Concurrent Radiation Chemotherapy for Locally Advanced Head and Neck Carcinoma: Are We Addressing Burning Subjects?

Improving the outcome for patients with locally advanced head and neck carcinomas (HNC) by rational modification of radiation fractionation regimens or combinations of radiation with chemotherapy has been the subject of intensive clinical investigations for more than three decades. The two prototypes of biologically sound-altered radiation fractionation regimens are hyperfractionation and accelerated fractionation. Hyperfractionation was based on preferential sparing of late-responding tissues when the radiation dose per fraction is reduced. Accelerated fractionation regimens emerged through the recognition that tumor clonogen proliferation occurring during radiotherapy has a detrimental effect on outcome. Results of large randomized trials addressing the optimization of radiation fractionation collectively show that a number of biologically sound altered fractionation schedules improve the locoregional (LR) control rate on the order of 10% to 15%, but have only a modest impact on overall survival. Although several altered fractionation regimens consistently induce more severe acute mucositis than standard 7-week radiotherapy, the general consensus is that late toxicities are not appreciably increased. Scores of clinical trials testing combined-modality therapy have also been published. Meta-analyses of studies completed before 1995 reveal that cytotoxic agents given before or after surgery or radiation do not significantly improve the therapeutic outcome over LR treatment alone. In contrast, chemotherapy given concurrently with radiation improves 2and 5-year overall survival rates by 8%. Although a variety of cytotoxic agents have been studied, cisplatin is the most extensively investigated, and will be the emphasis of this commentary. The data from four recent trials using standard radiation fractionation, with or without high-dose single-agent cisplatin given every 3 weeks, in the treatment of locally advanced non-nasopharyngeal HNC have been reported in the last 2 years. All four trials showed that the combined regimen was superior to radiation therapy alone in LR control or organ preservation; two trials also showed improvement in overall survival. A common finding, however, is that 100 mg/m of cisplatin given every 3 weeks during the course of radiotherapy substantially increases the severity of mucositis, apparently more so than altered fractionation regimens without chemotherapy. In addition, cisplatin induces systemic toxicity requiring intensive premedication and supportive care. Unfortunately, recording and reporting of the late morbidity of combined radiation-chemotherapy have not been sufficiently consistent and systematic. A thorough report of the long-term results of a French cooperative group (French Head and Neck Oncology and Radiotherapy Group GORTEC) trial revealed that the late complication rate of the combination of radiation with concurrent carboplatin and fluorouracil was significantly higher than that of radiation alone. Due to a lack of adequate reporting, there is controversy as to whether the late toxicity of the combination of standard radiation with 100 mg/m of cisplatin every 3 weeks might also be higher than radiation alone. Hopefully, longer and more complete follow-up data on late morbidities will be reported in the future. Although the collective data are strong in establishing the superiority of the combination of radiation with concurrent chemotherapy relative to standard radiation fractionation alone in the management of locally advanced HNC, there is variability of clinical trials in patient selection and regimens, leading to continuing debate as to which combined regimen should be considered standard. Furthermore, many questions remain to be answered, including whether the cisplatin dose can be altered to reduce acute JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 23 DECEMBER 1 2004