Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy

Abstract

Background: Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer. We report results of the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer.

Methods: Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3-T4) or hypopharynx (T2-T4), with regional lymph nodes in the neck staged as N0-N2 and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arm. In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles (60 Gy total). All nonresponders underwent salvage surgery and postoperative radiotherapy. The Kaplan-Meier method was used to obtain time-to-event data.

Results: The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68 to 1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm.

Conclusions: Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

Trial registration: ClinicalTrials.gov NCT00002839.

Figure 1

CONSORT diagram. The distribution of patients in the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer, which compared induction CT (sequential or control arm) with a rapidly alternating CT (alternating or experimental arm) and then RT. All patients were analyzed under the intention-to-treat principle. Under option 1, patients were evaluated at the end of the protocol, and under option 2, patients had an intermediate evaluation at day 42. CT = chemotherapy; RT = radiotherapy.

Figure 2

A) Overall survival. Estimates of overall survival at 5 years were 48.5 (95% CI = 41.6 to 55.1) in the sequential arm and 51.9 (95% CI = 44.8 to 58.4) in the alternating arm. B) Progression-free interval. Estimates of progression-free interval at 3 years were 49.7 (95% CI = 43.0 to 56.1) in the sequential arm and 50.6 (95% CI = 43.8 to 56.9) in the alternating arm. C) Survival with a functional larynx. Estimates of survival with a functional larynx at 3 years were 39.5 (95% CI = 33.0 to 45.8) in the sequential arm and 45.4 (95% CI = 38.8 to 51.8) in the alternating arm. All statistical tests were two-sided. CI = confidence interval.