LARYNX PRESERVATION IN PYRIFORM SINUS CANCER - PRELIMINARY-RESULTS OFA EUROPEAN ORGANIZATION FOR RESEARCH AND TREATMENT OF CANCER PHASE-III TRIAL

Background: As a general rule, surgery whenever possible, followed by irradiation is considered to be the standard treatment for cancer of t he hypopharynx, thus sacrificing natural speech. In most patients, sur gery includes removal of the larynx. Purpose: A prospective, randomize d phase III study was conducted by the European Organization for Resea rch and Treatment of Cancer (EORTC) starting in 1990 to compare a lary nx-preserving treatment (induction chemotherapy plus definitive, radia tion therapy in patients who showed a complete response or surgery in those who did not respond) with conventional treatment (total laryngec tomy with partial pharyngectomy, radical neck dissection, and postoper ative irradiation) in previously untreated and operable patients with histologically proven squamous cell carcinomas of the pyriform sinus o r aryepiglottic fold, but free of other cancers. Methods: Patients wer e randomly assigned to one of two treatment arms: 1) immediate surgery with postoperative radiotherapy (50-70 Gy) or 2) induction chemothera py (cisplatin [100 mg/m(2)] given as a bolus intravenous injection on day 1, followed by infusion of fluorouracil [1000 mg/m(2) per day] on days 1-5). An endoscopic evaluation was performed after each cycle of chemotherapy. After two cycles, only partial and complete responders r eceived a third cycle. Patients with a complete response after two or three cycles of chemotherapy were treated thereafter by irradiation (7 0 Gy); nonresponding patients underwent conventional surgery with post operative radiation (50-70 Gy). Salvage surgery was also performed whe n patients relapsed after chemotherapy and irradiation. The trial was designed to test the equivalence of the two treatment arms; i.e., the induction chemotherapy treatment would be judged equivalent to immedia te surgery if the relative risk of death for induction chemotherapy co mpared with immediate surgery was significantly less than 1.43 using a one-sided hypothesis test at the .05 level of significance. Results: Two hundred two patients entered the trial and were randomly assigned; only 194 were eligible for treatment (94 in the immediate-surgery arm and 100 in the induction-chemotherapy arm). In the induction-chemothe rapy arm, complete response was seen in 52 (54%) of 97 patients with l ocal disease (primary tumor) and in 31 (51%) of 61 patients with regio nal disease (involvement of the neck). Treatment failures at local, re gional, and second primary sites occurred at approximately the same fr equencies in the immediate-surgery arm (12%, 19%, and 16%, respectivel y) and in the induction-chemotherapy arm (17%, 23%, and 13%, respectiv ely). In contrast, there were fewer failures at distant sites in the i nduction-chemotherapy arm than in the immediate-surgery arm (25% versu s 36%, respectively; P = .041). The median duration of survival was 25 months in the immediate-surgery arm and 44 months in the induction-ch emotherapy arm and, since the observed hazard ratio was 0.86 (logrank test, P = .006), which was significantly less than 1.43, the two treat ments were judged to be equivalent. The 3- and 5-year estimates of ret aining a functional larynx in patients treated in the induction-chemot herapy arm were 42% (95% confidence interval 31%-53%) and 35% (95% con fidence interval = 22%-48%), respectively. Conclusions and Implication s: Larynx preservation without jeopardizing survival appears feasible in patients with cancer of the hypopharynx. On the basis of these obse rvations, the EORTC has now accepted the use of induction chemotherapy followed by radiation as the new standard treatment in its future pha se III larynx preservation trials.