PHASE-III TRIAL OF INITIAL CHEMOTHERAPY IN STAGE-III OR STAGE-IV HEADAND NECK CANCERS - A STUDY BY THE RUPPO-DI-STUDIO-SUI-TUMORI-DELLA-TESTA-E-DEL-COLLO

Background: The standard treatment for advanced (stage III and IV) hea d and neck squamous cell carcinoma (i.e., surgery with postoperative r adiotherapy in operable patients and radiotherapy alone in inoperable patients) has had poor results. A series of randomized trials of induc tion chemotherapy have up to now failed to demonstrate an improvement in survival. Purpose: This trial was designed to determine whether int ensive induction chemotherapy administered before locoregional treatme nt would improve survival of patients with advanced disease. Methods: Patients had previously untreated, advanced nonmetastatic (stages III and IV) squamous cell carcinoma of the oral cavity, oropharynx, hypoph arynx, and paranasal sinuses. The study design was a randomized, multi -institutional, phase Ill trial. Eligible patients (n = 237) were rand omly assigned to receive either initial chemotherapy (cisplatin and in fusional fluorouracil) followed by locoregional treatment (group A, n = 118) or loco-regional treatment alone (group B, n = 119). For operab le patients (group A, n = 34; group B, n = 32), loco-regional treatmen t included resection followed by adjuvant radiotherapy. For inoperable patients, radical irradiation was performed with a planned dose of 65 -70 Gy to involved areas. A dose of 45-50 Gy was also planned to the u ninvolved neck or postoperatively. The statistical (logrank) test was performed no earlier than 2 years after the randomization of the last patient. Results: Seventy-one patients (60%) in group A and 67 patient s (56%) in group B were considered free of disease after they complete d the treatment sequence. The analysis of time to distant metastases s howed an advantage for group A patients. (Respective 2- and 3-year val ues for inoperable patients were 15% and 24% for group A versus 36% an d 42% for group B, P = .04; only one operable group A patient had dist ant metastases after 49 months versus 26% [2 years] and 31% [3 years] for operable group B patients, P = .01.) For inoperable patients, the combined treatment was significantly associated with an increase in co mplete remission rate (group A, 44%) as compared with radiotherapy alo ne (group B, 30%) (P = .037). Inoperable patients also benefitted from induction chemotherapy in terms of disease-free survival (49% and 34% for group A versus 28% and 26% for group B; P = .06) and of overall s urvival (30% and 24% for group A versus 19% and 10% for group B; P = . 04). Conclusions: When all 237 randomly assigned patients were analyze d, there were no significant differences in the two treatment strategi es in loco-regional failure or in disease-free or overall survival, al though the development of distant metastases was reduced. For operable patients, the only benefit from neoadjuvant chemotherapy was a signif icant reduction in the incidence of distant metastases. For inoperable patients, neoadjuvant chemotherapy improved local control, decreased the incidence of distant metastases, and improved the complete remissi on rate and overall survival. Implications: Confirmatory studies with effective chemotherapy regimens delivered for an adequate number of cy cles are required.