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Michigan Oncology Journal Summer 2001
Organ Preservation Therapy in Head and Neck Cancer
P. Worden, M.D.
Susan G. Urba,
The standard treatment for patients with locally advanced head and neck cancer has been surgery, often followed by post-operative radiation therapy. However, head and neck cancers are relatively chemosensitive, which has allowed for the use of chemotherapy in many clinical settings. Since the late 1970s, induction chemotherapy prior to surgery has undergone evaluation, but most randomized studies have not demonstrated a survival benefit (1-3). Chemotherapy in combination with radiation therapy has also been studied with the goal of "organ preservation" as the endpoint, with particular success in patients with cancers of the larynx and hypopharynx (4, 5). Because these randomized trials have demonstrated similar survival rates for patients treated with chemoradiation, compared to conventional surgery and post-operative radiation, the organ preservation approach is now an accepted alternative to immediate radical surgery for patients with laryngeal and hypopharyngeal tumors. This treatment strategy is also the focus of active investigation nationally for other head and neck tumor sites.
Optimal therapy for patients with advanced (Stage III/IV) laryngeal cancer has evolved over the past decade with some amount of controversy. Standard treatment options have included total laryngectomy with or without radiation therapy, or radiation therapy alone with surgical salvage. In the United States, total laryngectomy has been the mainstay of treatment. Radiation therapy alone, followed by salvage laryngectomy, is generally discouraged since historical data suggest a lower survival when compared to surgery.
Because laryngectomy can be associated with significant functional morbidity, the Department of Veteran's Affairs (VA) Cooperative Studies Group conducted a prospective randomized trial of 322 patients comparing organ preservation to conventional laryngectomy and radiation therapy (4). In this study, experimental treatment began with two cycles of combination chemotherapy (cisplatin and 5-fluorouracil), after which tumor response was assessed. Patients received a third cycle of chemotherapy if at least a 50% tumor reduction was evident, followed by definitive radiation therapy. Laryngectomy was performed for non-responders to initial chemotherapy and in patients who developed locally recurrent cancers. Final results demonstrated comparable two-, three- and four-year survival rates between the two treatment groups, and larynx preservation was noted in 64% of patients who were randomized to initial chemotherapy. Patterns of recurrence differed significantly between the two groups, with more local recurrences and fewer distant metastases in the chemotherapy group compared to the surgery group. This was a landmark study for the treatment of laryngeal cancers. The results indicated that patients might be successfully selected for radiation treatment based on the biologic response of their cancer to cytotoxic chemotherapy, without compromise of survival. Whether similar results might be achieved with radiation therapy alone remains unknown. A large intergroup study designed to answer this question recently completed patient accrual, but results are not yet available.
Because there is no documented survival advantage, the VA larynx study has been criticized for adding length and cost to the treatment of patients with advanced laryngeal cancer. Moreover, it is not certain whether three cycles of induction chemotherapy is warranted, since significant tumor reduction is seen following one or two cycles of chemotherapy. It is also not clear that the benefit of induction chemotherapy is the reduction of tumor burden or the selection of a favorable patient population to receive radiation therapy. Unpublished data from the VA study, which analyzed the rates of successful organ preservation, found no significant differences among patients who responded after two verses three cycles of chemotherapy. In addition, recent randomized trials have shown that the use of concurrent chemoradiation in advanced head and neck cancer patients yields higher response rates and improved survival compared to radiation therapy alone (6, 7). Therefore, a pilot study is currently in progress at the University of Michigan Cancer Center to determine the feasibility of using a single cycle of induction chemotherapy followed by concomitant chemotherapy with radiation and two cycles of adjuvant chemotherapy as a new organ preservation strategy for patients with advanced laryngeal cancer.
In this pilot study, patients with stage III and IV laryngeal cancer receive one cycle of chemotherapy with cisplatin and 5-flourouracil. Patients who achieve at least a 50% reduction in tumor volume receive concurrent chemoradiation. Those not responding by 50% undergo salvage surgery followed by radiation therapy. Following chemoradiation, patients with complete histologic responses receive two cycles of adjuvant chemotherapy with cisplatin and 5-fluorouracil. Those with residual disease will undergo salvage surgery. Thus far, 54 patients have been enrolled. Approximately two-thirds of the patients have had a greater than 50% response and received chemoradiation. Of these patients, 86% were complete histologic responders after the chemoradiation and were referred for adjuvant chemotherapy. Five patients have required late salvage laryngectomy for recurrence. Overall survival rate at one year is 91%, and is 78% at three years. From these observations, it appears that one cycle of chemotherapy can predict a group of patients who will be very sensitive to chemoradiation for larynx preservation. While the survival rates are very encouraging, the study is still ongoing, the data is preliminary, and survival comparisons cannot be drawn from a Phase II trial.
Patients with cancer of the hypopharynx and base of tongue (BOT) usually experience substantial loss of function of speech or swallowing as a result of standard surgery. Thus, these patients are good candidates for treatment with a non-surgical approach. In 1996, the European Organization for Research and Treatment of Cancer (EORTC) conducted a prospective study in which 194 patients with advanced hypopharyngeal cancer were randomized to receive either surgery or induction chemotherapy followed by radiation in complete responders (5). Fifty-four percent of patients treated with chemotherapy had a complete response at the primary tumor site, and survival was equivalent between the randomization arms. The three- and five-year estimates of retaining a functional larynx for patients treated with induction chemotherapy were 42% and 35% respectively.
Currently, the Southwest Oncology Group (SWOG) is conducting a study for patients with advanced, resectable cancer of the hypopharynx and BOT. In this study, complete histologic response rates of the primary tumor site are being evaluated after treatment with induction chemotherapy (two cycles of cisplatin and 5-fluorouracil) followed by concomitant chemoradiation in those patients demonstrating a greater than 50% reduction at the primary tumor site. Accrual has been completed for patients with BOT cancer and final results will soon be reported, while the hypopharynx arm is still actively accruing patients.
Non-randomized trials have also been conducted to determine the possibility of organ preservation at various other sites of head and neck cancer. The University of Michigan reported 43 patients with cancer of the oral cavity, pharynx, larynx or sinuses who were treated with induction chemotherapy (three cycles of mitoguazone, 5-fluorouracil and cisplatin) (8). Patients who demonstrated a complete response or whose tumor was downstaged to T1N1 were treated with definitive radiation therapy. The overall response rate to chemotherapy was 84%, with a 43% complete response rate at the primary site. Fifty-one percent of patients were spared all surgery and an another 19% required only a neck dissection. Two additional studies, published from the University of Michigan in December 2000, also have suggested that organ preservation in select patients with nonlaryngeal head and neck cancers will not compromise survival (9). These phase II trials were conducted sequentially. In the first study, patients were treated with three cycles of carboplatin and 5-fluorouracil. Patients who achieved a 50% or greater reduction in tumor volume received definitive radiation therapy. Patients enrolled in the second trial received carboplatin, 5-fluorouracil and leukovorin for three cycles. Responders were then treated with accelerated radiation therapy. Collectively, initial organ preservation was 58% for patients with oropharyngeal cancer and 59% for those with cancers of the hypopharynx. For all patients, median survival was 28 months and survival at three and five years was 40% and 24%, respectively. Further evaluation of organ preservation for patients with advanced head and neck carcinomas is ongoing. More aggressive treatment regimens with newer agents may improve response rates. Current studies at the University of Michigan Comprehensive Cancer Center are combining chemotherapy and radiotherapy in an effort to achieve local-regional disease control in patients with resectable cancers of the oral cavity and oropharynx.
2.Schuller DE, Metch B, Stein DW, Mattox, McCracken JD. Preoperative chemotherapy in advanced resectable head and neck cancer: final report of the Southwest Oncology Group. Laryngoscope. 1988; 98:1205-1211.
3. Martin M, Hazan A, Vergnes L, et al. Randomized study of 5-fluorouracil and cisplatin as neoadjuvant therapy in head and neck cancer: a preliminary report. Int J Radiat Oncol Biol Phys. 1985; 11:1887-1893.
4. The Department of Veteran's Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991; 324:1685-1690.
5.Lefebvre JL, Chevalier D, Luboinski B, Kirpatrick A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: preliminary results of a European organization for research and treatment of cancer phase III trial. J Natl Cancer Inst. 1996; 88:890-895.
6.Wendt TG, Grabenbauer GC, Rodel CM, et al. Simultaneous radiochemotherapy verses radiotherapy alone in advanced head and neck cancer: A randomized multicenter study. J Clin Oncol. 1998; 16:1318-1324.
8. Urba S, Forastiere A, Wolf G, Esclamado RM, McLaughlin PW, Thornton AF. Intensive induction chemotherapy and radiation therapy for organ preser-vation in patients with advanced resectable head and neck carcinoma. J Clin Oncol. 1994; 12: 946-953.