Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy-results of a multicentric randomized German trial in advanced head-and-neck cancer

Purpose: To demonstrate the efficacy of radiochemotherapy (RCT) as the firs t choice of treatment for advanced unresectable head-and-neck cancer. To pr ove an expected benefit of simultaneously given chemotherapy, a two-arm ran domized study with hyperfractionated accelerated radiochemotherapy (HF-ACC- RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiat ed. The primary endpoint was 1-year survival with local control (SLC). Methods and Materials: Patients with Stage III and IV (UICC) unresectable o ro- and hypopharyngeal carcinomas were randomized or HF-ACC-RCT with 2 cycl es of 5-FU (600 mg/m(2)/day)/carboplatinum (70 mg/m(2)) on days 1-5 and 29- 33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second ran domization for testing the effect of prophylactically given G-CSF (263 mug, days 15-19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1-3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 p atients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors). Results: This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tole rable in both arms, with a higher mucosal toxicity after RCT. Restaging sho wed comparable nonsignificant different CR + PR rates of 92.4% after RCT an d 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, 1 - and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-yea r SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oroph aryngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no stat istical benefit of RCT (p = 0.84). For both tumor locations, prophylactical ly given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: G-CSF, p = 0.0072). Conclusion: With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standar d fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC- RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF re sulted in an unexpected reduced local control and should be given in radiot herapy regimen only with strong hematologic indication. (C) 2001 Elsevier S cience Inc.