Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information

TNM Definitions AJCC Stage Groupings

Treatment Option Overview
Stage I Oropharyngeal Cancer

Current Clinical Trials

Stage II Oropharyngeal Cancer

Current Clinical Trials

Stage III Oropharyngeal Cancer

Current Clinical Trials

Stage IV Oropharyngeal Cancer

Resectable Oropharyngeal Cancer Unresectable Oropharyngeal Cancer Current Clinical Trials

Recurrent Oropharyngeal Cancer

Current Clinical Trials

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Changes to This Summary (11/06/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of oropharyngeal cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Risk factors and signs and symptoms.
• Anatomy and histology.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

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General Information

Oropharyngeal cancer is uncommon. Worldwide, cancers of the oropharynx and hypopharynx account for an estimated 123,000 new cases per year, with an estimated mortality of 79,000 deaths.[1] Typically, oropharyngeal cancer involves patients in the fifth through seventh decades of life; men are afflicted 3 to 5 times more often than women.[1-3]

Similar to other cancers of the head and neck, tobacco and alcohol abuse represent the most significant risk factors for the development of oropharyngeal cancer.[3,4] (Refer to the PDQ summaries on Hypopharyngeal Cancer Treatment and Lip and Oral Cavity Cancer Treatment for more information.) Other risk factors may include:[5]

• A diet poor in fruits and vegetables.[6]
• The consumption of maté, a stimulant beverage commonly consumed in South America.[7]
• The chewing of betel quid, a stimulant preparation commonly used in parts of Asia.[8]
• Infection with the human papillomavirus (HPV), especially HPV-type-16, also known as HPV-16.[9,10]

Defective elimination of acetaldehyde, a carcinogen generated by alcohol metabolism, poses an additional risk factor for oropharyngeal cancers. In individuals, primarily East Asians, carrying an inactive mutant allele of alcohol dehydrogenase-2, alcohol consumption is associated with a susceptibility to multiple metachronous oropharyngeal cancers that are caused by the decreased elimination of acetaldehyde.[11]

Anatomically, the oropharynx is located between the soft palate superiorly and the hyoid bone inferiorly; it is continuous with the oral cavity anteriorly and communicates with the nasopharynx superiorly and the supraglottic larynx and hypopharynx inferiorly. The oropharynx is divided into the following sites:[12]

• Base of the tongue, which includes the pharyngoepiglottic folds and the glossoepiglottic folds.
• Tonsillar region, which includes the fossa and the anterior and posterior pillars.
• Soft palate, which includes the uvula.
• Pharyngeal walls, that is, posterior and lateral.

The regional lymph node anatomy of the head and neck contains lymph nodes that run parallel to the jugular veins, spinal accessory nerve, and facial artery and into the submandibular triangle; an understanding of this anatomy and the status of regional lymph nodes is critical to the care of head and neck cancer patients.[3,13] The regions of the neck have been characterized by levels (I–V) to facilitate communication regarding the lymph node anatomy:

• Level I contains the submental and submandibular lymph nodes.
• Level II contains the upper jugular lymph nodes, which are above the digastric muscle.
• Level III contains the mid-jugular lymph nodes, which are between the omohyoid muscle and the digastric muscle.
• Level IV contains the lower jugular lymph nodes.
• Level V contains the lymph nodes of the posterior triangle.

Histologically, almost all oropharyngeal cancers are squamous cell carcinomas (SCCs).[3] Other cancers in this area include minor salivary gland carcinomas, lymphomas, and lymphoepitheliomas, also known as tonsillar fossa. (Refer to the PDQ summaries on Salivary Gland Cancer Treatment, Adult Hodgkin Lymphoma Treatment, and Adult Non-Hodgkin Lymphoma Treatment for more information.)

The concept of field cancerization may be responsible in part for the multiple, synchronous primary SCCs that occur in oropharyngeal cancer. This concept, originally described in 1953, proposes that tumors develop in a multifocal fashion within a field of tissue chronically exposed to carcinogens.[14] Molecular studies detecting genetic alterations in histologically normal tissue from high-risk individuals have provided strong support for the field cancerization concept.[15-19]

Clinically, cancers of the base of the tongue are insidious. These cancers can grow in either an infiltrative or exophytic pattern. Because the base of the tongue is devoid of pain fibers, these tumors are often asymptomatic until they have progressed significantly.[12] Symptoms may include pain, dysphagia, weight loss, referred otalgia secondary to cranial nerve involvement, trismus secondary to pterygoid muscle involvement, fixation of the tongue that is caused by infiltration of the deep muscle, and a mass in the neck.[3,12] (Refer to the PDQ Pain summary and for more information on weight loss, refer to the Nutrition in Cancer Care summary.) Lymph node metastasis is common because of the rich lymphatic drainage of the base of the tongue. Approximately 70% or more of the patients have ipsilateral cervical nodal metastases; 30% or fewer of the patients have bilateral cervical lymph node metastases.[12,20] The cervical lymph nodes involved commonly include levels II and III.

The symptoms of tonsillar lesions include pain, dysphagia, weight loss, ipsilateral referred otalgia, and a mass in the neck.[3,12] The anterior tonsillar pillar and tonsil is the most common location for a primary tumor of the oropharynx.[12] Lesions involving the anterior tonsillar pillar may appear as areas of dysplasia, inflammation, or a superficial spreading lesion. These cancers can progress across a broad region including the lateral soft palate, retromolar trigone and buccal mucosa, and tonsillar fossa.[3,12] The lymphatic drainage is primarily to level II nodes.

Lesions of the tonsillar fossa may be either exophytic or ulcerative and have a pattern of extension similar to those of the anterior tonsillar pillar. These tumors present in advanced-stage disease more often than cancers of the tonsillar pillar. Approximately 75% of patients will present with stage III or stage IV disease.[3,12] The lymphatic drainage is primarily to level V nodes. Tumors of the posterior tonsillar pillar can extend inferiorly to involve the pharyngoepiglottic fold and the posterior aspect of the thyroid cartilage. These lesions more frequently involve level V nodes.

Soft palate tumors are primarily found on the anterior surface.[12] Lesions in this area may remain superficial and in early stages.[3] The lymphatic drainage is primarily to level II nodes.

Tumors of the pharyngeal wall are typically diagnosed in an advanced stage because of the silent location in which they develop.[3,12] Symptoms may include pain, bleeding, weight loss, and a neck mass. These lesions can spread superiorly to involve the nasopharynx, posteriorly to infiltrate the prevertebral fascia, and inferiorly to involve the pyriform sinuses and hypopharyngeal walls. Primary lymphatic drainage is to the retropharyngeal nodes and level II and III nodes. Because most pharyngeal tumors extend past the midline, bilateral cervical metastases are common.

Precancerous lesions of the oropharynx include leukoplakia, erythroplakia, and mixed erythroleukoplakia.[5] These are clinical terms that have no specific histopathologic connotations.[21] Leukoplakia, the most common of the three conditions, is defined by the World Health Organization as “a white patch or plaque that cannot be characterized clinically or pathologically as any other disease.”[22] The diagnosis of leukoplakia is one of exclusion; conditions such as candidiasis, lichen planus, leukoedema, and others must be ruled out before a diagnosis of leukoplakia can be made.[5]

The prevalence of leukoplakia in the United States is decreasing; this decline has been related to a reduction of tobacco consumption.[23] Although erythroplakia is not as common as leukoplakia, it is much more likely to be associated with dysplasia or carcinoma.[5,24]

The clinical anatomic staging of oropharyngeal cancers involves both clinical assessment and imaging techniques.[3,13] One study has reported that positron emission tomography scans are more accurate than computed tomographic scans or magnetic resonance imaging in detecting occult nodal disease.[25] Diagnostic methods under development involve the molecular analysis of tissue from the margins of lip and oral cavity SCCs (i.e., molecular staging) to detect tumor-associated genetic alterations in cells that appear normal by conventional light microscopy. Molecular staging may predict the likelihood of recurrence and may help to establish the relationship between index lesions of SCCs and subsequent lesions.[26,27]

Traditionally, surgery and/or radiation therapy have been the standards for treatment of oropharyngeal cancers; these treatment modalities are frequently complicated by suboptimal control of locoregional disease and significant long-term functional deficits.[3,28] Although specific indications for primary surgical resection exist, some investigators suggest that the concurrent use of multiagent chemotherapy and radiation has become the standard of care for the management of patients with late-stage disease, and surgery is often reserved for salvage of those patients who fail definitive nonoperative treatment.[26,28,29] Studies using aggressive and uncompromised radiation therapy with concurrent multiagent chemotherapy have consistently demonstrated a survival and locoregional control benefit.[30-34] This treatment approach emphasizes organ preservation and functionality. New treatments under development include various biologic therapies (i.e., vaccines, growth factor-receptor antagonists, cyclin-dependent kinase inhibitors, oncolytic viruses, and others) and photodynamic therapy.[26,35-42]

The rate of curability of cancers of the oropharynx varies depending on the stage and specific site. Local control rates for early base-of-tongue cancers approximate 85%.[3] In a large retrospective study involving 262 patients with base-of-tongue cancer, the overall 5-year disease-specific survival rate for patients with all stages of disease was approximately 50%. Treatment modalities included surgery with and without radiation therapy and radiation therapy alone. None of the treatment modalities had a significant survival advantage either overall or within the stages.[43,44]

In a retrospective study involving 162 patients with tonsil carcinoma, 84 patients were treated with primary surgery, which was followed by radiation therapy and/or chemotherapy if histologic signs of aggressive behavior were identified. Survival rates were 89% for stage I, 91% for stage II, 79% for stage III, and 52% for stage IV.[45] In a retrospective study of 188 patients with SCC of the soft palate, uvula, and anterior tonsillar pillar, treatment to the primary site consisted of radiation therapy for 150 patients, surgery for 28 patients, and combined therapy for 10 patients. The overall determinant survival was 80% at 2 years, but it fell to 67% at 5 years.[46] In another retrospective study, 148 patients received definitive radiation therapy for SCC of the pharyngeal wall. Cause-specific survival rates were 89% for stage I, 88% for stage II, 44% for stage III, and 34% for stage IV. Twice-daily fractionation, stage I to stage II disease, and an oropharyngeal primary site were associated with improved locoregional control.[47]

HPV-positive oropharyngeal cancers may represent a distinct disease entity that is causally associated with HPV infection and that is also associated with an improved prognosis. Several studies indicate that individuals with HPV-positive tumors have significantly improved survivals.[10,48,49] In a prospective study involving 253 patients with newly diagnosed or recurrent head and neck SCC, HPV was detected in 25% of the cases. Poor tumor grade and an oropharyngeal site independently increased the probability of HPV presence.[10]

The risk of developing a second primary tumor in patients with tumors of the upper aerodigestive tract has been estimated to be 3% to 7% per year.[50,51] Because of this risk, surveillance of these patients should be lifelong. Patients should be counseled that continued smoking and alcohol consumption after treatment has been associated with the development of second primary tumors of the aerodigestive tract.[52-54] (Refer to the PDQ Smoking Cessation and Continued Risk in Cancer Patients summary for more information.)

To date, SCC of the oropharynx has not been associated with any specific chromosomal or genetic abnormalities. Genetic/chromosomal aberrations in these cancers are complex.[55,56] Despite the lack of specific genetic abnormalities, testing for genetic alterations or ploidy in early oropharyngeal lesions may identify patients who are at the greatest risk for progression and may lead to more definitive therapy.[26]

References

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2. American Cancer Society.: Cancer Facts and Figures 2004. Atlanta, Ga: American Cancer Society, 2004. Also available online. Last accessed January 21, 2008. 
   
   
3. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 
   
   
4. Licitra L, Bernier J, Grandi C, et al.: Cancer of the oropharynx. Crit Rev Oncol Hematol 41 (1): 107-22, 2002.  [PUBMED Abstract]
   
   
5. Neville BW, Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin 52 (4): 195-215, 2002 Jul-Aug.  [PUBMED Abstract]
   
   
6. Sánchez MJ, Martínez C, Nieto A, et al.: Oral and oropharyngeal cancer in Spain: influence of dietary patterns. Eur J Cancer Prev 12 (1): 49-56, 2003.  [PUBMED Abstract]
   
   
7. Goldenberg D, Golz A, Joachims HZ: The beverage maté: a risk factor for cancer of the head and neck. Head Neck 25 (7): 595-601, 2003.  [PUBMED Abstract]
   
   
8. Ho PS, Ko YC, Yang YH, et al.: The incidence of oropharyngeal cancer in Taiwan: an endemic betel quid chewing area. J Oral Pathol Med 31 (4): 213-9, 2002.  [PUBMED Abstract]
   
   
9. Mork J, Lie AK, Glattre E, et al.: Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344 (15): 1125-31, 2001.  [PUBMED Abstract]
   
   
10. Gillison ML, Koch WM, Capone RB, et al.: Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92 (9): 709-20, 2000.  [PUBMED Abstract]
    
    
11. Yokoyama A, Watanabe H, Fukuda H, et al.: Multiple cancers associated with esophageal and oropharyngolaryngeal squamous cell carcinoma and the aldehyde dehydrogenase-2 genotype in male Japanese drinkers. Cancer Epidemiol Biomarkers Prev 11 (9): 895-900, 2002.  [PUBMED Abstract]
    
    
12. Hu KS, Harrison LB, Culliney B, et al.: Cancer of the oropharynx. In: Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 2nd ed. Philadelphia Pa: Lippincott Williams & Wilkins, 2004, pp 306-51. 
    
    
13. Pharynx (including base of tongue, soft palate and uvula). In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 31-46. 
    
    
14. Slaughter DP, Southwick HW, Smejkal W: Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 6 (5): 963-8, 1953. 
    
    
15. Braakhuis BJ, Tabor MP, Leemans CR, et al.: Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions. Head Neck 24 (2): 198-206, 2002.  [PUBMED Abstract]
    
    
16. Braakhuis BJ, Tabor MP, Kummer JA, et al.: A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res 63 (8): 1727-30, 2003.  [PUBMED Abstract]
    
    
17. Tabor MP, Brakenhoff RH, van Houten VM, et al.: Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 7 (6): 1523-32, 2001.  [PUBMED Abstract]
    
    
18. Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ, et al.: Multiple head and neck tumors frequently originate from a single preneoplastic lesion. Am J Pathol 161 (3): 1051-60, 2002.  [PUBMED Abstract]
    
    
19. Ha PK, Califano JA: The molecular biology of mucosal field cancerization of the head and neck. Crit Rev Oral Biol Med 14 (5): 363-9, 2003.  [PUBMED Abstract]
    
    
20. Lindberg R: Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 29 (6): 1446-9, 1972.  [PUBMED Abstract]
    
    
21. Oral cavity and oropharynx. In: Rosai J, ed.: Ackerman's Surgical Pathology. 8th ed. St. Louis, Mo: Mosby, 1996, pp 223-55. 
    
    
22. Kramer IR, Lucas RB, Pindborg JJ, et al.: Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 46 (4): 518-39, 1978.  [PUBMED Abstract]
    
    
23. Scheifele C, Reichart PA, Dietrich T: Low prevalence of oral leukoplakia in a representative sample of the US population. Oral Oncol 39 (6): 619-25, 2003.  [PUBMED Abstract]
    
    
24. Shafer WG, Waldron CA: Erythroplakia of the oral cavity. Cancer 36 (3): 1021-8, 1975.  [PUBMED Abstract]
    
    
25. Ng SH, Yen TC, Chang JT, et al.: Prospective study of [18F]fluorodeoxyglucose positron emission tomography and computed tomography and magnetic resonance imaging in oral cavity squamous cell carcinoma with palpably negative neck. J Clin Oncol 24 (27): 4371-6, 2006.  [PUBMED Abstract]
    
    
26. Forastiere A, Koch W, Trotti A, et al.: Head and neck cancer. N Engl J Med 345 (26): 1890-900, 2001.  [PUBMED Abstract]
    
    
27. Brennan JA, Mao L, Hruban RH, et al.: Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. N Engl J Med 332 (7): 429-35, 1995.  [PUBMED Abstract]
    
    
28. Adelstein DJ: Oropharyngeal cancer: the role of chemotherapy. Curr Treat Options Oncol 4 (1): 3-13, 2003.  [PUBMED Abstract]
    
    
29. Forastiere AA, Trotti A: Radiotherapy and concurrent chemotherapy: a strategy that improves locoregional control and survival in oropharyngeal cancer. J Natl Cancer Inst 91 (24): 2065-6, 1999.  [PUBMED Abstract]
    
    
30. Adelstein DJ, Saxton JP, Lavertu P, et al.: A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck 19 (7): 567-75, 1997.  [PUBMED Abstract]
    
    
31. Wendt TG, Grabenbauer GG, Rödel CM, et al.: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 16 (4): 1318-24, 1998.  [PUBMED Abstract]
    
    
32. 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 338 (25): 1798-804, 1998.  [PUBMED Abstract]
    
    
33. Denis F, Garaud P, Bardet E, et al.: Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22 (1): 69-76, 2004.  [PUBMED Abstract]
    
    
34. Staar S, Rudat V, Stuetzer H, et al.: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 50 (5): 1161-71, 2001.  [PUBMED Abstract]
    
    
35. Chang AE, Li Q, Jiang G, et al.: Generation of vaccine-primed lymphocytes for the treatment of head and neck cancer. Head Neck 25 (3): 198-209, 2003.  [PUBMED Abstract]
    
    
36. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21 (14): 2787-99, 2003.  [PUBMED Abstract]
    
    
37. Senderowicz AM: Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms. Cancer Chemother Pharmacol 52 (Suppl 1): S61-73, 2003.  [PUBMED Abstract]
    
    
38. Chiocca EA: Oncolytic viruses. Nat Rev Cancer 2 (12): 938-50, 2002.  [PUBMED Abstract]
    
    
39. Copper MP, Tan IB, Oppelaar H, et al.: Meta-tetra(hydroxyphenyl)chlorin photodynamic therapy in early-stage squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 129 (7): 709-11, 2003.  [PUBMED Abstract]
    
    
40. Biel MA: Photodynamic therapy and the treatment of head and neck neoplasia. Laryngoscope 108 (9): 1259-68, 1998.  [PUBMED Abstract]
    
    
41. Lou PJ, Jones L, Hopper C: Clinical outcomes of photodynamic therapy for head-and-neck cancer. Technol Cancer Res Treat 2 (4): 311-7, 2003.  [PUBMED Abstract]
    
    
42. Hopper C: Photodynamic therapy: a clinical reality in the treatment of cancer. Lancet Oncol 1: 212-9, 2000.  [PUBMED Abstract]
    
    
43. Sessions DG, Lenox J, Spector GJ, et al.: Analysis of treatment results for base of tongue cancer. Laryngoscope 113 (7): 1252-61, 2003.  [PUBMED Abstract]
    
    
44. Mendenhall WM, Morris CG, Amdur RJ, et al.: Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29 (1): 32-9, 2006.  [PUBMED Abstract]
    
    
45. Galati LT, Myers EN, Johnson JT: Primary surgery as treatment for early squamous cell carcinoma of the tonsil. Head Neck 22 (3): 294-6, 2000.  [PUBMED Abstract]
    
    
46. Weber RS, Peters LJ, Wolf P, et al.: Squamous cell carcinoma of the soft palate, uvula, and anterior faucial pillar. Otolaryngol Head Neck Surg 99 (1): 16-23, 1988.  [PUBMED Abstract]
    
    
47. Hull MC, Morris CG, Tannehill SP, et al.: Definitive radiotherapy alone or combined with a planned neck dissection for squamous cell carcinoma of the pharyngeal wall. Cancer 98 (10): 2224-31, 2003.  [PUBMED Abstract]
    
    
48. Ringström E, Peters E, Hasegawa M, et al.: Human papillomavirus type 16 and squamous cell carcinoma of the head and neck. Clin Cancer Res 8 (10): 3187-92, 2002.  [PUBMED Abstract]
    
    
49. Schwartz SR, Yueh B, McDougall JK, et al.: Human papillomavirus infection and survival in oral squamous cell cancer: a population-based study. Otolaryngol Head Neck Surg 125 (1): 1-9, 2001.  [PUBMED Abstract]
    
    
50. Khuri FR, Lippman SM, Spitz MR, et al.: Molecular epidemiology and retinoid chemoprevention of head and neck cancer. J Natl Cancer Inst 89 (3): 199-211, 1997.  [PUBMED Abstract]
    
    
51. León X, Quer M, Diez S, et al.: Second neoplasm in patients with head and neck cancer. Head Neck 21 (3): 204-10, 1999.  [PUBMED Abstract]
    
    
52. Do KA, Johnson MM, Doherty DA, et al.: Second primary tumors in patients with upper aerodigestive tract cancers: joint effects of smoking and alcohol (United States). Cancer Causes Control 14 (2): 131-8, 2003.  [PUBMED Abstract]
    
    
53. Khuri FR, Kim ES, Lee JJ, et al.: The impact of smoking status, disease stage, and index tumor site on second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial. Cancer Epidemiol Biomarkers Prev 10 (8): 823-9, 2001.  [PUBMED Abstract]
    
    
54. Day GL, Blot WJ, Shore RE, et al.: Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst 86 (2): 131-7, 1994.  [PUBMED Abstract]
    
    
55. Tremmel SC, Götte K, Popp S, et al.: Intratumoral genomic heterogeneity in advanced head and neck cancer detected by comparative genomic hybridization. Cancer Genet Cytogenet 144 (2): 165-74, 2003.  [PUBMED Abstract]
    
    
56. Brieger J, Jacob R, Riazimand HS, et al.: Chromosomal aberrations in premalignant and malignant squamous epithelium. Cancer Genet Cytogenet 144 (2): 148-55, 2003.  [PUBMED Abstract]
    
    

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Cellular Classification

Most oropharyngeal cancers are squamous cell carcinomas (SCCs).[1,2] Other oropharyngeal cancers include minor salivary gland tumors, lymphomas, and lymphoepitheliomas (e.g., tonsillar fossa). (Refer to the PDQ summaries on Salivary Gland Cancer Treatment, Adult Hodgkin Lymphoma Treatment, and Adult Non-Hodgkin Lymphoma Treatment for more information.)

SCCs may be noninvasive or invasive. For noninvasive SCC, the term carcinoma in situ is used. Histologically, invasive carcinomas are well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated. SCCs are usually moderately or poorly differentiated.[2] Grading the deep invasive margins (i.e., invasive front) of SCC may provide better prognostic information than grading of the entire tumor.[3]

Immunohistochemical examination of tissues for the expression of the biomarker Ki-67, a proliferation antigen, may complement histologic grading. As a molecular indicator of epithelial dysplasia of the oropharynx, Ki-67 expression appears to correlate well with loss of heterozygosity (LOH) in tumor cells. In a retrospective study involving 43 tissue samples from 25 patients, the assessment of proliferation with Ki-67 was found to be a better surrogate for LOH than histologic grading.[4]

Leukoplakia should be used only as a clinically descriptive term meaning that the observer sees a white patch that does not rub off, the significance of which depends on the histologic findings.[5] Leukoplakia can range from hyperkeratosis to an actual early invasive carcinoma or may only represent a fungal infection, lichen planus, or other benign oral disease. See General Information section.

References

1. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 
   
   
2. Oral cavity and oropharynx. In: Rosai J, ed.: Ackerman's Surgical Pathology. 8th ed. St. Louis, Mo: Mosby, 1996, pp 223-55. 
   
   
3. Bryne M, Boysen M, Alfsen CG, et al.: The invasive front of carcinomas. The most important area for tumour prognosis? Anticancer Res 18 (6B): 4757-64, 1998 Nov-Dec.  [PUBMED Abstract]
   
   
4. Tabor MP, Braakhuis BJ, van der Wal JE, et al.: Comparative molecular and histological grading of epithelial dysplasia of the oral cavity and the oropharynx. J Pathol 199 (3): 354-60, 2003.  [PUBMED Abstract]
   
   
5. Neville BW, Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin 52 (4): 195-215, 2002 Jul-Aug.  [PUBMED Abstract]
   
   

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Stage Information

The staging systems for oropharyngeal cancer are all clinical, based on the best possible estimate of the extent of disease before treatment. The assessment of the primary tumor is based on inspection and palpation when possible and by indirect mirror examination. The appropriate nodal drainage areas are examined by careful palpation.

The tumor must be confirmed histologically, and any other pathologic data obtained from a biopsy may be included. Additional radiographic studies may be included. As an adjunct to clinical examination, magnetic resonance imaging is used to evaluate the extent of disease in the soft tissues; computed tomography is used to evaluate the mandible and maxilla.[1] Positron emission tomography has been investigated as an imaging modality for recurrent oropharyngeal cancer.[2]

Complete endoscopy, typically under general anesthesia, is performed after completion of other staging studies to assess the surface extent of the tumor accurately, to assess deep involvement by palpation for muscle invasion, and to facilitate biopsy. Because of the incidence of multiple primary tumors occurring simultaneously, a careful search for other primary tumors of the upper aerodigestive tract is indicated.[3]

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[3] Nonepithelial tumors such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included.

Primary tumor (T)

• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• Tis: Carcinoma in situ
• T1: Tumor 2 cm or smaller in greatest dimension
• T2: Tumor larger than 2 cm but 4 cm or smaller in greatest dimension
• T3: Tumor larger than 4 cm in greatest dimension
• T4a: Tumor invades the larynx, deep/extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible
• T4b: Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery

Regional lymph nodes (N)

• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension
• N2: Metastasis in a single ipsilateral lymph node, larger than 3 cm but 6 cm or smaller in greatest dimension, or in multiple ipsilateral lymph nodes, 6 cm or smaller in greatest dimension, or in bilateral or contralateral lymph nodes, 6 cm or smaller in greatest dimension
  • N2a: Metastasis in a single ipsilateral lymph node larger than 3 cm but 6 cm or smaller in greatest dimension
  • N2b: Metastasis in multiple ipsilateral lymph nodes, 6 cm or smaller in greatest dimension
  • N2c: Metastasis in bilateral or contralateral lymph nodes, 6 cm or smaller in greatest dimension
• N3: Metastasis in a lymph node larger than 6 cm in greatest dimension

In clinical evaluation, the actual size of the nodal mass should be measured, and allowance should be made for intervening soft tissues. Most masses larger than 3 cm in diameter are not single nodes but confluent nodes or tumors in soft tissues of the neck. There are three stages of clinically positive nodes: N1, N2, and N3. The use of subgroups a, b, and c is not required but is recommended. Midline nodes are considered homolateral nodes.

Distant metastasis (M)

• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

Stage 0

• Tis, N0, M0

Stage I

• T1, N0, M0

Stage II

• T2, N0, M0

Stage III

• T3, N0, M0
• T1, N1, M0
• T2, N1, M0
• T3, N1, M0

Stage IVA

• T4a, N0, M0
• T4a, N1, M0
• T1, N2, M0
• T2, N2, M0
• T3, N2, M0
• T4a, N2, M0

Stage IVB

• T4b, any N, M0
• Any T, N3, M0

Stage IVC

• Any T, any N, M1

References

1. Weber AL, Romo L, Hashmi S: Malignant tumors of the oral cavity and oropharynx: clinical, pathologic, and radiologic evaluation. Neuroimaging Clin N Am 13 (3): 443-64, 2003.  [PUBMED Abstract]
   
   
2. Wong RJ, Lin DT, Schöder H, et al.: Diagnostic and prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography for recurrent head and neck squamous cell carcinoma. J Clin Oncol 20 (20): 4199-208, 2002.  [PUBMED Abstract]
   
   
3. Pharynx (including base of tongue, soft palate and uvula). In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 31-46. 
   
   

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Treatment Option Overview

On attempting to define the optimal therapeutic approach to the oropharynx, it becomes clear that no single therapeutic regimen offers a clear-cut superior survival over other regimens. The literature is filled with reports highlighting various therapeutic options but does not contain reports presenting any valid comparative studies of therapeutic options. The ultimate therapeutic choice will depend on a careful review of each individual case, paying attention to the staging of the neoplasm, the general physical condition of the patient, the emotional status of the patient, the experience of the treating team, and the available treatment facilities.

A review of published clinical results of radical radiation therapy for head and neck cancer suggests a significant loss of local control when the administration of radiation therapy was prolonged; therefore, lengthening of standard treatment schedules should be avoided whenever possible.[1,2] Patients who smoke during treatment with radiation therapy appear to have lower response rates and shorter survival durations than those who do not;[3] therefore, patients should be counseled to stop smoking before beginning radiation therapy. The posttherapy performance status of patients with base-of-tongue primary tumors appears to be better following radiation therapy than following surgery. Local control and survival is similar in both, which suggests that radiation therapy may be superior.[4,5]

Accumulating evidence has demonstrated a high incidence (i.e., >30%–40%) of hypothyroidism in patients who have received external-beam radiation therapy to the entire thyroid gland or to the pituitary gland. Thyroid function testing of patients should be considered prior to therapy and as part of posttreatment follow-up.[6,7]

References

1. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992.  [PUBMED Abstract]
   
   
2. Allal AS, de Pree C, Dulguerov P, et al.: Avoidance of treatment interruption: an unrecognized benefit of accelerated radiotherapy in oropharyngeal carcinomas? Int J Radiat Oncol Biol Phys 45 (1): 41-5, 1999.  [PUBMED Abstract]
   
   
3. Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993.  [PUBMED Abstract]
   
   
4. Harrison LB, Zelefsky MJ, Armstrong JG, et al.: Performance status after treatment for squamous cell cancer of the base of tongue--a comparison of primary radiation therapy versus primary surgery. Int J Radiat Oncol Biol Phys 30 (4): 953-7, 1994.  [PUBMED Abstract]
   
   
5. Mendenhall WM, Morris CG, Amdur RJ, et al.: Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29 (1): 32-9, 2006.  [PUBMED Abstract]
   
   
6. Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995.  [PUBMED Abstract]
   
   
7. Constine LS: What else don't we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995.  [PUBMED Abstract]
   
   

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Stage I Oropharyngeal Cancer

When radiation is given, careful choice of radiation technique by a radiation oncologist experienced in managing head and neck cancers is essential. The choice of treatment is dictated by the anticipated functional, cosmetic, and socioeconomic results of the treatment options as well as by the available expertise of the surgeon or radiation therapist. Treatment is individualized for each patient.

Standard treatment options:

Surgery or radiation are equally successful in controlling this stage of oropharyngeal cancer.

1. Radiation may be the preferred modality where the functional deficit will be great, such as the tongue base or tonsil.[1]



2. Surgery may be the preferred modality where the functional deficit will be minimal, such as tonsil pillar.

Treatment options under clinical evaluation:

• Radiation clinical trials evaluating hyperfractionation schedules should be considered.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I oropharyngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Mendenhall WM, Amdur RJ, Stringer SP, et al.: Radiation therapy for squamous cell carcinoma of the tonsillar region: a preferred alternative to surgery? J Clin Oncol 18 (11): 2219-25, 2000.  [PUBMED Abstract]
   
   

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Stage II Oropharyngeal Cancer

When radiation is given, careful choice of radiation technique by a radiation oncologist experienced in managing head and neck cancers is essential. Interstitial radiation techniques may be used when indicated. The choice of treatment is dictated by the anticipated functional, cosmetic, and socioeconomic results of the treatment options as well as by the available expertise of the surgeon or radiation therapist. Treatment is individualized for each patient.

Standard treatment options:

• Surgery or radiation therapy are equally successful in controlling this stage of oropharyngeal cancer. Radiation may be the preferred modality as evidenced in the RTOG-9003 trial, for example, where the functional deficit will be great, such as the tongue base or tonsil.[1-3]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II oropharyngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Mendenhall WM, Amdur RJ, Stringer SP, et al.: Radiation therapy for squamous cell carcinoma of the tonsillar region: a preferred alternative to surgery? J Clin Oncol 18 (11): 2219-25, 2000.  [PUBMED Abstract]
   
   
2. Fu KK, Pajak TF, Trotti A, et al.: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 48 (1): 7-16, 2000.  [PUBMED Abstract]
   
   
3. Mendenhall WM, Morris CG, Amdur RJ, et al.: Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29 (1): 32-9, 2006.  [PUBMED Abstract]
   
   

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Stage III Oropharyngeal Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

The management of stage III carcinomas of the oropharynx is complex and requires multidisciplinary input to establish the optimal treatment. New surgical techniques for resection and reconstruction developed in the last 7 to 10 years that provide access and at least partial function restoration have extended the surgical options. External-beam radiation therapy augmented with interstitial implantation and multiple daily treatment schemes have given new insights into the use of radiation for this group of tumors.[1] All of these patients may be considered for entry into neoadjuvant chemotherapy trials.

In general, the preferred treatment as evidenced in the RTOG-7303 trial, for example, has been to combine surgery with postoperative radiation therapy when possible.[2] This approach has become the standard in this specific grouping whenever it can be applied. Aggressive radiation therapy alone will give equivalent control rates to surgery for cancers originating in the tonsil or on the base of the tongue.[3,4]

Specific surgical procedures and their modifications are not designated here because of the wide variety of surgical approaches to the area, the variety of opinions about the role of modified neck dissections, and the multiple reconstructive techniques that may give the same results. This group of patients should be managed by surgeons who are skilled in the multiple procedures available and actively and frequently involved in the care of these patients.

Standard treatment options:

1. A combination of surgery with postoperative radiation therapy or postoperative chemoradiation for selected high-risk patients.[2]



2. Radiation therapy for patients with cancer of the tonsil.[3] Hyperfractionated radiation therapy yields a higher control rate than standard fractionated radiation therapy for patients with stage III cancer of the oropharynx,[5] but this has not resulted in an increase in overall survival.[6][Level of evidence: 1iiA]



3. Chemoradiation therapy.[7-10]

Treatment options under clinical evaluation:

1. Neoadjuvant chemotherapy as given in clinical trials has been used to shrink tumors and thereby render them more definitively treatable with either surgery or radiation. Chemotherapy is given prior to the other modalities, hence the designation neoadjuvant to distinguish it from standard adjuvant therapy, which is given after or during definitive therapy with radiation or after surgery. Many drug combinations have been used in neoadjuvant chemotherapy.[11-15]



2. Chemotherapy has been combined with radiation therapy in patients who have locally advanced disease that is surgically unresectable.[16-22] The best chemotherapy to use and the appropriate way to integrate the two modalities is still unresolved.[23]



3. Radiation clinical trials such as RTOG-8313, for example, evaluating hyperfractionation schedules and/or brachytherapy should be considered.[24]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III oropharyngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Puthawala AA, Syed AM, Eads DL, et al.: 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 14 (5): 839-48, 1988.  [PUBMED Abstract]
   
   
2. Tupchong L, Scott CB, Blitzer PH, et al.: Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 20 (1): 21-8, 1991.  [PUBMED Abstract]
   
   
3. Mendenhall WM, Amdur RJ, Stringer SP, et al.: Radiation therapy for squamous cell carcinoma of the tonsillar region: a preferred alternative to surgery? J Clin Oncol 18 (11): 2219-25, 2000.  [PUBMED Abstract]
   
   
4. Mendenhall WM, Morris CG, Amdur RJ, et al.: Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29 (1): 32-9, 2006.  [PUBMED Abstract]
   
   
5. Horiot JC, Le Fur R, N'Guyen T, et al.: Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 25 (4): 231-41, 1992.  [PUBMED Abstract]
   
   
6. Bourhis J, Lapeyre M, Tortochaux J, et al.: Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial. J Clin Oncol 24 (18): 2873-8, 2006.  [PUBMED Abstract]
   
   
7. Denis F, Garaud P, Bardet E, et al.: Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22 (1): 69-76, 2004.  [PUBMED Abstract]
   
   
8. Olmi P, Crispino S, Fallai C, et al.: Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55 (1): 78-92, 2003.  [PUBMED Abstract]
   
   
9. Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004.  [PUBMED Abstract]
   
   
10. Semrau R, Mueller RP, Stuetzer H, et al.: Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 64 (5): 1308-16, 2006.  [PUBMED Abstract]
    
    
11. Al-Kourainy K, Kish J, Ensley J, et al.: Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer. Cancer 59 (2): 233-8, 1987.  [PUBMED Abstract]
    
    
12. Stupp R, Weichselbaum RR, Vokes EE: Combined modality therapy of head and neck cancer. Semin Oncol 21 (3): 349-58, 1994.  [PUBMED Abstract]
    
    
13. Ensley J, Crissman J, Kish J, et al.: The impact of conventional morphologic analysis on response rates and survival in patients with advanced head and neck cancers treated initially with cisplatin-containing combination chemotherapy. Cancer 57 (4): 711-7, 1986.  [PUBMED Abstract]
    
    
14. Pfister DG, Harrison LB, Strong EW, et al.: Organ-function preservation in advanced oropharynx cancer: results with induction chemotherapy and radiation. J Clin Oncol 13 (3): 671-80, 1995.  [PUBMED Abstract]
    
    
15. Dimery IW, Hong WK: Overview of combined modality therapies for head and neck cancer. J Natl Cancer Inst 85 (2): 95-111, 1993.  [PUBMED Abstract]
    
    
16. Al-Sarraf M, Pajak TF, Marcial VA, et al.: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 59 (2): 259-65, 1987.  [PUBMED Abstract]
    
    
17. Bachaud JM, David JM, Boussin G, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: preliminary report of a randomized trial. Int J Radiat Oncol Biol Phys 20 (2): 243-6, 1991.  [PUBMED Abstract]
    
    
18. Merlano M, Corvo R, Margarino G, et al.: Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial. Cancer 67 (4): 915-21, 1991.  [PUBMED Abstract]
    
    
19. Browman GP, Cripps C, Hodson DI, et al.: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 12 (12): 2648-53, 1994.  [PUBMED Abstract]
    
    
20. Merlano M, Benasso M, Corvò 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 88 (9): 583-9, 1996.  [PUBMED Abstract]
    
    
21. Jeremic B, Shibamoto Y, Stanisavljevic B, et al.: Radiation therapy alone or with concurrent low-dose daily either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: a prospective randomized trial. Radiother Oncol 43 (1): 29-37, 1997.  [PUBMED Abstract]
    
    
22. 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 18 (7): 1458-64, 2000.  [PUBMED Abstract]
    
    
23. Taylor SG 4th, Murthy AK, Vannetzel JM, et al.: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 12 (2): 385-95, 1994.  [PUBMED Abstract]
    
    
24. Cox JD, Pajak TF, Marcial VA, et al.: Dose-response for local control with hyperfractionated radiation therapy in advanced carcinomas of the upper aerodigestive tracts: preliminary report of radiation therapy oncology group protocol 83-13. Int J Radiat Oncol Biol Phys 18 (3): 515-21, 1990.  [PUBMED Abstract]
    
    

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Stage IV Oropharyngeal Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

The management of stage IV carcinomas of the oropharynx is complex and requires multidisciplinary input to establish the optimal treatment. New surgical techniques for resection and reconstruction developed in the last 7 to 10 years that provide access and at least partial function restoration have extended the surgical options. External-beam radiation therapy augmented with interstitial implantation and multiple daily treatment schemes have given new insights into the use of radiation for this group of tumors.[1] All of these patients may be considered for entry into neoadjuvant chemotherapy trials.

In general, the preferred treatment, as evidenced in RTOG-7303, for example, has been to combine surgery with postoperative radiation therapy when possible.[2] This approach has become the standard in this specific grouping whenever it can be applied. Patients with stage IVA cancer of the tonsil treated by aggressive radiation therapy alone have similar results to patients treated with combination therapy.[3][Level of evidence: 3iiiDiii]

Specific surgical procedures and their modifications are not designated here because of the wide variety of surgical approaches to the area, the variety of opinions about the role of modified neck dissections, and the multiple reconstructive techniques that may give the same results. This group of patients should be managed by surgeons who are skilled in the multiple procedures available and actively and frequently involved in the care of these patients.

Standard treatment options:

1. A combination of surgery with postoperative radiation therapy plus chemotherapy in high-risk patients.[2]



2. Radiation therapy alone for patients with stage IVA cancer of the tonsil that does not deeply invade the tongue base.[3,4]

Treatment options under clinical evaluation:

1. Chemotherapy has been combined with radiation therapy in patients who have locally advanced disease that is surgically unresectable.[5-10] The best chemotherapy to use and the appropriate way to integrate the two modalities are still unresolved.[11,12]

   Similar approaches in patients with resectable disease, when resection would lead to a major functional deficit, are also being explored in randomized trials.[13] A trial has shown that chemotherapy (i.e., carboplatin plus fluorouracil) with radiation therapy provides better local control and improved 3-year actuarial overall survival (OS) and disease-free survival than daily radiation therapy alone.[14,15]

   A meta-analysis of 63 randomized prospective trials published between 1965 and 1993 showed an 8% absolute survival advantage in the subset of patients receiving concomitant chemotherapy and radiation therapy.[16][Level of evidence: 2A] Patients receiving adjuvant or neoadjuvant chemotherapy had no survival advantage. Cost, quality of life, and morbidity data, however, were not available; no standard regimen existed; and, the trials were felt to be too heterogenous to provide definitive recommendations. The results of 18 ongoing trials may further clarify the role of concomitant chemotherapy and radiation therapy in the management of oropharyngeal cancer.

2. Radiation clinical trials such as RTOG-8313, for example, evaluating hyperfractionation schedules and/or brachytherapy should be considered.[17] One trial has shown a higher local control rate with very accelerated radiation therapy, but the OS was not improved with this approach.[18][Level of evidence: 1iiA]

Standard treatment options:

• These patients are candidates for radiation therapy or chemoradiation therapy.[14,19,20]

Treatment options under clinical evaluation:

Neoadjuvant chemotherapy as given in clinical trials has been used to shrink tumors and thereby render them more definitively treatable with either surgery or radiation. Many drug combinations have been used in neoadjuvant chemotherapy.[21-26]

1. Concomitant chemotherapy, i.e., chemotherapy with radiation clinical trials as well as with radiosensitizers.[7]



2. Radiation clinical trials evaluating hyperfractionation schedules and/or brachytherapy should be considered.[17]



3. Simultaneous chemotherapy and hyperfractionated radiation therapy.[27]



4. Particle-beam radiation therapy.



5. Hyperthermia combined with radiation therapy.

Posttreatment follow-up:

• These patients should have a careful head and neck examination to look for recurrence monthly for the first posttreatment year, every 2 months for the second year, every 3 months for the third year, and every 6 months thereafter.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV oropharyngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Puthawala AA, Syed AM, Eads DL, et al.: 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 14 (5): 839-48, 1988.  [PUBMED Abstract]
   
   
2. Tupchong L, Scott CB, Blitzer PH, et al.: Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 20 (1): 21-8, 1991.  [PUBMED Abstract]
   
   
3. Mendenhall WM, Amdur RJ, Stringer SP, et al.: Radiation therapy for squamous cell carcinoma of the tonsillar region: a preferred alternative to surgery? J Clin Oncol 18 (11): 2219-25, 2000.  [PUBMED Abstract]
   
   
4. Mendenhall WM, Morris CG, Amdur RJ, et al.: Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29 (1): 32-9, 2006.  [PUBMED Abstract]
   
   
5. Bachaud JM, David JM, Boussin G, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: preliminary report of a randomized trial. Int J Radiat Oncol Biol Phys 20 (2): 243-6, 1991.  [PUBMED Abstract]
   
   
6. Merlano M, Corvo R, Margarino G, et al.: Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial. Cancer 67 (4): 915-21, 1991.  [PUBMED Abstract]
   
   
7. Al-Sarraf M, Pajak TF, Marcial VA, et al.: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 59 (2): 259-65, 1987.  [PUBMED Abstract]
   
   
8. Browman GP, Cripps C, Hodson DI, et al.: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 12 (12): 2648-53, 1994.  [PUBMED Abstract]
   
   
9. Merlano M, Benasso M, Corvò 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 88 (9): 583-9, 1996.  [PUBMED Abstract]
   
   
10. Jeremic B, Shibamoto Y, Stanisavljevic B, et al.: Radiation therapy alone or with concurrent low-dose daily either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: a prospective randomized trial. Radiother Oncol 43 (1): 29-37, 1997.  [PUBMED Abstract]
    
    
11. Taylor SG 4th, Murthy AK, Vannetzel JM, et al.: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 12 (2): 385-95, 1994.  [PUBMED Abstract]
    
    
12. Zakotnik B, Smid L, Budihna M, et al.: Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. Int J Radiat Oncol Biol Phys 41 (5): 1121-7, 1998.  [PUBMED Abstract]
    
    
13. Adelstein DJ, Lavertu P, Saxton JP, et al.: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88 (4): 876-83, 2000.  [PUBMED Abstract]
    
    
14. Denis F, Garaud P, Bardet E, et al.: Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22 (1): 69-76, 2004.  [PUBMED Abstract]
    
    
15. Semrau R, Mueller RP, Stuetzer H, et al.: Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 64 (5): 1308-16, 2006.  [PUBMED Abstract]
    
    
16. Pignon JP, Bourhis J, Domenge C, et al.: 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. Lancet 355 (9208): 949-55, 2000.  [PUBMED Abstract]
    
    
17. Cox JD, Pajak TF, Marcial VA, et al.: Dose-response for local control with hyperfractionated radiation therapy in advanced carcinomas of the upper aerodigestive tracts: preliminary report of radiation therapy oncology group protocol 83-13. Int J Radiat Oncol Biol Phys 18 (3): 515-21, 1990.  [PUBMED Abstract]
    
    
18. Bourhis J, Lapeyre M, Tortochaux J, et al.: Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial. J Clin Oncol 24 (18): 2873-8, 2006.  [PUBMED Abstract]
    
    
19. Olmi P, Crispino S, Fallai C, et al.: Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55 (1): 78-92, 2003.  [PUBMED Abstract]
    
    
20. Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004.  [PUBMED Abstract]
    
    
21. Al-Kourainy K, Kish J, Ensley J, et al.: Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer. Cancer 59 (2): 233-8, 1987.  [PUBMED Abstract]
    
    
22. Stupp R, Weichselbaum RR, Vokes EE: Combined modality therapy of head and neck cancer. Semin Oncol 21 (3): 349-58, 1994.  [PUBMED Abstract]
    
    
23. Ensley J, Crissman J, Kish J, et al.: The impact of conventional morphologic analysis on response rates and survival in patients with advanced head and neck cancers treated initially with cisplatin-containing combination chemotherapy. Cancer 57 (4): 711-7, 1986.  [PUBMED Abstract]
    
    
24. Pfister DG, Harrison LB, Strong EW, et al.: Organ-function preservation in advanced oropharynx cancer: results with induction chemotherapy and radiation. J Clin Oncol 13 (3): 671-80, 1995.  [PUBMED Abstract]
    
    
25. Dimery IW, Hong WK: Overview of combined modality therapies for head and neck cancer. J Natl Cancer Inst 85 (2): 95-111, 1993.  [PUBMED Abstract]
    
    
26. 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 18 (7): 1458-64, 2000.  [PUBMED Abstract]
    
    
27. Weissler MC, Melin S, Sailer SL, et al.: Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 118 (8): 806-10, 1992.  [PUBMED Abstract]
    
    

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Recurrent Oropharyngeal Cancer

Standard treatment options:

1. Surgical resection if radiation therapy fails and if technically feasible.[1]



2. Radiation therapy when surgery fails if not previously given in curative doses that preclude further treatment.[2]



3. Surgical salvage when surgery fails and if technically feasible.[1]

Treatment options under clinical evaluation:

1. Clinical trials evaluating the use of chemotherapy should be considered.[3-6]



2. Clinical trials evaluating the use of hyperthermia and radiation therapy.

Posttreatment follow-up:

• These patients should have a careful head and neck examination to look for recurrence monthly for the first posttreatment year, every 2 months for the second year, every 3 months for the third year, and every 6 months thereafter. If the patient has metastatic disease or local recurrence that is no longer amenable to surgery or radiation, chemotherapy should be considered.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent oropharyngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Wong LY, Wei WI, Lam LK, et al.: Salvage of recurrent head and neck squamous cell carcinoma after primary curative surgery. Head Neck 25 (11): 953-9, 2003.  [PUBMED Abstract]
   
   
2. Vikram B, Strong EW, Shah JP, et al.: Intraoperative radiotherapy in patients with recurrent head and neck cancer. Am J Surg 150 (4): 485-7, 1985.  [PUBMED Abstract]
   
   
3. Hong WK, Bromer R: Chemotherapy in head and neck cancer. N Engl J Med 308 (2): 75-9, 1983.  [PUBMED Abstract]
   
   
4. Kish JA, Ensley JF, Jacobs J, et al.: A randomized trial of cisplatin (CACP) + 5-fluorouracil (5-FU) infusion and CACP + 5-FU bolus for recurrent and advanced squamous cell carcinoma of the head and neck. Cancer 56 (12): 2740-4, 1985.  [PUBMED Abstract]
   
   
5. Vogl SE, Schoenfeld DA, Kaplan BH, et al.: A randomized prospective comparison of methotrexate with a combination of methotrexate, bleomycin, and cisplatin in head and neck cancer. Cancer 56 (3): 432-42, 1985.  [PUBMED Abstract]
   
   
6. Jacobs C, Lyman G, Velez-García E, et al.: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10 (2): 257-63, 1992.  [PUBMED Abstract]
   
   

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Write to us

For more information from the NCI, please write to this address:

NCI Public Inquiries Office

Suite 3036A

6116 Executive Boulevard, MSC8322

Bethesda, MD 20892-8322

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615.

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Changes to This Summary (11/06/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

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More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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