Stage III Hypopharyngeal Cancer
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 (PORT) 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:
- The combination of surgery and radiation, most often postoperative as seen in a follow-up study of preoperative versus PORT (RTOG-7303), has become the usual form of therapy for this group of patients in the United States.[1-3]
- 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 who present with advanced disease to improve locoregional control or survival, despite the lack of data from randomized, prospective trials. The use of neoadjuvant chemotherapy to increase organ preservation has also been advocated. In a prospective randomized trial, referred to as the GORTEC-TREMPLIN trial (NCT00169247), the European Organization for the Treatment and Research of Cancer compared surgery plus PORT to induction chemotherapy (i.e., cisplatin plus 5-fluorouracil [5-FU]) followed by radiation in responding patients. 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 (OS) were the same. A functional larynx was preserved in 42% of patients at 3 years and 35% at 5 years in patients who were receiving induction chemotherapy.[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 PORT when compared with chemotherapy and radiation therapy.[Level of evidence: 1iiA,1iiC] Although organ preservation was not discussed in this study, chemotherapy in combination with radiation therapy without surgery should not be considered standard.
- Patients with stage III 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 with postoperative, adjuvant radiation therapy plus concurrent chemotherapy. Both the OS (P < .01) and the disease-free survival (P < .02) were better in the group of patients receiving radiation therapy plus concurrent chemotherapy.[Level of evidence:1iiA] In another study, primary site preservation was improved, though OS was not improved when chemotherapy was administered concomitantly with radiation therapy.[8,9]
(Refer to the Stage IV Hypopharyngeal Cancer, Unresectable section of this summary for more information about treatment options for stage III hypopharyngeal cancer.)
Treatment options under clinical evaluation:
- Other studies suggest that chemotherapy combined with radiation therapy is beneficial in patients who have locally advanced disease.[10-12]
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.[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.
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 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.
- 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]
- Mendenhall WM, Parsons JT, Devine JW, et al.: Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head Neck Surg 10 (2): 88-92, 1987 Nov-Dec. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Browman GP, Cripps C, Hodson DI, et al.: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 12 (12): 2648-53, 1994. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]