Resectable Hypopharyngeal Cancer
Unresectable Hypopharyngeal Cancer
Current Clinical Trials

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 patients with resectable hypopharyngeal cancer 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 of 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 as seen in a follow-up study of preoperative versus postoperative radiation therapy (RTOG-7303), 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 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. Neoadjuvant chemotherapy is commonly used to treat patients presenting with advanced disease to improve locoregional control or survival, despite the lack of data from randomized, prospective trials.[3] The use of neoadjuvant chemotherapy to increase organ preservation has also been advocated. In a prospective randomized trial (NCT-00169247), the European Organization for the Research and Treatment of Cancer has compared surgery plus postoperative radiation therapy to induction chemotherapy (i.e., cisplatin plus 5-fluorouracil [5-FU]) followed by radiation in responding patients.[4] Local and regional failures were similar in both 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.[4][Level of evidence: 1iiA, 1iiC] In contrast to this, another randomized prospective trial has demonstrated a statistically significant survival advantage for patients undergoing chemotherapy (i.e., cisplatin plus 5-FU) followed by laryngopharyngectomy and postoperative radiation therapy when compared with chemotherapy and radiation therapy.[5][Level of evidence: 1iiA,1iiC] Although organ preservation was not discussed, chemotherapy in combination with radiation therapy without surgery should not be considered standard.



3. Patients with stage IV hypopharyngeal cancer should be considered for treatment with combined postoperative, adjuvant radiation therapy and chemotherapy. In a prospective randomized trial, postoperative, adjuvant radiation therapy alone was compared to postoperative, adjuvant radiation therapy plus concurrent chemotherapy. Both the overall survival (P <.01) and the disease-free survival (P <.02) were better in the group of patients receiving radiation therapy plus concurrent chemotherapy.[6][Level of evidence: 1iiA] In another study, primary site preservation was improved, though overall survival was not improved when chemotherapy was administered concomitantly with radiation therapy.[7,8]

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.[9-11] In a randomized trial, the 3-year projected overall survival for patients with stage III or stage IV inoperable disease receiving single daily fractionated radiation with concurrent cisplatin was 37% (P = .14).[11][Level of evidence:1iiA]

Treatment options under clinical evaluation:

• Radiation therapy clinical trials evaluating hyperfractionation schedules should be considered with chemotherapy.[12-17]

  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.[18][Level of evidence: 2A] Patients receiving adjuvant or neoadjuvant chemotherapy had no survival advantage. Cost, quality of life, and morbidity data were not available; no standard regimen existed; and the trials were 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 two modalities is still unresolved.[19]

Posttreatment follow-up:

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

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV hypopharyngeal 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. 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): 1819-25, 1983.  [PUBMED Abstract]
   
   
2. Tupchong L, Scott CB, Blitzer PH, et al.: Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 20 (1): 21-8, 1991.  [PUBMED Abstract]
   
   
3. Harari PM: Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? J Clin Oncol 15 (5): 2050-5, 1997.  [PUBMED Abstract]
   
   
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. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88 (13): 890-9, 1996.  [PUBMED Abstract]
   
   
5. Beauvillain C, Mahé 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): 648-53, 1997.  [PUBMED Abstract]
   
   
6. Bachaud JM, Cohen-Jonathan E, Alzieu C, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys 36 (5): 999-1004, 1996.  [PUBMED Abstract]
   
   
7. Adelstein DJ, Lavertu P, Saxton JP, et al.: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88 (4): 876-83, 2000.  [PUBMED Abstract]
   
   
8. 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]
   
   
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): 259-65, 1987.  [PUBMED Abstract]
   
   
10. Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996.  [PUBMED Abstract]
    
    
11. Adelstein DJ, Li Y, Adams GL, et al.: An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21 (1): 92-8, 2003.  [PUBMED Abstract]
    
    
12. Weissler MC, Melin S, Sailer SL, et al.: Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 118 (8): 806-10, 1992.  [PUBMED Abstract]
    
    
13. Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000.  [PUBMED Abstract]
    
    
14. Staar S, Rudat V, Stuetzer H, et al.: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 50 (5): 1161-71, 2001.  [PUBMED Abstract]
    
    
15. Wendt TG, Grabenbauer GG, Rödel CM, et al.: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 16 (4): 1318-24, 1998.  [PUBMED Abstract]
    
    
16. Brizel DM, Albers ME, Fisher SR, et al.: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338 (25): 1798-804, 1998.  [PUBMED Abstract]
    
    
17. 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]
    
    
18. Pignon JP, Bourhis J, Domenge C, et al.: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355 (9208): 949-55, 2000.  [PUBMED Abstract]
    
    
19. Taylor SG 4th, Murthy AK, Vannetzel JM, et al.: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 12 (2): 385-95, 1994.  [PUBMED Abstract]
    
    

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