Phase III study on larynx preservation comparing induction chemotherapy and radiotherapy versus alternating chemoradiotherapy in resectable hypopharynx and larynx cancers. EORTC protocol 24954–22950

LBA6016 Background: Final analysis of a larynx preservation study comparing sequential induction chemotherapy and radiotherapy (XRT) versus alternating chemoradiotherapy in treating resectable hypopharynx and larynx cancers. Methods: Patients (pts) with untreated, resectable T3-T4 larynx or T2-T3-T4 hypopharynx, N0-N2, M0 squamous cell carcinoma (SCC) were randomized in this prospective Phase III trial. Pts received in the control arm (SEQ) 2 cycles of cisplatin/5-FU (CF), followed in case of response by 2 additional cycles of CF, followed on day 80 by XRT (70 Gy / 35 fractions / 7 weeks), or in the experimental arm a CF cycle in weeks 1, 4, 7 and 10, alternated with XRT (20 Gy / 10 fractions) during the three 2-week intervals (ALT). Pts had surgery and postoperative XRT in case of non- response. The primary endpoint was survival with a functional larynx (FLS), with events including local relapse, laryngectomy, tracheotomy, gastrostomy, feeding tube, and death. With 450 patients and 3 yrs minimum followup per pt, this trial was planned to provide 80% power to detect a difference of 11% (from 28% to 39%) in this endpoint at 3 years by 2-sided Logrank test (Type I error 5%). Results: The trial enrolled 450 pts (224 to SEQ, 226 to ALT) from July 1996 to May 2004. Median followup is 6.5 years (yrs). 76 pts discontinued treatment for toxicity (34 on SEQ, 42 on ALT). Hazard ratio (HR) for FLS was 0.84 (95% CI 0.67–1.05, p=0.12) with medians 1.6 yrs on SEQ and 2.3 yrs on ALT. OS (medians of 4.4 and 5.2 yrs) and PFS (medians of 3.0 and 3.1 yrs) were similar for SEQ and ALT, respectively. At 3 yrs, cumulative incidence of larynx events was 46% on SEQ and 38% on ALT (HR 0.79, p=0.09). Grade 3/4 mucositis was seen in 32% of pts who received RTX on SEQ, and 21% on ALT. Late severe edema and/or fibrosis was observed in 16% of pts in SEQ and 11% in ALT. Conclusion: A 8% difference in larynx function preservation rate at 3 yrs favoring ALT did not translate into statistically significant differences. ALT, as a form of chemoradiation, did not lead to increased incidence and severity of mucositis. There were no relevant long-term sequelae in either arm. No significant financial relationships to disclose.