Hypopharyngeal cancer

208/01500 General Information Cellular Classification Stage Information Treatment Option Overview Stage I Hypopharyngeal Cancer Stage II Hypopharyngeal Cancer Stage III Hypopharyngeal Cancer Stage IV Hypopharyngeal Cancer Recurrent Hypopharyngeal Cancer

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Information from PDQ -- for Health Professionals GENERAL INFORMATION

Patients with carcinoma of the head and neck require a careful work-up and a multidisciplinary team approach, which includes the head and neck surgeon, the radiation oncologist, the medical oncologist, the pathologist, the dentist, and social services personnel to determine the optimal management. General endoscopy under general anesthesia with mapping of the lesion using the written word and specific diagrams is indicated. Biopsy and histopathologic confirmation of the lesion as cancer is mandatory. Esophagoscopy is carried out together with laryngoscopy during evaluation of the oral cavity and pharynx. This is done because there is approximately a 10% to 15% incidence of synchronous primary tumors in the head and neck (occurring at the same time as the presenting primary tumor). The esophagus is the most frequent site where subclinical second primary tumors are discovered. Bronchoscopy is not as productive as a chest x-ray in defining a second primary tumor

and is, thus, not mandatory. In the oral cavity, the lesions are tattooed using India ink. This will facilitate later surgical procedures, particularly when cytoreduction occurs as a result of adjuvant radiation therapy and/or chemotherapy. Neither the liver-spleen scan nor the bone scan has been found to be of important diagnostic value in the evaluation of patients with head and neck cancer. Computed tomographic (CT) scans and magnetic resonance imaging (MRI) scans are often valuable to further delineate disease extent at the primary site and in the neck.[1] Other diagnostic evaluation besides the panendoscopy, including CT scan, angiography, Cine pharyngoesophagogram and other modalities, are to be used as indicated.[2] Generally, as one proceeds anatomically from the lips posteriorly to the hypopharynx, the prognosis worsens. More important, however, is the relationship of cure rates to the size of the initial tumor burden. Early T1 cancers involving sites such as the glottic larynx and lip have 5-year cure rates as high as 80% to 90%. Advanced cancers, however, carry a very poor prognosis, with cure rates as low as 10% to 15% despite the use of combined modalities. Most treatment failures occur within the first 2 years following definitive therapy. For this reason, patient follow-up must be frequent and careful during this period. It is also important to be aware that from 20% to 30% of patients with head and neck cancer develop second primary cancers in the upper aerodigestive tract.[3] For this reason, longterm follow-up beyond 2 years is also important. The most common cause of failure of treatment of the primary tumor is local and/or regional recurrence. Distant metastases are less frequent but are found in up to 60% of those patients whose primary tumors do not respond to treatment. The hypopharynx has the highest incidence of distant metastases, followed by the base of the tongue and anterior tongue.[4] There are not many well-designed, controlled prospective studies comparing treatment modalities in patients with head and neck cancer. Therefore, it is difficult to unequivocally state the ideal therapy for a specific site or stage of cancer originating in the head and neck. In general, it can be said that stage I and stage II cancers respond equally well to radiation or surgery, although stage II pyriform sinus cancer is usually treated with the combination of surgery and radiation therapy. The preferred treatment is based on the skills of the treating physician, the needs of the patient, and, most importantly and ideally, the treatment that causes the least functional disability. Stage III and operable stage IV cancers are most commonly managed with a combination of radiation therapy and surgery. Most often the radiation therapy is given postoperatively. Patients with advanced inoperable disease are frequently palliated with radiation therapy. Patients with stage III and advanced resectable stage IV cancer should be considered for a larynx preservation approach including adjuvant radiation therapy and chemotherapy.[5] Further, advanced nonresectable stage IV cancers should also be considered for clinical trials involving chemotherapy with radiation or radiation sensitizers with radiation. Tumors of the head and neck have been related to tobacco consumption, heavy ingestion of alcohol, and the use of chewing tobacco. Poor oral hygiene, mechanical irritation, and

the Plummer-Vinson syndrome have been implicated in the etiology of head and neck cancer. This topic has been reviewed.[6]

References:
1. Zbaren P, Becker M, Lang H: Pretherapeutic staging of hypopharyngeal carcinoma: clinical findings, computed tomography, and magnetic resonance imaging compared with histopathologic evaluation. Archives of Otolaryngology, Head and Neck Surgery 123(9): 908-913, 1997. 2. McGuirt WF: Panendoscopy as a screening examination for simultaneous primary tumors in head and neck cancer: a prospective sequential study and review of the literature. Laryngoscope 92(5): 569-576, 1982. 3. Cooper JS, Pajak TF, Rubin P, et al.: Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience. International Journal of Radiation Oncology, Biology, Physics 17(3): 449-456, 1989. 4. Kotwall C, Sako K, Razack MS, et al.: Metastatic patterns in squamous cell cancer of the head and neck. American Journal of Surgery 154(4): 439-442, 1987. 5. Lefebvre JL, Chevalier D, Luboinski B, et al.: Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. Journal of the National Cancer Institute 88(13): 890-899, 1996. 6. Spitz MR: Epidemiology and risk factors for head and neck cancer. Seminars in Oncology 21(3): 281-288, 1994.

CELLULAR CLASSIFICATION
Most head and neck cancers are of the squamous cell variety and may be preceded by various precancerous lesions. They are divided into 2 groups: keratinizing or nonkeratinizing. Minor salivary gland tumors occur in these sites but are not common. Specimens removed from the lesions may show the carcinomas to be noninvasive, in which case the term "carcinoma-in-situ" is applied. An invasive carcinoma will be either well-differentiated, poorly differentiated, or undifferentiated. Tumor grading is recommended using Broder's classification (tumor grade G): G1: well-differentiated G2: moderately well-differentiated G3: poorly differentiated G4: very poorly differentiated Although the grade of the tumor does not enter into staging of the tumor, it should be recorded. There is no statistically significant correlation between degree of differentiation and the biologic behavior of the cancer.

Other tumors of glandular epithelium, odontogenic apparatus, lymphoid tissue, soft tissue, and bone and cartilage origin require special consideration and are not included. Reference to the World Health Organization (WHO) nomenclature is recommended. The term "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. It can range from hyperkeratosis to an actual early invasive carcinoma or may represent only a fungal infection, lichen planus, or other benign oral disease.

STAGE INFORMATION
The staging systems are all clinical staging, 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 both indirect mirror examination and direct endoscopy. The tumor must be confirmed histologically, and any other pathologic data obtained from a biopsy may be included. Additional radiographic studies may be included. Computed tomography examination in addition to clinical examination will more accurately stage carcinomas of the larynx and hypopharynx.[1] The appropriate nodal drainage areas are examined by careful palpation. If a patient relapses, complete restaging must be done to select the appropriate additional therapy. <TABLE BORDER=1><TR><TD><pre> The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[2]

TNM definitions
Primary tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ T1: Tumor limited to 1 subsite* of the hypopharynx and 2 cm or less in greatest dimension T2: Tumor involves more than 1 subsite* of the hypopharynx or an adjacent site, or measures more than 2 cm but not more than 4 cm in greatest diameter without fixation of hemilarynx T3: Tumor measures more than 4 cm in greatest dimension or with fixation of hemilarynx T4: Tumor invades adjacent structures (e.g., thyroid/cricoid cartilage, carotid artery, soft tissues of neck, prevertebral fascia/muscles, thyroid and/or esophagus) *Subsites of the hypopharynx are as follows:

pharyngo-esophageal junction (postcricoid area), extending from the level of the arytenoid cartilages and connecting folds to the inferior border of the cricoid cartilage pyriform sinus, extending from the pharyngo-epiglottic fold to the upper end of the esophagus, bounded laterally by the thyroid cartilage and medially by the surface of the aryepiglottic fold and the arytenoid and cricoid cartilages posterior pharyngeal wall, extending from the level of the floor of the vallecula to the level of the crico-arytenoid joints 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 less in greatest dimension N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N2a: Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension N2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N3: Metastasis in a lymph node more 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 over 3 centimeters in diameter are not single nodes but confluent nodes or tumors in soft tissues of the neck. There are 3 stages of clinically positive nodes: N1, N2, and N3. The use of subgroups a, b, and c is not required but recommended. Midline nodes are considered homolateral nodes. Distant metastasis (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis

AJCC stage groupings 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 T4, N0, M0 T4, N1, M0
Any T, N2, M0

Stage IVB
Any T, N3, M0

Stage IVC
Any T, Any N, M1 </pre></TD></TR></TABLE>

References:
1. Thabet HM, Sessions DG, Gado MH, et al.: Comparison of clinical evaluation and computed tomographic diagnostic accuracy for tumors of the larynx and hypopharynx. Laryngoscope 106(5 pt 1): 589-594, 1996. 2. Pharynx (including base of tongue, soft palate and uvula). In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 31-39.

TREATMENT OPTION OVERVIEW

The hypopharynx extends from the plane of the hyoid bone above to the plane of the lower border of the cricoid cartilage below. It does not include the larynx and has 3 parts: the pyriform sinus, the postcricoid area, and the posterior pharyngeal wall.

The lymphatic drainage from the pharynx is into the jugulodigastric, jugulo-omohyoid, upper and middle deep cervical, and retropharyngeal nodes. This anatomic region when involved by cancer does not give rise to symptoms until late in the course of the disease. As a result of this fact and the high incidence of metastasis early in the course of the disease, survival rates for carcinoma of the hypopharynx are perhaps the lowest of all sites in the head and neck. Almost all malignancies arising in this region are squamous cell carcinomas. A history of excess use of tobacco or alcohol is commonly associated with these malignancies. The Plummer-Vinson syndrome, characterized clinically by achlorhydria, sideropenic anemia, and atrophy of the mucous membranes of the mouth, pharynx, and esophagus, is frequently associated with carcinoma of the hypopharynx, oral cavity, or esophagus in women.[1] The pyriform sinus is the most frequently involved site in the hypopharynx. Postcricoid and posterior hypopharyngeal wall carcinomas account for only one- third of hypopharyngeal cancers. Cervical node metastasis is frequent, occurring in 70% of pyriform sinus lesions, 40% of postcricoid carcinomas, and 50% of posterior hypopharyngeal wall lesions.[2] On attempting to define the optimal therapeutic approach to the hypopharynx, it becomes quite 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 contains few 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.[3,4] 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.[5,6] Patients who smoke during radiation therapy appear to have lower response rates and shorter survival durations than those who do not;[7] therefore, patients should be counseled to stop smoking before beginning radiation therapy. Accumulating evidence has demonstrated a high incidence (>30%-40%) of hypothyroidism in patients who have received external-beam irradiation 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 post-treatment follow-up.[8,9] The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References:

1. Ahlbom HE: Simple achlorhydric anaemia, Plummer-Vinson syndrome, and carcinoma of the mouth, pharynx, and oesophagus in women. British Medical Journal 2(3945): 331-333, 1936. 2. Truluck CH, Putney FJ: Survival rates in cancer of the tongue, tonsil, and hypopharynx. Archives of Otolaryngology, Head and Neck Surgery 93(3): 271274, 1971. 3. Thawley SE, Panje WR, Batsakis JG, et al.: Comprehensive Management of Head and Neck Tumors. New York: W.B. Saunders Company, 1986. 4. Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, Ed.: Radiation Therapy of Head and Neck Cancer. Berlin: Springer-Verlag, 1989, pp 107-124. 5. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. International Journal of Radiation Oncology, Biology, Physics 23(2): 457-467, 1992. 6. Hansen O, Overgaard J, Hansen HS, et al.: Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation. Radiotherapy and Oncology 43(1): 47-51, 1997. 7. Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. New England Journal of Medicine 328(3): 159-163, 1993. 8. Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. International Journal of Radiation Oncology, Biology, Physics 31(2): 279-283, 1995. 9. Constine LS: What else don't we know about the late effects of radiation in patients treated for head and neck cancer? International Journal of Radiation Oncology, Biology, Physics 31(2): 427-429, 1995.

STAGE I HYPOPHARYNGEAL CANCER

Except for the very early T1 cancers of this region, treatment has been primarily surgery usually followed with postoperative radiation therapy. Because these tumors are clinically "silent" until they reach advanced stages, it is very unusual to diagnose these tumors at the T1 N0 stage. In most available retrospective reviews T1 N0 cases represent only 1% to 2% of all patients seen. In the case of exophytic T1 N0 lesions, radiation therapy alone may be considered for treatment.[1,2] Standard treatment options: Laryngopharyngectomy and neck dissection has been the most frequently used therapy for hypopharyngeal cancers. In very selected cases of pyriform sinus cancers (arising in the upper lateral wall) a partial laryngopharyngectomy may be successfully used preserving vocal function. All groups who use radiation advocate high-dose treatment to the primary site and both sides of the neck to include the retropharyngeal and lateral ervical nodes.[1]

References:
1. Mendenhall WM, Parsons JT, Devine JW, et al.: Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head and Neck Surgery 10(2): 88-92, 1987. 2. Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, Ed.: Radiation Therapy of Head and Neck Cancer. Berlin: Springer-Verlag, 1989, pp 107-124.

STAGE II HYPOPHARYNGEAL 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.) Treatment has been primarily surgery usually followed with postoperative radiation therapy. Because these tumors are clinically "silent" until they reach advanced stages, it is very unusual to diagnose these tumors at the T2 N0 stage. Standard treatment options: 1. Laryngopharyngectomy and neck dissection has been the most frequently used therapy for hypopharyngeal cancers. In very selected cases of pyriform sinus cancers (arising in the upper medial wall) a partial laryngopharyngectomy may be successfully used, preserving vocal function. In T2 cases postoperative radiation has been given in combination with surgery in an effort to improve the local control rates of surgery alone. There are however, advocates of preoperative radiation therapy, but all groups giving radiation advocate high- dose treatment to the primary site and both sides of the neck to include the retropharyngeal and lateral cervical nodes.[1,2] 2. 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. The 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. Although neoadjuvant chemotherapy has not been proven in randomized, prospective trials to improve locoregional control or survival, it is commonly used to treat patients presenting with advanced disease with those objectives as the rationale.[3] The use of neoadjuvant chemotherapy to increase organ preservation has also been advocated. In a prospective randomized trial, the EORTC has compared surgery plus postoperative radiation therapy to induction chemotherapy(cisplatin plus 5-FU) followed by irradiation in responding patients. Local and regional failures were similar in the 2 groups. Although median survival was 25 months in the immediate surgery arm of the study and 44 months in the induction

chemotherapy arm (p=.006), 5-year disease-free and overall survival were the same. A functional larynx was preserved in 42% of patients at 3 years and 35% at 5 years in patients who received induction chemotherapy. These data have not been confirmed by other phase III trials but suggest that larynx preservation may be feasible without jeopardizing survival.[4][Level of evidence: 1iiA,C] Most neoadjuvant chemotherapy clinical trials have included stage II hypopharyngeal carcinoma patients for the trials because of the low survival rates for this group of patients.[5]

References:
1. Mendenhall WM, Parsons JT, Devine JW, et al.: Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head and Neck Surgery 10(2): 88-92, 1987. 2. Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, Ed.: Radiation Therapy of Head and Neck Cancer. Berlin: Springer-Verlag, 1989, pp 107-124. 3. Harari PM: Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? Journal of Clinical Oncology 15(5): 2050-2055, 1997. 4. Lefebvre JL, Chevalier D, Luboinski B, et al.: Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. Journal of the National Cancer Institute 88(13): 890-899, 1996. 5. Meoz-Mendez RT, Fletcher GH, Guillamondegui OM, et al.: Analysis of the results of irradiation in the treatment of squamous cell carcinomas of the pharyngeal walls. International Journal of Radiation Oncology, Biology, Physics 4(7/8): 579-585, 1978.

STAGE III HYPOPHARYNGEAL 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 this group of patients is complex and requires multidisciplinary input to establish the optimal treatment regimen. New surgical techniques and reconstructions using the gastric pull up operation or free jejunal transfers have greatly reduced the morbidity associated with resection of these tumors and have almost eliminated the need for multistage reconstructions. This has greatly aided the combined treatment regimens because these patients have a high likelihood of beginning postoperative radiation therapy within 3 to 4 weeks following resection.

Details of surgical procedures and their modifications of radiation fields or dosage schedules are not specifically designated here because there are legitimate variations in techniques that (according to various retrospective data) give similar survival results in different treatment centers. This group of patients should be managed by surgeons and radiation oncologists who are skilled in the multiple procedures and techniques available and who are actively and frequently involved in the care of these patients. Standard treatment options: 1. The combination of surgery and radiation (most often postoperative) has become the usual form of therapy for this group of patients in the United States.[1-3] 2. 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. Although neoadjuvant chemotherapy has not been proven in randomized, prospective trials to improve locoregional control or survival, it is commonly used to treat patients presenting with advanced disease with those objectives as the rationale.[4] The use of neoadjuvant chemotherapy to increase organ preservation has also been advocated. In a prospective randomized trial,the EORTC has compared surgery plus postoperative radiation therapy to induction chemotherapy (cisplatin plus 5-FU) followed by irradiation in responding patients. Local and regional failures were similar in the 2 groups. Although median survival was 25 months in the immediate surgery arm of the study and 44 months in the induction chemotherapy arm (p=.006),5-year disease-free and overall survival were the same. A functional larynx was preserved in 42% of patients at 3 years and 35% at 5 years inpatients who received induction chemotherapy. In contrast to this,however, another randomized prospective trial has demonstrated a statistically significant better survival for patients undergoing chemotherapy (cisplatin plus 5-FU) followed by laryngopharyngectomy and postoperative radiation therapy when compared to chemotherapy and radiation therapy.[5,6][Level of evidence: 1iiA,C] Although organ preservation was not discussed, chemotherapy in combination with radiation therapy without surgery should not be considered standard. Patients with stage III hypopharyngeal cancer should be considered for randomization into clinical trials evaluating the use of adjuvant or neoadjuvant chemotherapy.[7,8] Treatment options under clinical evaluation: Chemotherapy has been combined with radiation therapy in patients who have locally advanced disease.[7-12] Although overall survival has not been improved when chemotherapy has been administered concomitantly with radiation, primary site preservation was improved in one study.[13]

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.[14][Level of evidence: 2A] Patients receiving adjuvant or neoadjuvant chemotherapy had no survival advantage. However, cost, quality of life, and morbidity data were not available; there was no standard regimen; and the trials were felt to be too heterogenous to provide definitive recommendations. The results of ongoing trials may further clarify the role of concomitant chemotherapy and radiation therapy in the management of hypopharyngeal cancer. The best chemotherapy to use and the appropriate way to integrate the 2 modalities is still unresolved.[15] Similar approaches in the patient with resectable disease, where resection would lead to a major functional deficit are also being explored in randomized trials but cannot be recommended at this time as standard.

References:
1. Arriagada R, Eschwege F, Cachin Y, et al.: The value of combining radiotherapy with surgery in the treatment of hypopharyngeal and laryngeal cancers. Cancer 51(10): 1819-1825, 1983. 2. Mendenhall WM, Parsons JT, Devine JW, et al.: Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head and Neck Surgery 10(2): 88-92, 1987. 3. Tupchong L, Phil D, Scott CB, 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. International Journal of Radiation Oncology, Biology, Physics 20(1): 21-28, 1991. 4. Harari PM: Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? Journal of Clinical Oncology 15(5): 2050-2055, 1997. 5. Lefebvre JL, Chevalier D, Luboinski B, et al.: Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. Journal of the National Cancer Institute 88(13): 890-899, 1996. 6. Beauvillain C, Mahe M, Bourdin S, et al.: Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas. Laryngoscope 107(5): 648-653, 1997. 7. Bachaud J, David J, 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. International Journal of Radiation Oncology, Biology, Physics 20(2): 243-246, 1991.

8. 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): 915-921, 1991. 9. 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): 259-265, 1987. 10. 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. Journal of Clinical Oncology 12(12): 2648-2653, 1994. 11. Merlano M, Benasso M, Corvo R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. Journal of the National Cancer Institute 88(9): 583-589, 1996. 12. 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. Journal of Clinical Oncology 18(7): 1458-1464, 2000. 13. 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 and Neck 19(7): 567-575, 1997. 14. Pignon JP, Bourhis J, et al., on behalf of the MACH-NC Collaborative Group: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. Lancet 355(9208): 949-955, 2000. 15. Taylor SG, 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. Journal of Clinical Oncology 12(2): 385-395, 1994.

STAGE IV HYPOPHARYNGEAL 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.)

Resectable
The management of this group of patients is complex and requires multidisciplinary input to establish the optimal treatment regimen. New surgical techniques and reconstructions using the gastric pull up operation or free jejunal transfers have greatly reduced the morbidity associated with resection of these tumors and have almost eliminated the need for multistage reconstructions. This has greatly aided the combined treatment regimens

because these patients have a high likelihood of beginning postoperative radiation therapy within 3 to 4 weeks following resection. Details of surgical procedures and their modifications of radiation fields or dosage schedules are not specifically designated here because there are legitimate variations in techniques that (according to various retrospective data) give similar survival results in different treatment centers. This group of patients should be managed by surgeons and radiation oncologists who are skilled in the multiple procedures and techniques available and who are actively and frequently involved in the care of these patients. Standard treatment options: 1. The combination of surgery and radiation (most often postoperative) has become the usual form of therapy for this group of patients in the United States.[1,2] 2. 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. Although neoadjuvant chemotherapy has not been proven in randomized, prospective trials to improve locoregional control or survival, it is commonly used to treat patients presenting with advanced disease with those objectives as the rationale.[3] The use of neoadjuvant chemotherapy to increase organ preservation has also been advocated. In a prospective randomized trial, the EORTC has compared surgery plus postoperative radiation therapy to induction chemotherapy (cisplatin plus 5-FU) followed by irradiation in responding patients. Local and regional failures were similar in the 2 groups. Although median survival was 25 months in the immediate surgery arm of the study and 44 months in the induction chemotherapy arm (p=.006), 5-year disease-free and overall survival were the same. A functional larynx was preserved in 42% of patients at 3 years and 35% at 5 years in patients who received induction chemotherapy. In contrast to this, however, another randomized prospective trial has demonstrated a statistically significant better survival for patients undergoing chemotherapy (cisplatin plus 5-FU) followed by laryngopharyngectom and postoperative radiation therapy when compared to chemotherapy and radiation therapy.[4,5][Level of evidence: 1iiA,C] Although organ preservation was not discussed, chemotherapy in combination with radiation therapy without surgery should not be considered standard. These patients should be considered for randomization into clinical trials evaluating the use of neoadjuvant and adjuvant chemotherapy.[6-8]

Unresectable
Standard treatment options: 1. These patients are candidates for radiation therapy.

2. Chemotherapy has been combined with radiation therapy in patients who have locally advanced disease.[7-11] Although overall survival has not been improved when chemotherapy has been administered concomitantly with radiation, primary site preservation was improved in one study.[12] The best chemotherapy to use and the appropriate way to integrate the 2 modalities is still unresolved.[13] Similar approaches in the patient with unresectable disease, where resection would lead to a major functional deficit, are also being explored in randomized trials but cannot be recommended at this time as standard. Treatment options under clinical evaluation: Radiation therapy clinical trials evaluating hyperfractionation schedules should be considered with or without chemotherapy.[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. However, cost, quality of life, and morbidity data were not available; there was no standard regimen; and the trials were felt to be too heterogenous to provide definitive recommendations. The results of ongoing trials may further clarify the role of concomitant chemotherapy and radiation therapy in the management of hypopharyngeal cancer. Post-treatment follow-up: These patients should have a careful head and neck examination, looking for recurrence monthly for the first post-treatment year, every 2 months for the second year, every 3 months the third, and every 6 months thereafter.

References:
1. Arriagada R, Eschwege F, Cachin Y, et al.: The value of combining radiotherapy with surgery in the treatment of hypopharyngeal and laryngeal cancers. Cancer 51(10): 1819-1825, 1983. 2. Tupchong L, Phil D, Scott CB, 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. International Journal of Radiation Oncology, Biology, Physics 20(1): 21-28, 1991. 3. Harari PM: Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? Journal of Clinical Oncology 15(5): 2050-2055, 1997. 4. Lefebvre JL, Chevalier D, Luboinski B, et al.: Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and

Treatment of Cancer phase III trial. Journal of the National Cancer Institute 88(13): 890-899, 1996. 5. Beauvillain C, Mahe M, Bourdin S, et al.: Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas. Laryngoscope 107(5): 648-653, 1997. 6. Head and Neck Contracts Program: Adjuvant chemotherapy for advanced head and neck squamous carcinoma: final report of the Head and Neck Contracts Program. Cancer 60(3): 301-311, 1987. 7. Bachaud J, David J, 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. International Journal of Radiation Oncology, Biology, Physics 20(2): 243-246, 1991. 8. 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): 915-921, 1991. 9. 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): 259-265, 1987. 10. 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. Journal of Clinical Oncology 12(12): 2648-2653, 1994. 11. Merlano M, Benasso M, Corvo R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. Journal of the National Cancer Institute 88(9): 583-589, 1996. 12. 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 and Neck 19(7): 567-575, 1997. 13. Taylor SG, 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. Journal of Clinical Oncology 12(2): 385-395, 1994. 14. Weissler MC, Melin S, Sailer SL, et al.: Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Archives of Otolaryngology, Head and Neck Surgery 118(8): 806-810, 1992. 15. 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. Journal of Clinical Oncology 18(7): 1458-1464, 2000. 16. Pignon JP, Bourhis J, et al., on behalf of the MACH-NC Collaborative Group: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. Lancet 355(9208): 949-955, 2000.

RECURRENT HYPOPHARYNGEAL CANCER

Standard treatment options: 1. Surgical resection if radiation therapy fails and if technically feasible. 2. Radiation therapy when surgery fails if not previously used in curative doses that preclude further treatment. 3. Surgical salvage if technically feasible, when surgery fails. 4. Chemotherapy for metastatic disease.[1] Treatment options under clinical evaluation: Clinical trials evaluating the use of chemotherapy should be considered.[2] Post-treatment follow-up: These patients should have a careful head and neck examination, looking for recurrence monthly for the first post-treatment year, every 2 months for the second year, every 3 months the third, and every 6 months thereafter.

References:
1. Adelstein DJ, Tan EH, Lavertu P: Treatment of head and neck cancer: the role of chemotherapy. Critical Reviews in Oncology/Hematology 24(2): 97-116, 1996. 2. Jacobs C, Lyman G, Velez-Garcia 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. Journal of Clinical Oncology 10(2): 257-263, 1992. Date Last Modified: 02/2002 This information from PDQ is reviewed regularly by members of the PDQ Editorial Boards. If you have specific comments on the content of this information, direct them to: PDQ Editorial Board, CIPS/NCI, 6116 Executive Boulevard, Suite 3002B, MSC-8321, 20892-8321, fax: 301-480-8105. * * The PDQ database also contains listings of clinical trial protocols and directories of organizations and physicians who treat cancer patients, but this information is not available through CancerMail. For more information on accessing PDQ, consult the CancerMail Contents List.
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