Altered fractionation radiotherapy combined with concurrent low-dose or high-dose cisplatin in head and neck cancer: A systematic review of literature and meta-analysis

Objectives: Altered fractionation radiotherapy and concomitant chemoradiotherapy represent commonly used intensification strategies in the management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). This meta-analysis compares compliance, safety, and efficacy between two single-agent cisplatin schedules given concurrently with altered fractionation radiotherapy. Methods: We systematically searched for prospective trials of patients with LA-SCCHN who received post-operative or definitive altered fractionation concurrent chemoradiotherapy. High-dose cisplatin once every three to four weeks (100 mg/m(2), 2 doses) was compared with a weekly low-dose protocol (<= 50 mg/m2, >= 4 doses). The primary outcome was overall survival. The secondary endpoints comprised treatment adherence, acute and late toxicities, and objective response rate. Results: Twelve studies with 1373 patients treated with definitive chemoradiotherapy were included. Compared to the weekly low-dose cisplatin regimen, the three-to four-weekly high-dose cisplatin regimen improved overall survival (p = .0185), was more compliant with respect to receiving all planned cycles of cisplatin (71% versus 95%, p = .0353), and demonstrated less complications in terms of severe (grade 3-4) acute mucositis and/or stomatitis (75% versus 40%, p =. 0202) and constipation (8% versus 1%, p = .0066), toxic deaths (4%, versus 1%, p = .0168), 30-day mortality (8% versus 3%, p = .0154), and severe late subcutaneous fibrosis (21% versus 2%, p < .0001). Overall and complete response rates were similar between both chemotherapy schedules. Conclusion: In chemoradiotherapy incorporating altered fractionation, two cycles of high-dose cisplatin with a three to four week interval are superior to weekly low-dose schedules. Further studies should identify those who might derive the greatest benefit from this intensified approach.