robotic surgery (TORS), followed by neck dissection as a two-step procedure, is increasingly used in a number of tertiary centers. In a single-arm prospective study at University of Pennsylvania, 47 patients with locally advanced oropharyngeal cancer underwent TORS as a primary treatment modality. Of these, 89% received adjuvant radiotherapy. Disease-specific survival rates were 98% at 1 year and 90% at 2 years; with a mean follow-up of 26.6 months, the reported rates of local and regional recurrence were 2% and 4%, respectively.68

5.3. Chemotherapy

• In a meta-analysis of 63 trials (10,741 patients), locoregional treatment with chemotherapy yielded a pooled hazard ratio of death of 0.90 (95% CI: 0.85–0.94, P < 0.0001), corresponding to an absolute survival benefit of 4% at 2 and 5 years as compared with patients receiving no chemotherapy.71 There was no significant benefit associated with adjuvant or neoadjuvant chemotherapy in this analysis; however, the potential benefit should be further evaluated.

• EORTC trial 24971/TAX 323 was conducted to compare cisplatinum plus 5-fluorouracil with and without docetaxel in 358 patients with unresectable head and neck cancers, including 165 in the oropharynx. Vermorken et al.72reported median overall survival of the docetaxel cohort to be 18.8 months versus 14.5 months in the control group. From their data, at median 51-month follow-up, overall survival was 29% versus 18%, in the docetaxel and the control group, respectively, indicating a benefit for addition of docetaxel in these patients.

• Chemotherapy given concomitantly with radiotherapy demonstrated significant benefits in several randomized trials.66,67,73,74 In a multi-institutional study, Calais et al.67 demonstrated improved 3-year locoregional control (66% vs 47%) and overall survival (51% vs 31%) in the concomitant chemoradiation arm in 226 patients with oropharyngeal cancer by using 70 Gy conventional radiation with carboplatin and 5-FU starting on days 1, 22, and 43 versus radiotherapy alone.

• In a randomized study from Singapore, surgery followed by radiotherapy (60 Gy in 30 fractions) was compared to concurrent chemoradiation (cisplatin and 5-fluorouracil-based regimen) in 119 patients with stage III/IV nonmetastatic head and neck cancers (21% oropharyngeal). There was no significant difference in 3-year disease-free survival rates between the two arms, and the overall organ preservation rate in the chemoradiation arm was 45%, leading the authors to recommend chemoradiotherapy as the preferred first course treatment aimed at organ preservation.60

• Altered fractionation schemes with concurrent chemotherapy were also shown to be effective in improving survival. Jeremic et al.74 established 5-year survival of 46% (vs 25% in controls) by using 77 Gy (1.1 Gy twice/day) with cisplatin (6 mg/m2/d). Also, the phase II Radiation Therapy Oncology Group75 99-14 trial of concomitant boost radiation (72 Gy over 6 weeks) plus concurrent cisplatin for advanced head and neck carcinomas reported 2-year and 4-year survival rates of 70% and 54%, respectively.76 Newlin et al.77 investigated lower dose cisplatinum (30 mg/m2/week) combined with altered fractionated RT. Five-year locoregional control was 79% and overall survival 59%; but 54% of patients required a feeding tube before or during RT. Also, Bourhis et al.78 reported results from GORTEC 99-02 indicating that altered fractionation schedules had no benefit in concurrent chemoradiation with carboplatinum and FU.

• Newer drug combinations, usually containing cisplatin, have shown high complete response rates in nonkeratinizing head and neck cancers and may improve results of treatment.7981 A phase III European trial82 involving 224 patients (53% oropharynx) with 10-year follow-up showed significant benefit for addition of cisplatinum to hyperfractionated RT. Locregional control, distant metastasis-free survival, and disease-specific survival were higher in the cisplatinum arm (40% vs 32%, 56% vs 41%, and 55% vs 43%, respectively) than in the non-cisplatinum arm; however overall survival was similar. A large international phase III trial (n = 861) comparing chemoradiation with cisplatinum with and without addition of a hypoxic cytotoxin, tirapazamine, showed no survival benefit. It should be noted that this study used conventional RT rather than IMRT.83 Currently RTOG phase III trial H-0129 is evaluating cisplatin (100 mg/m2, every 3 weeks) plus an accelerated concomitant boost radiotherapy (72 Gy in 6 weeks) versus standard fractionation (70 Gy in 7 weeks) for patients with stages III–IV head and neck cancers. The trial arms are accelerated concomitant boost RT + cisplatin × 2 cycles versus standard fractionation RT + cisplatin × 3 cycles. In a preliminary presentation of the results at the 2010 American Society of Clinical Oncology Annual Meeting, the authors reported no significant difference in 5-year overall survival rates between the two arms. On secondary analysis, however, both decreased RT duration and increased cumulative cisplatin dose were found to positively impact survival outcomes. A final report of the trial results is pending at this time.

• The addition of cetuximab, a monoclonal antibody against EGFR, to radiotherapy has been found to improve 5-year overall survival rates from 36.4% to 45.6% in patients with locoregionally advanced head and neck cancers84; in contrast an earlier 3-year study reported no such benefit.85 In addition, a phase II study of cisplatin, cetuximab, and concomitant boost radiotherapy for patients with stage III or IV head and neck cancers reported a 3-year overall survival rate of 76%, 3-year progression-free survival rate of 56%, and 3-year locoregional control rate of 71%. However, the study was closed due to severe adverse effects, and the authors concluded that further investigation into the safety profile of this regimen was needed.86 A subsequent retrospective report from the same group87 showed similar toxicities but worse outcomes with cetuximab/RT compared with cisplatinum/RT. Gefitinib, an EGFR tyrosine kinase inhibitor, showed no significant benefit for squamous cell carcinoma when given in combination with cisplatinum/RT.88 In this regard, Nowsheen et al.89 found that cetuximab did augment cytotoxicity in cell lines when used in combination with inhibitors of poly (ADP-ribose) polymerase activity. Currently, RTOG 1016 phase III trial is underway to compare radiotherapy with cetuximab to radiotherapy with cisplatin in patients with HPV-associated oropharynx cancer.

• Agents that selectively enhance the effects of irradiation in the tumor are under investigation, such as hypoxic cell sensitizers, chemical modifiers, hyperthermia, and high linear energy transfer irradiation.

6. INTENSITY-MODULATED RADIATION THERAPY IN OROPHARYNX CANCER

6.1. Target Volume Determination

• Gross tumor volume for oropharyngeal carcinoma is the volume seen on CT or MRI.

• If chemotherapy has been delivered before radiation, the targets should be outlined on the planning CT according to their prechemotherapy extent.

• Lymph node groups at risk in the oropharyngeal region include the following:

(a) Submandibular nodes (surgical level I): all cases.

(b) Upper deep jugular (junctional, parapharyngeal) nodes: all cases.

(c) Subdigastric (jugulodigastric), midjugular, lower neck, and supraclavicular nodes (levels II–IV): all cases.

(d) Posterior cervical nodes (level V): when levels II and III are involved.

(e) Retropharyngeal nodes: all cases.

• The target volume specification for definitive and postoperative intensity-modulated radiation therapy (IMRT) in oropharyngeal cancer is discussed in Chapter 4.

• Suggested target volume determination for oropharyngeal carcinoma is shown in Table 8-11.

• CTV1 (high-risk volume) encompasses the primary and nodal gross tumor volume (GTV) plus a 10-mm margin. The CTV expansion may need adjustments to exclude skin, air, and bony structures if these are not invaded by tumor. In patients receiving postoperative IMRT, CTV1 encompasses the residual tumor and the region adjacent to it but not directly involved with it, the surgical bed with soft-tissue invasion by the tumor, or the extracapsular extension by metastatic neck nodes.

• Areas adjacent to those included in CTV1 are considered part of CTV2 (intermediate-risk volume). In patients with node-positive disease, CTV2 includes nodal stations in the ipsilateral neck, which are adjacent to those involved by disease.

• CTV3 (low-risk volume) includes the remainder of ipsilateral neck, as well as the contralateral neck in all cases except T1–T2 N0 tonsillar cancers, where only the ipsilateral neck is treated.

• In the N0 neck, the upper jugular digastric nodal chain (level II) is contoured up to the level of the C1 transverse process. In the setting of N+ disease, these nodal contours are extended superiorly to the base of skull to include the retrostyloid space.

• Laterally, CTV2 contours of level II, III, and IV chains should include part of the sternocleidomastoid muscle.

• Retropharyngeal (RPN) lymph nodes, lying medial to the internal carotid artery and lateral to the prevertebral muscles at the levels of C1–C3 vertebrae, should be included as part of CTV3 in all cases except T1–T2 N0 tonsil.

• Inferiorly, CTV2 should extend to the sternoclavicular (SC) joint, while CTV3 is delineated to 2 cm above the SC joint.

6.2. Target Volume Delineation

6.2.1. Tonsil

• Clinical target volume (CTV1, CTV2, and CTV3) delineation in a patient with clinically T2N0M0 squamous cell carcinoma of the tonsil is shown in Figure 8-5. The patient presented with a right tonsillar lesion; no lymphadenopathy seen. Bilateral neck lymph node levels II–V were included in the low-risk volume in this case. However, it may be noted that in select cases of tonsillar cancers where the primary tumor is well lateralized, prophylactic radiation to the contralateral neck may be omitted as the rates of contralateral neck failure are quite low.46,90

• CTV1, CTV2, and CTV3 delineation in a patient with clinically T2N2bM0 squamous cell carcinoma of the tonsil who received definitive IMRT is shown in Figure 8-6. This patient was found to have a right tonsillar lesion along with two pathological level II lymph nodes. Hence, CTV1 included the primary tumor area along with the involved nodal station, while ipsilateral levels Ib and III were included in the intermediate-risk volume (CTV2), and the remaining ipsilateral and contralateral neck nodes were treated prophylactically as part of CTV3.

• Figure 8-7 shows CTV1 and CTV2 delineation for a patient with T3N2c squamous cell carcinoma of the right tonsil. The patient was found to have pathologic level II lymph nodes bilaterally. He received definitive IMRT and chemotherapy.

• CTV1, CTV2, and CTV3 delineation for a patient who presented with a right tonsillar lesion as well as a right-sided jugular digastric (level II/III) lymph node >6 cm in size is shown in Figure 8-8. His disease was staged T3N3M0, and he was treated with chemotherapy concomitantly with definitive IMRT.

• CTV1, CTV2, and CTV3 delineation in a patient with T4N2b squamous cell carcinoma of the tonsil is shown in Figure 8-9. The patient had a right tonsillar mass extending to the pharyngeal wall; two ipsilateral level II lymph nodes were found.

FIGURE 8-5. Clinical target volume (CTV1, CTV2, and CTV3) delineation in a patient with clinically T2N0M0 squamous cell carcinoma of the tonsil. For clarity, the parotid glands are marked with lower case p.

FIGURE 8-6. CTV1, CTV2, and CTV 3 delineation in a patient with clinically T2N2bM0 squamous cell carcinoma of the tonsil who received definitive IMRT. For clarity, the parotid glands are marked with lower case p.

FIGURE 8-7. CTV1 and CTV2 delineation for a patient with T3N2c squamous cell carcinoma of the right tonsil. For clarity, the parotid glands are marked with lower case p.

FIGURE 8-8. CTV1, CTV2, and CTV3 delineation for a patient who presented with a right tonsillar lesion as well as a right-sided jugular digastric (level II/III) lymph node >6 cm in size; disease was staged T3N3M0. For clarity, the parotid glands are marked with lower case p.

6.2.2. Base of Tongue

• Clinical target volume delineation in a patient with T1N0M0 squamous cell carcinoma of BOT is shown in Figure 8-10. In this patient, the primary lesion was confined to the left BOT area, and no lymphadenopathy was seen. Bilateral neck level II–V lymph nodes were prophylactically treated as part of the low-risk volume (CTV3).

• Figure 8-11 shows CTV1, CTV2, and CTV3 delineation for a patient who presented with a left-sided BOT lesion and a single ipsilateral level II lymph node, which was <3 cm in size. The patient’s squamous cell carcinoma was staged as T2N1. The intermediate-risk volume (CTV2) included parts of the oropharynx adjacent to the primary tumor as well as ipsilateral neck levels Ib-V. The contralateral neck, levels II-V, was treated as a low-risk volume (CTV3).

FIGURE 8-9. CTV1, CTV2, and CTV3 delineation in a patient with T4N2b squamous cell carcinoma of the tonsil. For clarity, the parotid glands are marked with lower case p.

• Clinical target volume delineation for a T2N2c squamous cell carcinoma of BOT is shown in Figure 8-12. The patient’s primary lesion extended from the BOT toward the left lingual tonsil. Pathologic nodes were identified in the left level II and right level II/III stations. He was treated with chemotherapy concomitantly with definitive IMRT.

• Clinical target volume delineation for a T3N3 squamous cell carcinoma of BOT is shown in Figure 8-13. The patient presented with a left BOT lesion and a left jugular digastric (level II/III) node measuring >6 cm. CTV1, CTV2, and CTV3 were delineated as shown in the figure. The CTV1 covers the adjacent oropharynx, including the vallecula. The ipsilateral nodal CTV2 extends superiorly to the base of skull to include the retrostyloid area and inferiorly to the area immediately above the sternoclavicular joint.

• Figure 8-14 shows CTV1, CTV2, and CTV3 for a patient with T4N2b squamous cell carcinoma of BOT. The patient was treated concomitantly with chemotherapy and IMRT.

6.3. Normal Tissue Delineation

• Caution on sparing nontarget normal tissue cannot be overstated. Because IMRT will deliver radiation through multiple gantry angles, many nontarget normal tissues will be in the way of either the entrance or the exit beams. In oropharyngeal cancer, it is critical to impose dose constraints to these normal tissues to avoid unnecessary toxicity, such as mucositis. Figure 8-15 depicts the importance and consequences of omitting radiation dose constraints to the lips and oral cavity (aiming for <30 Gy).

6.4. Suggested Target and Normal Tissue Doses

• See Chapter 4 for suggested target and normal tissue doses.

6.5. Intensity-Modulated Radiation Therapy Results

• Following the above guidelines, we treated 74 patients with oropharyngeal carcinoma by using IMRT between February 1997 and December 2001 at Washington University.91 The primary site was the tonsil in 50 patients, BOT in 18 patients, and soft palate in 6 patients. A total of 43 patients were treated postoperatively, and 31 patients were treated with definitive IMRT. The T stages were T1 (16 patients), T2 (25 patients), T3 (14 patients), and T4 (19 patients). The N stages were N0 (12 patients), N1 (16 patients), N2 (42 patients), and N3 (4 patients) (AJCC staging: stage I [2 patients], stage II [3 patients], stage III [17 patients], and stage IV [52 patients]). The median follow-up time was 33 months (9 to 60 months); 10 locoregional recurrences were observed. Distant metastasis developed in 6 patients; 6 patients died of the disease; and 3 patients died of concurrent disease.

• A gastrostomy tube was placed in 17 patients during the course of IMRT. We observed no grade III or IV late complications in the patients who were treated with IMRT. Grade I late xerostomia was observed in 32 patients; grade II late xerostomia was observed in 9 patients; and grade I late mucositis was observed in 3 patients. In addition, trismus was observed in 3 patients after radiotherapy.

• In a comparison study of acute and late toxicity between conventional radiation beam therapy techniques (conformal radiation therapy [CRT]) and IMRT, 430 patients with oropharyngeal cancer (260 with tonsil primary tumors and 170 with BOT primary tumors) were treated with preoperative CRT, postoperative CRT, definitive CRT, postoperative IMRT, or definitive IMRT at Washington University.65 The AJCC stages were stage I (24 patients), stage II (88 patients), stage III (128 patients), and stage IV (190 patients). Median follow-up time was 3.9 years (1 to 23 years). Side effects were scored according to the Radiation Therapy Oncology Group radiation morbidity criteria.

• A significant reduction in late xerostomia was observed in patients who were treated with IMRT, based on parotid-sparing dosimetric advantages. When treated with CRT, 78% to 84% of patients experienced grade 2 or higher late salivary toxicity, as compared with only 17% to 30% of patients who were treated with IMRT (P < 0.0001).

• The Radiation Therapy Oncology Group75 conducted a multi-institutional, prospective study, RTOG 00-22, evaluating moderately accelerated hypofractionated IMRT for early oropharyngeal cancer. A total of 67 patients (33 with primary tonsil tumors, 26 with BOT tumors, and 8 with soft palate tumors) at 14 institutions were treated with definitive IMRT without chemotherapy. The AJCC stages were T1 (17 patients) or T2 (50 patients), N0 (38 patients) or N1 (29 patients), and M0 (Sixty-nine patients were recruited and treated, but two were retrospectively deemed ineligible and excluded from the analysis.) The prescribed PTV doses were 66 Gy in 2.2 Gy/fraction to the primary tumor and involved nodes; subclinical PTVs were treated simultaneously to 54 to 60 Gy in 1.8 to 2.0 Gy/fraction. With a median follow-up of 2.8 years, the estimated 2-year overall survival rate was 95.5%, disease-free survival rate was 82%, and locoregional failure rate was 9%. Maximal late toxicities of grade 2 or higher were as follows: skin 12%, mucosa 24%, salivary 67%, esophagus 19%, osteoradionecrosis 6%. Xerostomia of grade 2 or higher was observed in 55% of patients at 6 months but reduced to 16% at 2 years posttreatment.92

FIGURE 8-10. Clinical target volume delineation in a patient with T1N0M0 squamous cell carcinoma of base of tongue (BOT). For clarity, the parotid glands are marked with lower case p.

FIGURE 8-11. CTV1, CTV2, and CTV3 delineation for a patient who presented with a left-sided BOT squamous cell carcinoma and a single ipsilateral level II lymph node that was <3 cm. The disease was staged as T2N1. For clarity, the parotid glands are marked with lower case p.

FIGURE 8-12. Clinical target volume delineation for a T2N2c squamous cell carcinoma of BOT. For clarity, the parotid glands are marked with lower case p.

FIGURE 8-13. Clinical target volume delineation for a T3N3 squamous cell carcinoma of BOT. For clarity, the parotid glands are marked with lower case p.

• Lok et al.15 recently reported a study on 340 oropharyngeal cancer patients treated with IMRT with curative intent at Memorial Sloan-Kettering. Multivariate analysis showed that primary gross tumor volume and nodal stage were independent risk factors for overall survival. Two-year local, regional, and distant failure rates were 6.1%, 5.2%, and 12.2%, respectively. Two-year overall survival (OS) was 88.6%.

FIGURE 8-14. CTV1, CTV2, and CTV3 for a patient with T4N2b squamous cell carcinoma of BOT. The patient was treated concomitantly with chemotherapy and IMRT. For clarity, the parotid glands are marked with lower case p.

FIGURE 8-15. (A) After completing CTV contouring, the oral cavity should be delineated to avoid excessive entrance and exit beam dose. (B) Patients with excessive mucosal reaction to lips (C) and tongue after 3 weeks of treatment when dose constraints were not imposed on these nontarget normal tissues.

• Thariat et al.93 reported on a large cohort of 880 patients, of which 77% had oropharyngeal cancer. They found that for patients exhibiting complete response, there was no benefit for neck node dissection following RT.

• Schwartz et al.94 reported on initial outcomes in a prospective trial in 22 patients, 20 of whom had stage IV oropharyngeal cancer and treated with adaptive RT. This involved daily CT-guided setup and image registration; IMRT to CTV1 was 66 to 70 Gy in 30 to 33 daily fractions. With a median 31-month follow-up, they reported 2-year local control of 100%, with one nodal failure (regional control 95%). Significantly, treatment replanning due to CTV and normal tissue changes was required only once in all patients and a second replanning, in 36%.

• In an update from Memorial Sloan-Kettering Cancer Center by Setton et al.95 442 oropharyngeal carcinoma patients treated with IMRT had 3-year locoregional control rates of 94% and 3-year overall survival of 85%. Importantly, 94% of the patients were stage III or IV.

• University of Florida reported96 their IMRT oropharyngeal carcinoma experience with 130 patients; 90% had stage III or IV disease. Five-year locoregional control was 84%, and 5-year overall survival was 76%.

• Chen et al.97 treated 77 patients with head and neck cancers (51% in the oropharynx) with helical tomotherapy at doses of 60 to 72 Gy (median 66 Gy). Two-year estimates of OS, locoregional control, and disease-free survival were 82%, 77%, and 71%, respectively. The authors concluded that helical tomotherapy can achieve outcomes comparable to those of standard IMRT.

• Locoregional control and overall survival rates from published IMRT series are summarized in Table 8-12.

REFERENCES

1. Perez CA. Tonsillar fossa and faucial arc. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology, 3rd ed. Philadelphia, PA: Lippincott-Raven, 1998:1003–1032.

2. Fletcher GH. Textbook of Radiotherapy, 3rd ed. Philadelphia, PA: Lea & Febiger, 1980.

3. Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1972;29(6):1446–1449.

4. Chao KSC, Ozyigit G. Intensity Modulated Radiation Therapy for Head-and-Neck Cancer. Philadelphia, PA: Lippincott Williams & Wilkins, 2003.

5. Brunin F, Mosseri V, Jaulerry C, Point D, Cosset JM, Rodriguez J. Cancer of the base of the tongue: past and future. Head Neck 1999;21(8):751–759.

6. Harrison LB, Lee HJ, Pfister DG, et al. Long term results of primary radiotherapy with/without neck dissection for squamous cell cancer of the base of tongue. Head Neck 1998;20(8):668–673.

7. Iyer NG, Clark JR, Singham S, Zhu J. Role of pretreatment 18FDG-PET/CT in surgical decision-making for head and neck cancers. Head Neck 2010;32(9):1202–1208.

8. Broderick M, Leech M, Coffey M. Direct aperture optimization as a means of reducing the complexity of intensity modulated radiation therapy plans. Radia Oncol 2009;4:8.

9. Shukla-Dave A, Lee NY, Jansen JF, et al. Dynamic contrast-enhanced magnetic resonance imaging as a predictor of outcome in head-and-neck squamous cell carcinoma patients with nodal metastases. Int J Radiat Oncol Biol Phys 2012;82(5):1837–1844.

10. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual, 7th ed. New York, NY: Springer Verlag, 2010.

11. Bataini JP, Asselain B, Jaulerry C, et al. A multivariate primary tumour control analysis in 465 patients treated by radical radiotherapy for cancer of the tonsillar region: clinical and treatment parameters as prognostic factors. Radiother Oncol 1989;14(4):265–277.

12. Givens CD Jr., Johns ME, Cantrell RW. Carcinoma of the tonsil. Analysis of 162 cases. Arch Otolaryngol 1981;107(12):730–734.

13. Perez CA, Patel MM, Chao KSC, et al. Carcinoma of the tonsillar fossa: prognostic factors and long-term therapy outcome. Int J Radiat Oncol Biol Phys 1998;42(5):1077–1084.

14. Mendenhall WM, Amdur RJ, Stringer SP, Villaret DB, Cassisi NJ. Radiation therapy for squamous cell carcinoma of the tonsillar region: a preferred alternative to surgery? J Clin Oncol 2000;18(11):2219–2225.

15. Lok BH, Setton J, Caria N, et al. Intensity-modulated radiation therapy in oropharyngeal carcinoma: effect of tumor volume on clinical outcomes. Int J Radiat Oncol Biol Phys 2012;82(5):1851–1857.

16. Klussmann JP, Weissenborn SJ, Wieland U, et al. Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas. Cancer 2001;92(11):2875–2884.

17. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363(1):24–35.

18. Nguyen NP, Ly BH, Betz M, Vinh-Hung V. Importance of age as a prognostic factor for tonsillar carcinoma. Ann Surg Oncol 2010;17(10):2570–2577.

19. Kong CS, Narasimhan B, Cao H, et al. The relationship between human papillomavirus status and other molecular prognostic markers in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 2009;74(2):553–561.

20. Moeller BJ, Yordy JS, Williams MD, et al. DNA repair biomarker profiling of head and neck cancer: Ku80 expression predicts locoregional failure and death following radiotherapy. Clin Cancer Res 2011;17(7):2035–2043.

21. Mendenhall WM, Stringer SP, Amdur RJ, Hinerman RW, Moore-Higgs GJ, Cassisi NJ. Is radiation therapy a preferred alternative to surgery for squamous cell carcinoma of the base of tongue? J Clin Oncol 2000;18(1):35–42.

22. Reimers N, Kasper HU, Weissenborn SJ, et al. Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer 2007;120(8):1731–1738.

23. Lindquist D, Ahrlund-Richter A, Tarjan M, Tot T, Dalianis T. Intense CD44 expression is a negative prognostic factor in tonsillar and base of tongue cancer. Anticancer Res 2012;32(1):153–161.

24. Ildstad ST, Bigelow ME, Remensnyder JP. Squamous cell carcinoma of the tongue: a comparison of the anterior two thirds of the tongue with its base. Am J Surg 1983;146(4):456–461.

25. Moeller BJ, Rana V, Cannon BA, et al. Prospective imaging assessment of mortality risk after head-and-neck radiotherapy. Int J Radiat Oncol Biol Phys 2010;78(3):667–674.

26. Calvin DP, Hammond ME, Pajak TF, et al. Microvessel density >or=60 does not predict for outcome after radiation treatment for locally advanced head and neck squamous cell carcinoma: results of a correlative study from the Radiation Therapy Oncology Group (RTOG) 90-03 Trial. Am J Clin Oncol2007;30(4):406–419.

27. Chen AM, Chen LM, Vaughan A, et al. Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome. Int J Radiat Oncol Biol Phys 2011;79(2):414–419.

28. Chung CH, Zhang Q, Hammond EM, et al. Integrating epidermal growth factor receptor assay with clinical parameters improves risk classification for relapse and survival in head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2011;81(2):331–338.

29. Selek U, Garden AS, Morrison WH, Rosenthal DI, Ang KK. Results of radiation for early-stage carcinoma of the oropharynx. Int J Radiat Oncol Biol Phys 2003;57(Suppl):S404.

30. Soo KC, Tan EH, Wee J, et al. Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison. Br J Cancer 2005;93(3):279–286.

31. Soltys SG, Choi CY, Fee WE, Pinto HA, Le QT. A planned neck dissection is not necessary in all patients with N2-3 head-and-neck cancer after sequential chemoradiotherapy. Int J Radiat Oncol Biol Phys 2012;83(3):994–999.

32. Behar RA, Martin PJ, Fee WE Jr., Goffinet DR. Iridium-192 interstitial implant and external beam radiation therapy in the management of squamous cell carcinomas of the tonsil and soft palate. Int J Radiat Oncol Biol Phys 1994;28(1):221–227.

33. Foote RL, Schild SE, Thompson WM, et al. Tonsil cancer. Patterns of failure after surgery alone and surgery combined with postoperative radiation therapy. Cancer 1994;73(10):2638–2647.

34. Kramer S, Gelber RD, Snow JB, et al. Combined radiation therapy and surgery in the management of advanced head and neck cancer: final report of study 73-03 of the Radiation Therapy Oncology Group. Head Neck Surg 1987;10(1):19–30.

35. Amornmarn R, Prempree T, Jaiwatana J, Wizenberg MJ. Radiation management of carcinoma of the tonsillar region. Cancer 1984;54(7):1293–1299.

36. Dubois JB, Broquerie JL, Delard R, Pourquier H. Analysis of the results of irradiation in the treatment of tonsillar region carcinomas. Int J Radiat Oncol Biol Phys 1983;9(8):1195–1203.

37. Fayos JV, Lampe I. Radiation therapy of carcinoma of the tonsillar region. Am J Roentgenol Radium Ther Nucl Med 1971;111(1):85–94.

38. Lusinchi A, Wibault P, Marandas P, Kunkler I, Eschwege F. Exclusive radiation therapy: the treatment of early tonsillar tumors. Int J Radiat Oncol Biol Phys 1989;17(2):273–277.

39. Mantravadi RV, Liebner EJ, Ginde JV. An analysis of factors in the successful management of cancer of tonsillar region. Cancer 1978;41(3):1054–1058.

40. Mendenhall WM, Parsons JT, Cassisi NJ, Million RR. Squamous cell carcinoma of the tonsillar area treated with radical irradiation. Radiother Oncol 1987;10(1):23–30.

41. Mendenhall WM, Morris CG, Amdur RJ, et al. Definitive radiotherapy for tonsillar squamous cell carcinoma. Am J Clin Oncol 2006;29(3):290–297.

42. Perez CA, Carmichael T, Devineni VR, et al. Carcinoma of the tonsillar fossa: a nonrandomized comparison of irradiation alone or combined with surgery: long-term results. Head Neck 1991;13(4):282–290.

43. Pernot M, Malissard L, Hoffstetter S, et al. Influence of tumoral, radiobiological, and general factors on local control and survival of a series of 361 tumors of the velotonsillar area treated by exclusive irradiation (external beam irradiation+brachytherapy or brachytherapy alone). Int J Radiat Oncol Biol Phys 1994;30(5):1051–1057.

44. Wong CS, Ang KK, Fletcher GH, et al. Definitive radiotherapy for squamous cell carcinoma of the tonsillar fossa. Int J Radiat Oncol Biol Phys 1989;16(3):657–662.

45. Jackson SM, Hay JH, Flores AD, et al. Cancer of the tonsil: the results of ipsilateral radiation treatment. Radiother Oncol 1999;51(2):123–128.

46. O’Sullivan B, Warde P, Grice B, et al. The benefits and pitfalls of ipsilateral radiotherapy in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys 2001;51(2):332–343.

47. Gwozdz JT, Morrison WH, Garden AS, Weber RS, Peters LJ, Ang KK. Concomitant boost radiotherapy for squamous carcinoma of the tonsillar fossa. Int J Radiat Oncol Biol Phys 1997;39(1):127–135.

48. Garrett PG, Beale FA, Cummings BJ, et al. Carcinoma of the tonsil – the effect of dose-time-volume factors on local-control. Int J Radiat Oncol Biol Phys 1985;11(4):703–706.

49. Chronowski GM, Garden AS, Morrison WH, et al. Unilateral radiotherapy for the treatment of tonsil cancer. Int J Radiat Oncol Biol Phys 2012;83(1):204–209.

50. Bachar GY, Goh C, Goldstein DP, O’Sullivan B, Irish JC. Long-term outcome analysis after surgical salvage for recurrent tonsil carcinoma following radical radiotherapy. Eur Arch Oto-Rhino-Laryngol 2010;267(2):295–301.

51. Horton D, Tran L, Greenberg P, Selch MT, Parker RG. Primary radiation therapy in the treatment of squamous cell carcinoma of the soft palate. Cancer 1989;63(12):2442–2445.

52. Lo K, Fletcher GH, Byers RM, Fields RS, Peters LJ, Oswald MJ. Results of irradiation in the squamous cell carcinomas of the anterior faucial pillar-retromolar trigone. Int J Radiat Oncol Biol Phys 1987;13(7):969–974.

53. Leemans CR, Engelbrecht WJ, Tiwari R, et al. Carcinoma of the soft palate and anterior tonsillar pillar. Laryngoscope 1994;104(12):1477–1481.

54. Keus RB, Pontvert D, Brunin F, Jaulerry C, Bataini JP. Results of irradiation in squamous cell carcinoma of the soft palate and uvula. Radiother Oncol 1988;11(4):311–317.

55. Crook J, Mazeron JJ, Marinello G, et al. Combined external irradiation and interstitial implantation for T1 and T2 epidermoid carcinomas of base of tongue: the Creteil experience (1971–1981). Int J Radiat Oncol Biol Phys 1988;15(1):105–114.

56. Parsons JT, Million RR, Cassisi NJ. Carcinoma of the base of the tongue: results of radical irradiation with surgery reserved for irradiation failure. Laryngoscope 1982;92(6 Pt 1): 689–696.

57. Thawley SE, Simpson JR, Marks JE, Perez CA, Ogura JH. Preoperative irradiation and surgery for carcinoma of the base of the tongue. Ann Otol Rhinol Laryngol 1983; 92(5 Pt 1):485–490.

58. Rollo J, Rozenbom CV, Thawley S, et al. Squamous carcinoma of the base of the tongue: a clinicopathologic study of 81 cases. Cancer 1981;47(2):333–342.

59. Foote RL, Olsen KD, Davis DL, et al. Base of tongue carcinoma: patterns of failure and predictors of recurrence after surgery alone. Head Neck 1993;15(4):300–307.

60. Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Werning JW, Villaret DB. Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 2006;29(1):32–39.

61. Puthawala AA, Syed AM, Eads DL, Gillin L, Gates TC. Limited external beam and interstitial 192iridium irradiation in the treatment of carcinoma of the base of the tongue: a ten year experience. Int J Radiat Oncol Biol Phys 1988;14(5): 839–848.

62. Spanos WJ Jr., Shukovsky LJ, Fletcher GH. Time, dose, and tumor volume relationships in irradiation of squamous cell carcinomas of the base of the tongue. Cancer 1976;37(6):2591–2599.

63. Foote RL, Parsons JT, Mendenhall WM, Million RR, Cassisi NJ, Stringer SP. Is interstitial implantation essential for successful radiotherapeutic treatment of base of tongue carcinoma? Int J Radiat Oncol Biol Phys 1990;18(6):1293–1298.

64. Wang C. Carcinoma of the oropharynx. In: Wang C, ed. Radiation Therapy for Head and Neck Neoplasms, 3rd ed. New York, NY: Wiley-Liss, 1997:387.

65. Chao KSC, Majhail N, Huang CJ, et al. Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: a comparison with conventional techniques. Radiother Oncol 2001;61(3):275–280.

66. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998;338(25):1798–1804.

67. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999;91(24):2081–2086.

68. Weinstein GS, O’Malley BW Jr., Cohen MA, Quon H. Transoral robotic surgery for advanced oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 2010;136(11):1079–1085.

69. Goffinet DR, Fee WE, Wells J, et al. Ir-192 pharyngoepiglottic fold interstitial implants – the key to successful treatment of base tongue carcinoma by radiation-therapy. Cancer 1985;55(5):941–948.

70. Kraus DH, Vastola AP, Huvos AG, Spiro RH. Surgical management of squamous cell carcinoma of the base of the tongue. Am J Surg 1993;166(4):384–388.

71. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet2000;355(9208):949–955.

72. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357(17):1695–1704.

73. Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998;16(4):1318–1324.

74. Jeremic B, Shibamoto Y, Milicic B, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 2000;18(7):1458–1464.

75. Tio TL, Cohen P, Coene PP, Udding J, den Hartog Jager FC, Tytgat GN. Endosonography and computed tomography of esophageal carcinoma. Preoperative classification compared to the new (1987) TNM system. Gastroenterology 1989;96(6):1478–1486.

76. Garden AS, Harris J, Trotti A, et al. Long-term results of concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: a phase II trial of the Radiation Therapy Oncology Group (RTOG 99-14). Int J Radiat Oncol Biol Phys 2008;71(5):1351–1355.

77. Newlin HE, Amdur RJ, Riggs CE, Morris CG, Kirwan JM, Mendenhall WM. Concomitant weekly cisplatin and altered fractionation radiotherapy in locally advanced head and neck cancer. Cancer 2010;116(19):4533–4540.

78. Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol2012;13(2):145–153.

79. Merlano M, Benasso M, Corvo R, et al. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 1996;88(9):583–589.

80. Pfister DG, Harrison LB, Strong EW, et al. Organ-function preservation in advanced oropharynx cancer: results with induction chemotherapy and radiation. J Clin Oncol 1995;13(3):671–680.

81. Pfister DG. Chemotherapy in locally advanced, squamous cell head and neck cancer: limitations, lessons learned, and evolving standards of care. Cancer Invest 1995;13(1):134–136.

82. Ghadjar P, Simcock M, Studer G, et al. Concomitant cisplatin and hyperfractionated radiotherapy in locally advanced head and neck cancer: 10-year follow-up of a randomized phase III trial (SAKK 10/94). Int J Radiat Oncol Biol Phys 2012;82(2):524–531.

83. Rischin D, Peters LJ, O’Sullivan B, et al. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol 2010;28(18): 2989–2995.

84. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11(1):21–28.

85. Caudell JJ, Sawrie SM, Spencer SA, et al. Locoregionally advanced head and neck cancer treated with primary radiotherapy: a comparison of the addition of cetuximab or chemotherapy and the impact of protocol treatment. Int J Radiat Oncol Biol Phys 2008;71(3):676–681.

86. Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006;24(7):1072–1078.

87. Koutcher L, Sherman E, Fury M, et al. Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011;81(4):915–922.

88. Gregoire V, Hamoir M, Chen C, et al. Gefitinib plus cisplatin and radiotherapy in previously untreated head and neck squamous cell carcinoma: a phase II, randomized, double-blind, placebo-controlled study. Radiother Oncol 2011;100(1):62–69.

89. Nowsheen S, Bonner JA, LoBuglio AF, et al. Cetuximab augments cytotoxicity with poly (ADP-ribose) polymerase inhibition in head and neck cancer. Plos One 2011;6(8):e24148.

90. Rusthoven KE, Raben D, Schneider C, Witt R, Sammons S, Raben A. Freedom from local and regional failure of contralateral neck with ipsilateral neck radiotherapy for node-positive tonsil cancer: results of a prospective management approach. Int J Radiat Oncol Biol Phys2009;74(5):1365–1370.

91. Chao KSC, Ozyigit G, Blanco AI, et al. Intensity-modulated radiation therapy for oropharyngeal carcinoma: impact of tumor volume. Int J Radiat Oncol Biol Phys 2004;59(1):43–50.

92. Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol Biol Phys 2010;76(5):1333–1338.

93. Thariat J, Ang KK, Allen PK, et al. Prediction of neck dissection requirement after definitive radiotherapy for head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2012;82(3):E367–E374.

94. Schwartz DL, Garden AS, Thomas J, et al. Adaptive radiotherapy for head-and-neck cancer: initial clinical out comes from a prospective trial. Int J Radiat Oncol Biol Phys 2012;83(3):986–993.

95. Setton J, Caria N, Romanyshyn J, et al. Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: an update of the Memorial Sloan-Kettering Cancer Center experience. Int J Radiat Oncol Biol Phys 2012;82(1): 291–298.

96. Mendenhall WM, Amdur RJ, Morris CG, Kirwan JM, Li JG. Intensity-modulated radiotherapy for oropharyngeal squamous cell carcinoma. Laryngoscope 2010;120(11): 2218–2222.

97. Chen AM, Jennelle RL, Sreeraman R, et al. Initial clinical experience with helical tomotherapy for head and neck cancer. Head Neck 2009;31(12):1571-1578.

98. Daly ME, Le QT, Maxim PG, et al. Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: clinical outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 2010;76(5):1339–1346.

99. Clavel S, Nguyen DH, Fortin B, et al. Simultaneous integrated boost using intensity-modulated radiotherapy compared with conventional radiotherapy in patients treated with concurrent carboplatin and 5-fluorouracil for locally advanced oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys2012;82(2):582–589.

100. Huang K, Xia P, Chuang C, et al. Intensity-modulated chemoradiation for treatment of stage III and IV oropharyngeal carcinoma: the University of California-San Francisco experience. Cancer 2008;113(3):497–507.

101. Lawson JD, Otto K, Chen A, Shin DM, Davis L, Johnstone PA. Concurrent platinum-based chemotherapy and simultaneous modulated accelerated radiation therapy for locally advanced squamous cell carcinoma of the tongue base. Head Neck 2008;30(3):327–335.

102. Sanguineti G, Gunn GB, Endres EJ, Chaljub G, Cheruvu P, Parker B. Patterns of locoregional failure after exclusive IMRT for oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2008;72(3):737–746.

103. Schoenfeld GO, Amdur RJ, Morris CG, Li JG, Hinerman RW, Mendenhall WM. Patterns of failure and toxicity after intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2008;71(2): 377–385.

104. Garden AS, Morrison WH, Wong PF, et al. Disease-control rates following intensity-modulated radiation therapy for small primary oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;67(2):438–444.

105. Lee N, Nehmeh S, Schoder H, et al. Prospective trial incorporating pre-/mid-treatment [18F]-misonidazole positron emission tomography for head-and-neck cancer patients undergoing concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys 2009;75(1):101–108.