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 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 AND MATERIALS: 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). CONCLUSION: 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.

[Results of a prospective randomized trial with induction chemotherapy for cancer of the oral cavity and tonsils]. / Primäre Chemotherapie bei Mundhöhlen- und Tonsillenkarzinomen. Ergebnisse einer prospektiv randomisierten Studie.

Although induction chemotherapy administered prior to local therapy produces encouraging initial response rates in head and neck cancer, randomized studies have failed to demonstrate an improvement in survival rates. All randomized studies included only patients with advanced stage III and IV disease. In our opinion, this is the main reason for the low rate of complete responses demonstrated in the randomized trials (maximum 18%). Frei et al. estimate that a 40%-50% complete response rate is necessary before improved survival rates are seen. To date, such complete response rates with induction chemotherapy have only been attainable in resectable T2-T3, N0-N2 disease. Therefore, we initiated a prospective randomized trial including only patients with the mentioned disease stages. Patients (pts) were randomized to receive either induction chemotherapy with three cycles of carboplatin/5-FU prior to surgery and radiotherapy (arm A, 70 pts) or standard treatment with surgery and radiotherapy (arm B, 74 pts). Patients were classified according to primary tumour site and neck disease. The observed remission rate after chemotherapy confirmed the primary estimated rate for this subgroup of patients with head and neck cancer (CR: 43%, PR: 37%, NR: 15%, PD: 5%). After a follow-up of 12-96 months overall survival was 58% in arm A and 45% in arm B (n.s.). Disease-free survival in arm A (61%) is statistically significantly better than in arm B (43%, P=0. 03). Therefore, we recommend further controlled trials to investigate the role of induction chemotherapy in patients with primary resectable carcinomas of the oral cavity and tonsils and stage T2-T3 and N0-N2 disease prior to surgery.

[Preliminary results of a prospective randomized study of primary chemotherapy in carcinoma of the oral cavity and pharynx]. / Vorläufige Ergebnisse einer prospektiv randomisierten Studie zur primären Chemotherapie bei Mundhöhlen- und Pharynxkarzinomen.

Although induction chemotherapie given prior to local therapy produces encouraging initial response rates in head and neck cancer, randomized studies have failed to demonstrate an advantage in survival. All randomized studies have included only patients with far advanced stage III and IV disease. To us this is the main reason for the low rate of complete responses demonstrated (maximum, 18%). Frei et al. estimate that 40-50% complete responders are necessary before improved survival benefit will occur. To date, such complete response rates with induction chemotherapy are only attainable in resectable T2-T3, N0-N2 disease. Therefore, we started a prospective randomized trial that included only patients with earlier disease. Patients were randomized to receive either induction chemotherapy with 3 cycles of carboplatin/5-fluorouracil prior to surgery and radiotherapy (arm A, 49 patients) or standard treatment with surgery and radiotherapy (arm B, 48 patients). Patients were stratified by primary tumor site and neck disease. After a follow-up of 12-48 months, overall survival was 72% in arm A and 53% in arm B, but this difference was not significant. Considering only the results in patients with cancer of the oral cavity and tonsils, overall survival was 87% in arm A and 45% in arm B (p < 0.04). At present, the numbers of patients with cancers of the tongue base and hypopharynx are too small for a statistically significant statement. However, preliminary data indicate a better overall and disease-free survival without chemotherapy in these patients. Therefore, we now recommend induction chemotherapy in all patients with stage T2-T3 and N0-N2 carcinomas of the oral cavity and tonsils prior to surgery but not in patients with cancers of the hypopharynx and base of tongue.

[Cisplatin/5-FU versus carboplatin/5-FU. 5 year follow-up]. / Cisplatin/5-FU versus carboplatin/5-FU. Fünfjahresergebnisse.

Between March 1986 and October 1987, 73 patients with advanced squamous cell carcinomas of the head and neck underwent initial chemotherapy before surgery and/or radiotherapy. Chemotherapy consisted of three courses of carboplatin/5-FU or cisplatin/5-FU. Pretreatment tumor states, remission rates and ages of the patients were comparable. Carboplatin as a modification of cisplatin showed significantly less gastrointestinal nerval and ototoxic side effects. After five years of followup, 30% of the patients treated with carboplatin and 33% of the cisplatinum group were alive and clinically free of disease. In contrast, 97% of all patients treated with sequential chemoradiotherapy have died. The data fails to support a "downstaging" of disease. These results document that the only prognostic factor for long-term survival is histologically complete resection of tumor. Further studies must compare the influence of prior chemotherapy and surgery, both followed by conventional fractionated radiotherapy in resectable tumors. Findings show that induction chemotherapy should not be used for unresectable tumors or for sequential chemo-radiotherapy. The use of carboplatin is preferred since oncological efficiency is comparable while side-effects are significantly less.