International Journal of Radiation Oncology*Biology*Physics
Clinical investigation: head and neckIntensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy—results of a multicentric randomized German trial in advanced head-and-neck cancer☆
Introduction
Patients with advanced carcinomas of the head and neck have a dismal prognosis. Locoregional control poses a major therapeutic challenge. For tumors considered to be unresectable, the treatment has traditionally been conventionally fractionated radiation therapy up to total doses of 60–75 Gy administered in 6–8 weeks and resulting in 2-year survival rates of less than 30% 1, 2. Attempts to improve this poor outcome have been made by combining conventional radiotherapy regimen with simultaneously given chemotherapy, as well as introducing different alterations of radiation fractionation using hyperfractionated and/or accelerated treatment schedules 3, 4, 5, 6, 7. There is, however, no evidence that neoadjuvant chemotherapy followed by radiation therapy (RT) is more efficient than radiotherapy alone (8). The concurrent administration of chemotherapy and radiation therapy is a proven highly effective approach resulting in improved tumor response and control but associated with increased acute toxicities, especially mucositis. Several cytotoxic drugs have been tested with concomitant radiotherapy. By using cisplatin or carboplatin alone, randomized trials of concomitant radiochemotherapy (RCT) have reported either survival improvements (9) or no benefit of the combined modality treatment (10). Browman et al. (11) suggested a potential benefit of the combination of 5-fluorouracil (5-FU) and RT. Other studies have used multidrug combinations with alternating chemo- and RT, and they reported better results compared to standard radiation alone 12, 13. Compared with sequential application of chemo- and radiotherapy, based on a large meta-analysis of the role of chemotherapy, the concomitant treatment with cytotoxic drugs and radiation appeared to be the most effective (14).
Recently, accelerated repopulation of tumor clonogens during the conventional fractionated radiotherapy regimen has been recognized as an important determinant of local control and possible cause of treatment failure in head-and-neck carcinoma, especially if the overall treatment time is prolonged. This hypothesis is supported by laboratory as well as clinical data, which showed median potential doubling times in many tumors of only approximately 4 days 15, 16, 17. These observations have led to the development of accelerated fractionation schemes, whereby radiotherapy is administered in a shorter overall time using multiple daily fractions and/or including the weekends (17). The reduction of overall treatment time has the potential for improving tumor control by minimizing tumor clonogen regeneration. Various accelerated regimens have been used, e.g., the Polish trial (CAIR) (18), the Danish trial (DAHANCA) (19), the Vancouver trial (20), and the concomitant boost concept (21). These different trials have shown improved tumor control rates but also increased treatment-related acute toxicities.
Based on promising results of a prospective Phase II trial with simultaneous RCT using the concomitant boost concept up to a total dose of 66 Gy in 5 weeks with concomitant carboplatin in weeks 1 and 5 (22), in 1995, our German study group of 5 centers (in each center, the Departments of Otorhinolaryngology/Head and Neck Surgery and Radiation Oncology) initiated a prospective randomized multicenter Phase III trial. The purpose of this study was to test the hypothesis that combined simultaneous radiochemotherapy with 5-FU/carboplatin and accelerated radiotherapy using the concomitant boost concept leads to a better locoregional progression-free survival than the same regimen of accelerated radiotherapy alone. Despite the fact that the combination of 5-FU/cisplatin might be one of the most widely accepted standard regimens of chemotherapy in head-and-neck cancer, there is no randomized trial revealing a statistical superiority of cisplatin vs. carboplatin in this tumor entity. Carboplatin was used because of its reduced renal, digestive, and neurologic toxic side effects compared to cisplatin. This study was reviewed by the Leading Commission for Therapeutic Clinical Trials of the German Cancer Society and received generous financial support by the “Deutsche Krebshilfe.”
Section snippets
Patients and methods
The study opened in July 1995 and closed patient accrual at the end of April 1999. Patients were entered at five participating centers: the Universities of Heidelberg, Koeln, and Wuerzburg, and two community hospitals in Kassel and Oldenburg. A total of 263 patients had been randomized. Patient characteristics are summarized in Table 1.
Results
For 240 of 263 randomized patients (91%), therapy started until the end of April 1999, the closure of patient enrollment. A total of 113 patients were treated with RCT and 127 patients with RT. For this intention-to-treat population (itt), the two treatment arms were well balanced for site, grading, and TN-stage. At closure of database (July 1, 2000), the median time from start of RT to last follow-up was 22.3 months, with a range of 6–53 months for all surviving patients. Each patient had the
Discussion
This Phase III study proved that HF-AC-RTC ± simultaneous chemotherapy is feasible without planned treatment splits, and resulted in a total response of more than 90%. Radiotherapy compliance was excellent, with 96% of patients in both arms of the protocol completing radiation therapy within the planned dose range of 69.9 Gy ± 7 Gy.
This trial was limited to specific anatomic sites, the oro- and hypopharynx. Among those 240 patients evaluated for intention to treat, a total of 74% of patients
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Supported by “Deutsche Krebshilfe.”