title: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer.
abstract: OBJECTIVE
  To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC).
  
  
  METHODS
  Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles 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 randomization for testing the effect of prophylactically given G-CSF (263 microg, 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 patients 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 tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- 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-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: +/- G-CSF, p = 0.0072).
  
  
  CONCLUSIONS
  With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.
authors.affiliation: Department of Radiation Oncology, University of Cologne, Cologne, Germany. susanne.starr@medizin.uni-koeln.de
authors.forename: S
authors.initials: S
authors.lastname: Staar
authors.forename: V
authors.initials: V
authors.lastname: Rudat
authors.forename: H
authors.initials: H
authors.lastname: Stuetzer
authors.forename: A
authors.initials: A
authors.lastname: Dietz
authors.forename: P
authors.initials: P
authors.lastname: Volling
authors.forename: M
authors.initials: M
authors.lastname: Schroeder
authors.forename: M
authors.initials: M
authors.lastname: Flentje
authors.forename: H E
authors.initials: HE
authors.lastname: Eckel
authors.forename: R P
authors.initials: RP
authors.lastname: Mueller
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D005858:Germany / Q000453:epidemiology; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy*; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy; D015993:Life Tables; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009959:Oropharyngeal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011882:Radiotherapy, High-Energy / Q000379:methods*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D016190:Carboplatin; D005472:Fluorouracil