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Oropharyngeal Cancer Treatment (PDQ®)

Table of Contents

General Information About Oropharyngeal Cancer

Incidence and Mortality

Oropharyngeal cancer is uncommon and typically involves patients in the fifth through seventh decades of life; men are afflicted three to five times more often than women.[1-3]

Risk Factors

Oropharyngeal squamous cell carcinoma (SCC) risk factors may include:[4]

  • A smoking history of more than 10 pack years.
  • Infection with the human papillomavirus (HPV), especially HPV type16, also known as HPV-16.[5-7]

Similar to other cancers of the head and neck, tobacco use and heavy alcohol use represent significant risk factors for the development of oropharyngeal cancer.[3,8] (Refer to the PDQ summaries on Hypopharyngeal Cancer Treatment and Lip and Oral Cavity Cancer Treatment for more information.)

Because of the decreased incidence of smoking in the United States, HPV-negative, smoking-related oropharyngeal cancer is decreasing and HPV-associated oropharyngeal cancer is increasing in incidence. The prevalence of HPV in oropharyngeal cancers has increased by 225% from 1988 to 2004, and the HPV-negative cancers have declined by 50% according to the Surveillance, Epidemiology, and End Results (SEER) tissue repository data.[9][Level of Evidence: 3iii]

HPV-positive oropharyngeal cancers may represent a distinct disease entity that is causally associated with HPV infection and is also associated with an improved prognosis. Several studies indicate that individuals with HPV-positive tumors have significantly improved survivals.[6,10-12] 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 the presence of HPV.[6]

The prognosis of oropharyngeal carcinoma is based on HPV status, smoking history (pack-year smoking history of 10 or more years), tumor stage, and nodal stage. The following criteria are used to determine whether patients have low-, intermediate-, or high-risk oropharyngeal carcinoma and have been defined using recursive partitioning analysis in a retrospective analysis of a randomized trial of stage III and IV oropharyngeal SCC patients treated with chemoradiation:

  • Low-risk patients include those with HPV-positive tumors, a smoking history of 10 or fewer pack years, and N0 to N2a nodal disease.
  • Intermediate-risk patients include those with HPV-positive tumors, a smoking history of more than 10 pack years, and N2b–N3 disease; or, for those with HPV-negative tumors, a smoking history of 10 or fewer pack years, N2b or N3 disease, or T2–3 tumors.
  • High-risk patients include those with HPV-negative tumors and a smoking history of more than 10 pack years; or, for those with HPV-negative tumors, a smoking history of 10 or fewer pack years, and T4 disease.

The 3-year rates of overall survival (OS) were 93.0% (95% confidence interval [CI], 88.3–97.7) in the low-risk group, 70.8% (95% CI, 60.7–80.8) in the intermediate-risk group, and 46.2% (95% CI, 34.7–57.7) in the high-risk group.[12]

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.[13,14] Because of this risk, patients require lifelong surveillance. Patients need counseling about continued smoking and alcohol consumption after treatment, which has been associated with the development of second primary tumors of the aerodigestive tract.[15-17] (Refer to the PDQ Smoking Cessation and Continued Risk in Cancer Patients summary for more information.)

An analysis studied 2,230 patients with index SCC of the oropharynx to determine the likelihood of developing second primary malignancies compared with index SCC of nonoropharyngeal sites (i.e., oral cavity, larynx, and hypopharynx). The second primary malignancy rate was lower for patients with index oropharyngeal SCC than for patients with index nonoropharyngeal cancer (P < .001). Among patients with oropharyngeal SCC, former smokers had a 50% greater risk of second primary malignancy and current smokers had a 100% greater risk than never-smokers (P trend = .008). These data suggest that patients who fit the typical HPV phenotype have a very low, second-primary malignancy risk.[18]

To date, SCC of the oropharynx has not been associated with any specific chromosomal or genetic abnormalities. Genetic and chromosomal aberrations in these cancers are complex.[19,20] 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.[21]

Other risk factors may include the following:[4]

  • A diet poor in fruits and vegetables.[22]
  • The consumption of maté, a stimulant beverage commonly consumed in South America.[23]
  • The chewing of betel quid, a stimulant preparation commonly used in parts of Asia.[24]
  • Defective elimination of acetaldehyde, a carcinogen generated by alcohol metabolism. In individuals, primarily East Asians, who carry 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.[25]

Anatomy

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:[26]

  • 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, i.e., 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.[3,27] 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.
  • Retropharyngeal lymph nodes.

Traditionally, the retropharyngeal lymph nodes are at risk for nodal spread in oropharyngeal cancer; this incidence has not been well established until recently.

In a large, retrospective cohort from the MD Anderson Cancer Center, 981 oropharyngeal patients who underwent primary radiation therapy were analyzed.[28] The base of the tongue (47%) and the tonsil (46%) were the most common primary sites. The majority of patients had stage T1 to T2 primary tumors (64%), and 94% had stage 3 to 4B disease. The incidence of radiographic retropharyngeal–nodal involvement was 10% and was highest for the pharyngeal wall (23%) and lowest for the base of the tongue (6%). Retropharyngeal lymph-node involvement was associated with inferior 5-year local control and inferior recurrence-free, distant metastases-free, and OS on multivariate analysis.[28][Levels of evidence: 3iiA, 3iiDii] Histologically, almost all oropharyngeal cancers are 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 and are associated with a smoking history. This concept, originally described in 1953, proposes that tumors develop in a multifocal fashion within a field of tissue chronically exposed to carcinogens.[29] Molecular studies detecting genetic alterations in histologically normal tissue from high-risk individuals have provided strong support for the concept of field cancerization.[30-34]

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.[26]

Symptoms

Symptoms of base-of-the-tongue cancers may include the following:[3,26]

  • 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.
  • A mass in the neck.

(Refer to the PDQ summary on Pain and for more information on weight loss; also 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.[26,35] The cervical lymph nodes involved commonly include levels II, III, IV, V, and retropharyngeal lymph nodes.

The symptoms of tonsillar lesions may include the following:[3,26]

  • Pain.
  • Dysphagia.
  • Weight loss.
  • Ipsilateral referred otalgia.
  • A mass in the neck.

The anterior tonsillar pillar and tonsil is the most common location for a primary tumor of the oropharynx.[26] 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.[3,26] 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.[3,26] 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.[26] 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.[3,26]

Symptoms of pharyngeal wall tumors may include:

  • Pain.
  • Bleeding.
  • Weight loss.
  • A mass in the neck.

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.

Imaging Work-up

The clinical anatomic staging of oropharyngeal cancers involves both clinical assessment and imaging techniques.[3,27] Standard imaging techniques include a dedicated head and neck computed tomography (CT) scan with contrast, positron emission tomography (PET)-CT scan, and magnetic resonance imaging. A PET-CT scan yields morphologic and metabolic data to assess the detection of primary tumor, nodal disease, and distant metastatic disease; it may also be used to guide radiation therapy planning. Retrospective data demonstrate that morphologic and PET-glycolytic parameters, which are measured in fluorodeoxyglucose PET-CT, are significantly larger in HPV-negative disease compared with HPV-positive disease in the primary tumor for oropharyngeal carcinoma. However, the same PET parameters are frequently larger in the regional nodal disease in patients with HPV-positive disease.[36][Level of evidence: 3iiDiv]

References

  1. American Cancer Society: Cancer Facts and Figures 2004. Atlanta, Ga: American Cancer Society, 2004. Also available online. Last accessed July 24, 2014.
  2. Parkin DM, Bray F, Ferlay J, et al.: Estimating the world cancer burden: Globocan 2000. Int J Cancer 94 (2): 153-6, 2001. [PUBMED Abstract]
  3. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 729-80.
  4. Neville BW, Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin 52 (4): 195-215, 2002 Jul-Aug. [PUBMED Abstract]
  5. 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]
  6. 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]
  7. D'Souza G, Kreimer AR, Viscidi R, et al.: Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356 (19): 1944-56, 2007. [PUBMED Abstract]
  8. Licitra L, Bernier J, Grandi C, et al.: Cancer of the oropharynx. Crit Rev Oncol Hematol 41 (1): 107-22, 2002. [PUBMED Abstract]
  9. Chaturvedi AK, Engels EA, Pfeiffer RM, et al.: Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 29 (32): 4294-301, 2011. [PUBMED Abstract]
  10. 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]
  11. 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]
  12. Ang KK, Harris J, Wheeler R, et al.: Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363 (1): 24-35, 2010. [PUBMED Abstract]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. 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]
  18. Gan SJ, Dahlstrom KR, Peck BW, et al.: Incidence and pattern of second primary malignancies in patients with index oropharyngeal cancers versus index nonoropharyngeal head and neck cancers. Cancer 119 (14): 2593-601, 2013. [PUBMED Abstract]
  19. 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]
  20. 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]
  21. Forastiere A, Koch W, Trotti A, et al.: Head and neck cancer. N Engl J Med 345 (26): 1890-900, 2001. [PUBMED Abstract]
  22. 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]
  23. 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]
  24. 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]
  25. 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]
  26. Choi WH, Hu KS, Culliney B, et al.: Cancer of the oropharynx. In: Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Philadelphia, PA: Lippincott, William & Wilkins, 2009, pp 285-335.
  27. Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.
  28. Gunn GB, Debnam JM, Fuller CD, et al.: The impact of radiographic retropharyngeal adenopathy in oropharyngeal cancer. Cancer 119 (17): 3162-9, 2013. [PUBMED Abstract]
  29. Slaughter DP, Southwick HW, Smejkal W: Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 6 (5): 963-8, 1953. [PUBMED Abstract]
  30. 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]
  31. 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]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. Tahari AK, Alluri KC, Quon H, et al.: FDG PET/CT imaging of oropharyngeal squamous cell carcinoma: characteristics of human papillomavirus-positive and -negative tumors. Clin Nucl Med 39 (3): 225-31, 2014. [PUBMED Abstract]

Cellular Classification of Oropharyngeal Cancer

Most oropharyngeal cancers are squamous cell carcinomas (SCCs).[1,2] Other oropharyngeal cancers include:

  • Minor salivary gland tumors.
  • Lymphomas.
  • 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. (Refer to the General Information About Oropharyngeal Cancer section of this summary for more information.)

References

  1. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 729-80.
  2. Oral cavity and oropharynx. In: Rosai J, ed.: Rosai and Ackerman's Surgical Pathology. Vol. 1. 10th ed. New York, NY: Mosby Elsevier, 2011, pp. 237-264.
  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]

Stage Information for Oropharyngeal Cancer

The staging systems for oropharyngeal cancer are all clinical and are 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. Any other pathologic data obtained from a biopsy and 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]

Definitions of TNM

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

Table 1. Primary Tumor (T)a
aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.
bMucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not constitute invasion of larynx.
TXPrimary tumor cannot be assessed.
T0No evidence of primary tumor.
TisCarcinoma in situ.
T1Tumor ≤2 cm in greatest dimension.
T2Tumor >2 cm but ≤4 cm in greatest dimension.
T3Tumor >4 cm in greatest dimension or extension to lingual surface of epiglottis.
T4aModerately advanced local disease. Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible.b
T4bVery advanced local disease. Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base, or encases carotid artery.
Table 2. Regional Lymph Nodes (N)a,b
aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.
bMetastases at level VII are considered regional lymph node metastases.
NXRegional lymph nodes cannot be assessed.
N0No regional lymph node metastasis.
N1Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension.
N2Metastasis in a single ipsilateral lymph node, >3 cm but ≤6 cm in greatest dimension, or metastasis in multiple ipsilateral lymph nodes, ≤6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, ≤6 cm in greatest dimension.
N2aMetastasis in a single ipsilateral lymph node >3 cm but ≤6 cm in greatest dimension.
N2bMetastases in multiple ipsilateral lymph nodes, ≤6 cm in greatest dimension.
N2cMetastases in bilateral or contralateral lymph nodes, ≤6 cm in greatest dimension.
N3Metastasis in a lymph node >6 cm in greatest dimension.
Table 3. Distant Metastasis (M)a
aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.
M0No distant metastasis.
M1Distant metastasis.
Table 4. Anatomic Stage/Prognostic Groupsa
StageTNM
aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.
0TisN0M0
IT1N0M0
IIT2N0M0
IIIT3N0M0
T1N1M0
T2N1M0
T3N1M0
IVAT4aN0M0
T4aN1M0
T1N2M0
T2N2M0
T3N2M0
T4aN2M0
IVBT4bAny NM0
Any TN3M0
IVCAny TAny NM1

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. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.

Treatment Option Overview

An optimal therapeutic approach to the oropharynx is not easily defined because no single therapeutic regimen offers a clear-cut, superior-survival advantage 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 depends on a careful review of each case, 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.

Treatment Overview

Traditionally, surgery and radiation therapy have been the standards for treatment of oropharyngeal cancers. No randomized data are available to compare surgery, radiation therapy, or combined treatment.

A pooled analysis of 6,400 patients from 51 reported series who were treated for base-of-tongue oropharyngeal carcinoma between 1970 and 2000 demonstrated local control rates of 79% (surgery ± radiation) and 76% (radiation), (P = .087); locoregional control was 60% versus 69% (P = .009); 5-year survival was 49% for surgery with or without radiation therapy versus 52% (P = .2) for radiation therapy with or without neck dissection.[1] Severe complications were 32% for the surgery group versus 3.8% for the radiation therapy group (P < .001); fatal complications were 3.5% for the surgery group versus 0.4% for the radiation therapy group (P < .001). Similar findings showed equivalent overall and cause-specific survival between surgery versus radiation for tonsil carcinoma; however, 23% overall and cause-specific survival for severe complications in the surgery group versus 6% overall and cause-specific survival in the radiation therapy group (P < .001).

For patients with early-stage disease, single-modality treatment, usually radiation therapy alone, is preferred; however, emerging surgical techniques, including transoral surgery and transoral robotic surgery, are currently evolving. Nonrandomized comparisons suggest superior quality of life with minimally invasive surgical techniques.[2] Historically, more invasive surgical techniques were associated with inferior quality of life and greater morbidity.

Historically, the post-therapy performance status of patients with base-of-tongue primary tumors appeared to be better after radiation therapy than after surgery. Local control and survival is similar in both treatment options.[3,4] Prospective multicenter trials, including RTOG-1221 (NCT01953952) and ECOG-3311 (NCT01898494), are currently underway comparing transoral surgery approaches with definitive radiation or chemoradiation.

Definitive Radiation Therapy

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, the lengthening of standard treatment schedules is not beneficial.[5,6] Patients who smoke during treatment with radiation therapy appear to have lower response rates and shorter survival durations than those who do not;[7] therefore, counseling patients to stop smoking before beginning radiation therapy is beneficial.

Intensity-modulated radiation therapy (IMRT) has evolved over the past decade to become a standard technique for head and neck radiation therapy. IMRT allows a dose-painting technique also known as a simultaneous-integrated-boost (SIB) technique with a dose per fraction slightly higher than 2 Gy, which allows slight shortening of overall treatment time and increases the biologically equivalent dose to the tumor.

IMRT was studied in a phase II trial (RTOG-0022 [NCT00006360]) of 69 patients with stage T1–2, N0–1, M0 oropharyngeal carcinoma who were treated with primary radiation therapy without chemotherapy.[8] The median follow-up was 2.8 years. Prescribed planning target volume (PTV)-doses to the primary tumor and involved nodes was 66 Gy at 2.2 Gy per fraction over 6 weeks. Subclinical PTVs received simultaneously 54 to 60 Gy at 1.8 to 2.0 Gy per fraction using an SIB technique. The 2-year estimated local-regional failure rate was 9%. Two of four patients (50%), who had major underdose deviations, had locoregional failure compared with 3 of 49 patients (6%) without such deviations (P = .04). Maximal late toxicities with a grade of 2 or greater were skin (12%), mucosa (24%), salivary (67%), esophagus (19%), and osteoradionecrosis (6%).

Longer follow-up revealed reduced late toxicity in all categories. Xerostomia grade 2 or greater was observed in 55% of patients at 6 months but was reduced to 25% of patients at 12 months and 16% of patients at 24 months. The RTOG-0022 study showed high control rates and the feasibility of IMRT at a multi-institutional level; the study also showed high tumor control rates and reduced salivary toxicity compared with previous RTOG studies. However, major target underdose deviations were associated with a higher locoregional failure rate. Similar nonrandomized multicenter studies using fractionally escalated doses, which ranged from 2.3 to 2.5 Gy with IMRT, have been safe when given without concurrent chemotherapy for pharyngolaryngeal T2N0, T2N1, or laryngeal T3N0 squamous cell carcinoma. No toxicity difference was observed between the different dose-escalated groups.[9-13]

In a randomized trial (PARSPORT [NCT00081029]) conducted in the United Kingdom that compared conventional 3-dimensional conformal radiation therapy with IMRT, xerostomia rates were significantly lower in the IMRT group compared with the conventional group.[14][Level of evidence: 1iiA] Fatigue was more prevalent in the IMRT group. At 24 months, there were no significant differences seen in nonxerostomia late toxicities, locoregional control, or overall survival (OS).

For patients with well-lateralized oropharyngeal cancer, such as a T1 or T2 tonsil primary tumor with limited extension into the palate or tongue base, consideration of elective treatment to the ipsilateral lymph nodes results in only minimal risk of failure to the contralateral neck.[15] For T3 and T4 tumors that are midline or approach the midline, bilateral nodal treatment is a consideration. Retropharyngeal lymph nodes can also be encompassed in the elective nodal treatment in addition to the cervical lymph node chain.

Other late effects from radiation therapy include hypothyroidism in 30% to 40% of patients who have received external-beam radiation therapy to the entire thyroid gland. Thyroid function testing of patients should be considered before therapy and as part of posttreatment follow-up.[16,17]

Chemoradiation Therapy

For locally advanced disease, concurrent chemoradiation approaches are superior to radiation therapy alone.[18] This treatment approach emphasizes organ preservation and functionality.[19,20]

Concomitant Radiation Therapy With Targeted Agents

In a randomized trial of locally advanced head and neck cancer patients, curative-intent radiation therapy alone (213 patients) was compared with radiation therapy plus weekly cetuximab (211 patients).[21] The initial dose was 400 mg per square meter of body-surface area 1 week before starting radiation therapy followed by 250 mg per square meter weekly for the duration of the radiation therapy. At a median follow up of 54 months, patients treated with cetuximab and radiation therapy demonstrated significantly higher progression-free survival (hazard ratio for disease progression or death, 0.70; P = .006). Patients in the cetuximab arm experienced higher rates of acneiform rash and infusion reactions, although the incidence of other grade 3 or higher toxicities, including mucositis, did not differ significantly between the two groups. This study allowed altered-fractionation regimens to be used in both arms.[21,22][Level of evidence: 1iiA]

Postoperative Radiation Therapy (PORT) With or Without Chemotherapy

Depending on pathological findings after primary surgery, PORT or postoperative chemoradiation is used in the adjuvant setting for the following histological findings including:

  • T4 disease.
  • Perineural invasion.
  • Lymphovascular invasion.
  • Positive margins or margins less than 5 mm.
  • Extracapsular extension of a lymph node.
  • Two or more involved lymph nodes.

The benefit for OS has been demonstrated with postoperative chemoradiation therapy using cisplatin; an OS benefit has also been found for positive margins and extracapsular extension.[23-26][Level of evidence: 1iiA] The addition of chemotherapy to radiation therapy for other pathological risk factors is unclear. A postoperative randomized trial (RTOG-0920 [NCT00956007]) is evaluating the use of cetuximab with adjuvant radiation therapy in the postoperative setting.[23-26][Level of evidence: 1iiA]

References

  1. Parsons JT, Mendenhall WM, Stringer SP, et al.: Squamous cell carcinoma of the oropharynx: surgery, radiation therapy, or both. Cancer 94 (11): 2967-80, 2002. [PUBMED Abstract]
  2. Chen AM, Daly ME, Luu Q, et al.: Comparison of functional outcomes and quality of life between transoral surgery versus definitive chemoradiotherapy for oropharyngeal cancer. Head Neck : , 2014. [PUBMED Abstract]
  3. 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]
  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. 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]
  6. 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]
  7. 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]
  8. 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 76 (5): 1333-8, 2010. [PUBMED Abstract]
  9. Leclerc M, Maingon P, Hamoir M, et al.: A dose escalation study with intensity modulated radiation therapy (IMRT) in T2N0, T2N1, T3N0 squamous cell carcinomas (SCC) of the oropharynx, larynx and hypopharynx using a simultaneous integrated boost (SIB) approach. Radiother Oncol 106 (3): 333-40, 2013. [PUBMED Abstract]
  10. Buettner F, Miah AB, Gulliford SL, et al.: Novel approaches to improve the therapeutic index of head and neck radiotherapy: an analysis of data from the PARSPORT randomised phase III trial. Radiother Oncol 103 (1): 82-7, 2012. [PUBMED Abstract]
  11. Gulliford SL, Miah AB, Brennan S, et al.: Dosimetric explanations of fatigue in head and neck radiotherapy: an analysis from the PARSPORT Phase III trial. Radiother Oncol 104 (2): 205-12, 2012. [PUBMED Abstract]
  12. Kohler RE, Sheets NC, Wheeler SB, et al.: Two-year and lifetime cost-effectiveness of intensity modulated radiation therapy versus 3-dimensional conformal radiation therapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 87 (4): 683-9, 2013. [PUBMED Abstract]
  13. Gupta T, Agarwal J, Jain S, et al.: Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: a randomized controlled trial. Radiother Oncol 104 (3): 343-8, 2012. [PUBMED Abstract]
  14. Nutting CM, Morden JP, Harrington KJ, et al.: Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 12 (2): 127-36, 2011. [PUBMED Abstract]
  15. 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 51 (2): 332-43, 2001. [PUBMED Abstract]
  16. 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]
  17. 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]
  18. 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]
  19. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 729-80.
  20. Adelstein DJ: Oropharyngeal cancer: the role of chemotherapy. Curr Treat Options Oncol 4 (1): 3-13, 2003. [PUBMED Abstract]
  21. Bonner JA, Harari PM, Giralt J, et al.: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354 (6): 567-78, 2006. [PUBMED Abstract]
  22. Curran D, Giralt J, Harari PM, et al.: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25 (16): 2191-7, 2007. [PUBMED Abstract]
  23. Bernier J, Cooper JS, Pajak TF, et al.: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27 (10): 843-50, 2005. [PUBMED Abstract]
  24. Cooper JS, Zhang Q, Pajak TF, et al.: Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 84 (5): 1198-205, 2012. [PUBMED Abstract]
  25. Cooper JS, Pajak TF, Forastiere AA, et al.: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350 (19): 1937-44, 2004. [PUBMED Abstract]
  26. 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]

Stage I and Stage II Oropharyngeal Cancer

Surgery or radiation is equally successful in controlling stage I and stage II oropharyngeal cancer.

Standard treatment options:

  1. Radiation therapy using standard fractionation.
  2. Surgery.

When radiation is given, the 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 and cosmetic outcome of the treatment options and by the available expertise of the surgeon or radiation therapist. Treatment is individualized for each patient.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I oropharyngeal cancer and 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.

Stage III Oropharyngeal Cancer

The management of stage III carcinomas of the oropharynx is complex and requires multidisciplinary input to establish the optimal treatment.

Standard treatment options:

New surgical techniques for resection and reconstruction developed in the last 7 to 10 years that provide access and functional preservation have extended the surgical options. PORT is indicated based on pathological risk factors. High-risk features, including positive margins and extracapsular nodal extension, show additional locoregional control and survival benefit with the addition of concomitant chemotherapy.[1-4][Level of evidence: 1iiA] All of these patients may be considered for entry into neoadjuvant chemotherapy trials.

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 head and neck surgeons who are skilled in the multiple procedures available and actively and frequently involved in the care of these patients.

Surgery Followed by PORT or Chemoradiation Therapy

Postoperative chemoradiation therapy for oropharyngeal squamous cell carcinoma demonstrates a locoregional control and survival benefit compared with radiation therapy alone in patients who have extracapsular extension (ECE) of a lymph node or positive margins.[1-4][Level of evidence: 1iiA]

For patients with T3 and T4 disease (or stage III and stage IV disease), perineural infiltration, vascular embolisms, and clinically enlarged level IV or level V lymph nodes secondary to tumors arising in the oral cavity or oropharynx; two or more histopathologically involved lymph nodes without ECE; and close margins less than 5 mm, the addition of cisplatin chemotherapy given concurrently with PORT is unclear. The addition of cetuximab with radiation therapy in the postoperative setting for these risk factors is being tested in a randomized trial (RTOG-0920 [NCT00956007]).

Altered Fractionation

Radiation therapy alone with altered fractionation may be used for patients with locally advanced oropharyngeal cancer who are not candidates for chemotherapy. Altered fractionated radiation therapy yields a higher locoregional control rate than standard fractionated radiation therapy for patients with stage III and stage IV oropharyngeal cancer. The long-term analysis of randomized trial RTOG-9003 (NCT00771641) included the following four radiation therapy treatment arms:

  1. Standard fractionation (SFX) to 70 Gy in 35 daily fractions for 7 weeks.
  2. Hyperfractionation (HFX) to 81.6 Gy in 68 twice-daily fractions for 7 weeks.
  3. Accelerated fractionation (AFX-S) to 67.2 Gy in 42 fractions for 6 weeks with a 2-week rest after 38.4 Gy.
  4. Accelerated continuous fractionation (AFX-C) to 72 Gy in 42 fractions for 6 weeks.

The three experimental arms were to be compared with SFX. Only the HFX arm showed superior locoregional control and survival at 5 years compared with the SFX arm (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.62–1.00; P = .05). AFX-C was associated with increased late toxicity compared with SFX.[5-9,16][Level of evidence: 1iiA]

In a meta-analysis of 15 randomized trials with a total of 6,515 patients and a median follow-up of 6 years involving the assessment of HFX or AFX-S for patients with stage III and stage IV oropharyngeal cancer, there was a significant survival benefit with altered fractionated radiation therapy and a 3.4% absolute benefit at 5 years (HR, 0.92; 95% CI, 0.86–0.97; P = .003). Altered fractionated radiation therapy improves locoregional control, and the benefit is higher in younger patients. HFX demonstrated a greater survival benefit (8% at 5 years) than AFX-S (2% with accelerated fractionation without total dose-reduction and 1.7% with total dose-reduction at 5 years, P = .02).[17][Level of evidence: 1iiA]

Concomitant Radiation Therapy With Targeted Agents

In a randomized trial of locally advanced head and neck cancer patients, curative-intent radiation therapy alone (213 patients) was compared with radiation therapy plus weekly cetuximab (211 patients).[10] The initial dose was 400 mg/m2 of body-surface area 1 week before starting radiation therapy followed by a weekly dose of 250 mg/m2 of body-surface area for the duration of radiation therapy. At a median follow up of 54 months, patients treated with cetuximab and radiation therapy demonstrated significantly higher progression-free survival (HR for disease progression or death, 0.70; P = .006). Patients in the cetuximab arm experienced higher rates of acneiform rash and infusion reactions, although the incidence of other grade 3 or higher toxicities, including mucositis, did not differ significantly between the two groups. This study allowed altered fractionation regimens to be used in both arms.[10,11][Level of evidence: 1iiA]

Concomitant Chemoradiation Therapy

Concomitant chemoradiation therapy is a standard treatment option for locally advanced (stage III and stage IV) oropharyngeal carcinoma. A meta-analysis of 93 randomized, prospective head and neck cancer trials published between 1965 and 2000 showed a 4.5% absolute survival advantage in the subset of patients receiving chemotherapy and radiation therapy.[15][Level of evidence: 2A] Patients receiving concomitant chemotherapy had a greater survival benefit than those receiving induction chemotherapy.

Treatment options under clinical evaluation:

  1. Neoadjuvant chemotherapy as given in clinical trials has been used to shrink tumors and render them more definitively treatable with either surgery or radiation. Chemotherapy is given before the other modalities; therefore, 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.[18-22]
  2. In a randomized study (PARADIGM [NCT00095875]) of docetaxel, cisplatin, and fluorouracil (TPF) neoadjuvant chemotherapy followed by concomitant chemoradiation, no survival advantage was demonstrated in the neoadjuvant chemotherapy group over standard chemoradiation. This study did not stratify for human papillomavirus status, and the role of neoadjuvant chemotherapy that is administered before concurrent chemoradiation remains unclear.[23]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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. Bernier J, Cooper JS, Pajak TF, et al.: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27 (10): 843-50, 2005. [PUBMED Abstract]
  2. Cooper JS, Zhang Q, Pajak TF, et al.: Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 84 (5): 1198-205, 2012. [PUBMED Abstract]
  3. Cooper JS, Pajak TF, Forastiere AA, et al.: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350 (19): 1937-44, 2004. [PUBMED Abstract]
  4. 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]
  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. Overgaard J, Hansen HS, Specht L, et al.: Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 362 (9388): 933-40, 2003. [PUBMED Abstract]
  8. Overgaard J, Mohanti BK, Begum N, et al.: Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial. Lancet Oncol 11 (6): 553-60, 2010. [PUBMED Abstract]
  9. 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]
  10. Bonner JA, Harari PM, Giralt J, et al.: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354 (6): 567-78, 2006. [PUBMED Abstract]
  11. Curran D, Giralt J, Harari PM, et al.: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25 (16): 2191-7, 2007. [PUBMED Abstract]
  12. 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]
  13. 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]
  14. 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]
  15. Pignon JP, le Maître A, Maillard E, et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92 (1): 4-14, 2009. [PUBMED Abstract]
  16. Beitler JJ, Zhang Q, Fu KK, et al.: Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 89 (1): 13-20, 2014. [PUBMED Abstract]
  17. Baujat B, Bourhis J, Blanchard P, et al.: Hyperfractionated or accelerated radiotherapy for head and neck cancer. Cochrane Database Syst Rev (12): CD002026, 2010. [PUBMED Abstract]
  18. 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]
  19. Stupp R, Weichselbaum RR, Vokes EE: Combined modality therapy of head and neck cancer. Semin Oncol 21 (3): 349-58, 1994. [PUBMED Abstract]
  20. 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]
  21. 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]
  22. 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]
  23. Haddad R, O'Neill A, Rabinowits G, et al.: Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol 14 (3): 257-64, 2013. [PUBMED Abstract]

Stage IV Oropharyngeal Cancer

The management of stage IV carcinomas of the oropharynx is complex and requires multidisciplinary input to establish the optimal treatment.

Standard treatment options:

  1. A combination of surgery with postoperative radiation therapy (PORT) or postoperative chemoradiation for selected high-risk patients.[1-4][Level of evidence: 1iiA]
  2. Concomitant chemoradiation therapy.[5]
  3. Concomitant radiation therapy with targeted agents.[6,7][Level of evidence: 1iiA]
  4. Neoadjuvant chemotherapy followed by concomitant chemoradiation therapy.[8]
  5. Radiation therapy alone (with altered fractionation) for patients who are not candidates for chemotherapy.[9,10] Altered fractionated radiation therapy yields a higher control rate and survival rate than standard fractionated radiation therapy (SFX) only for patients with stage IV cancer of the oropharynx.[9-11,11-13][Level of evidence: 1iiA]

New surgical techniques for resection and reconstruction developed in the last 7 to 10 years that provide access and functional preservation have extended the surgical options. PORT is indicated based on pathological risk factors. High-risk features including positive margins and extracapsular nodal extension show additional locoregional control and survival benefit with the addition of concomitant chemotherapy.[1-4][Level of evidence: 1iiA]

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 head and neck surgeons who are skilled in the multiple procedures available and actively and frequently involved in the care of these patients.

Surgery Followed by PORT or Chemoradiation Therapy

Postoperative chemoradiation therapy for oropharyngeal squamous cell carcinoma demonstrates a locoregional control and survival benefit compared with radiation therapy alone in patients who have extracapsular extension (ECE) of a lymph node or positive margins.[1-4][Level of evidence: 1iiA]

For patients with T3 and T4 disease (or stage III and stage IV disease), perineural infiltration, vascular embolisms, and clinically enlarged level IV or level V lymph nodes secondary to tumors arising in the oral cavity or oropharynx; two or more histopathologically involved lymph nodes without ECE, and close margins less than 5 mm, the addition of cisplatin chemotherapy given concurrently with PORT is unclear. The addition of cetuximab with radiation therapy in the postoperative setting for these risk factors is being tested in a randomized trial (RTOG-0920 [NCT00956007]).

Concomitant Chemoradiation Therapy

Concomitant chemoradiation therapy is a standard treatment option for locally advanced (stage III and stage IV) oropharyngeal carcinoma. A meta-analysis of 93 randomized, prospective head and neck cancer trials published between 1965 and 2000 showed a 4.5% absolute survival advantage in the subset of patients receiving chemotherapy and radiation therapy.[5][Level of evidence: 2A] Patients receiving concomitant chemotherapy had a greater survival benefit than those receiving induction chemotherapy.

Concomitant Radiation Therapy With Targeted Agents

In a randomized trial of locally advanced head and neck cancer patients, curative-intent radiation therapy alone (213 patients) was compared with radiation therapy plus weekly cetuximab (211 patients).[6] The initial dose was 400 mg/m2 of body-surface area a week before starting radiation therapy followed by a weekly dose of 250 mg/m2 of body-surface area for the duration of radiation therapy. At a median follow-up of 54 months, patients treated with cetuximab and radiation therapy demonstrated significantly higher progression-free survival (hazard ratio [HR] for disease progression or death, 0.70; P = .006). Patients in the cetuximab arm experienced higher rates of acneiform rash and infusion reactions, although the incidence of other grade 3 or higher toxicities, including mucositis, did not differ significantly between the two groups. This study allowed altered-fractionation regimens to be used in both arms.[6,7][Level of evidence: 1iiA]

Induction Chemoradiation Therapy Followed by Concomitant Chemoradiation Therapy

Two published, randomized trials that compared concomitant chemoradiation therapy with induction chemotherapy followed by concomitant chemoradiation therapy for locally advanced oropharyngeal cancer failed to show a survival advantage for induction chemotherapy regimens.[8,14] However, these studies did not stratify for human papillomavirus status, and the role of induction chemotherapy remains unclear.

Altered Fractionation

Radiation therapy alone with altered fractionation may be used for patients with locally advanced oropharyngeal cancer who are not candidates for chemotherapy. Altered fractionation radiation therapy yields a higher locoregional control rate than SFX for patients with stage III and stage IV oropharyngeal cancer. The long-term analysis of randomized trial RTOG-9003 (NCT00771641) included the following four radiation therapy treatment arms:

  1. Standard fractionation (SFX) to 70 Gy in 35 daily fractions for 7 weeks.
  2. Hyperfractionation (HFX) to 81.6 Gy in 68 twice-daily fractions for 7 weeks.
  3. Accelerated fractionation to 67.2 Gy in 42 fractions for 6 weeks with a 2-week rest after 38.4 Gy.
  4. Accelerated continuous fractionation (AFX-C) to 72 Gy in 42 fractions for 6 weeks.

The three experimental arms were to be compared with SFX. Only the HFX arm showed superior locoregional control and survival at 5 years compared with the SFX arm (HR, 0.79; 95% confidence interval, 0.62–1.00; P = .05). AFX-C was associated with increased late toxicity compared with SFX.[9-13,15,16][Level of evidence: 1iiA]

Posttreatment follow-up:

  • A careful head and neck examination of the patient allows the physician to look for recurrence every 6 to12 weeks for the first posttreatment year, every 3 months for the second year, every 3 to 4 months for the third year, and every 6 months thereafter.

Treatment options under clinical evaluation:

  • Neoadjuvant chemotherapy before surgery.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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. Bernier J, Cooper JS, Pajak TF, et al.: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27 (10): 843-50, 2005. [PUBMED Abstract]
  2. Cooper JS, Zhang Q, Pajak TF, et al.: Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 84 (5): 1198-205, 2012. [PUBMED Abstract]
  3. Cooper JS, Pajak TF, Forastiere AA, et al.: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350 (19): 1937-44, 2004. [PUBMED Abstract]
  4. 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]
  5. Pignon JP, le Maître A, Maillard E, et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92 (1): 4-14, 2009. [PUBMED Abstract]
  6. Bonner JA, Harari PM, Giralt J, et al.: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354 (6): 567-78, 2006. [PUBMED Abstract]
  7. Curran D, Giralt J, Harari PM, et al.: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25 (16): 2191-7, 2007. [PUBMED Abstract]
  8. Haddad R, O'Neill A, Rabinowits G, et al.: Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol 14 (3): 257-64, 2013. [PUBMED Abstract]
  9. Overgaard J, Hansen HS, Specht L, et al.: Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 362 (9388): 933-40, 2003. [PUBMED Abstract]
  10. Overgaard J, Mohanti BK, Begum N, et al.: Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial. Lancet Oncol 11 (6): 553-60, 2010. [PUBMED Abstract]
  11. 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]
  12. 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]
  13. 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]
  14. Hitt R, Grau JJ, López-Pousa A, et al.: A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol 25 (1): 216-25, 2014. [PUBMED Abstract]
  15. Beitler JJ, Zhang Q, Fu KK, et al.: Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 89 (1): 13-20, 2014. [PUBMED Abstract]
  16. Baujat B, Bourhis J, Blanchard P, et al.: Hyperfractionated or accelerated radiotherapy for head and neck cancer. Cochrane Database Syst Rev (12): CD002026, 2010. [PUBMED Abstract]

Recurrent and Metastatic 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]
  4. Chemotherapy for metastatic or unresectable locoregionally recurrent disease.
  5. Reirradiation therapy using conventionally fractionated radiation therapy, or hyperfractionated radiation therapy (HFX) with concomitant chemotherapy.[3]

Treatment options under clinical evaluation:

  1. Clinical trials evaluating the use of chemotherapy and antiepidermal growth factor receptor–monoclonal targeted therapy should be considered.[4-9]
  2. Clinical trials evaluating reirradiation therapy using HFX with concomitant chemotherapy, targeted therapy, or stereotactic body radiation therapy.[10]

Posttreatment follow-up:

  • A careful head and neck examination allows the physician 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 is the next consideration.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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. Spencer SA, Harris J, Wheeler RH, et al.: RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck. Int J Radiat Oncol Biol Phys 51 (5): 1299-304, 2001. [PUBMED Abstract]
  4. Hong WK, Bromer R: Chemotherapy in head and neck cancer. N Engl J Med 308 (2): 75-9, 1983. [PUBMED Abstract]
  5. 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]
  6. 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]
  7. 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]
  8. Vermorken JB, Mesia R, Rivera F, et al.: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359 (11): 1116-27, 2008. [PUBMED Abstract]
  9. Vermorken JB, Stöhlmacher-Williams J, Davidenko I, et al.: Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol 14 (8): 697-710, 2013. [PUBMED Abstract]
  10. Tortochaux J, Tao Y, Tournay E, et al.: Randomized phase III trial (GORTEC 98-03) comparing re-irradiation plus chemotherapy versus methotrexate in patients with recurrent or a second primary head and neck squamous cell carcinoma, treated with a palliative intent. Radiother Oncol 100 (1): 70-5, 2011. [PUBMED Abstract]

Changes to This Summary (11/18/2014)

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.

General Information About Oropharyngeal Cancer

Editorial changes were made to this section.

Cellular Classification of Oropharyngeal Cancer

Editorial changes were made to this section.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of oropharyngeal cancer. It 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.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Oropharyngeal Cancer Treatment are:

  • Scharukh Jalisi, MD, FACS (Boston University Medical Center)
  • Eva Szabo, MD (National Cancer Institute)
  • Minh Tam Truong, MD (Boston University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Oropharyngeal Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/oropharyngeal/HealthProfessional. Accessed <MM/DD/YYYY>.

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  • Updated: November 18, 2014