Gemcitabine-based chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck: A literature review and meta-analysis

Background: Cisplatin-based concurrent chemoradiotherapy (CRT) has become the standard of care for non-surgical management of locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Despite improvements in overall survival (OS) when compared to radiotherapy alone, the therapy-induced morbidity of platinum-based CRT has a negative impact on the quality of life of the patients. Thus, alternative ways to increase the safety profile while maintaining high efficacy are worth exploring. Gemcitabine is one of the most potent radiosensitizers and has an overall favourable safety profile. In this work, we reviewed the clinical experience with gemcitabine-based CRT in the treatment of patients with LA-SCCHN.

Material and Methods: A systematic literature review was carried out to summarize the clinical experience with radiotherapy combined with either single agent gemcitabine or gemcitabine/cisplatin-based polychemotherapy for the treatment of patients with LA-SCCHN excluding nasopharyngeal cancer. We searched English literature for full-text articles published up to April 2015 from the National Library of Medicine and the Cochrane Library. A meta-analysis was performed to calculate pooled proportions with 95% confidence intervals (CIs) for complete response rate (CR) and grade 3–4 acute mucositis rate.

Results: A total of 13 papers were fully eligible for the literature review (8 trials using gemcitabine as a single-agent and 5 trials on gemcitabine/cisplatin-based combinations). For schedules using a gemcitabine dose intensity (DI) <50mg/m²/week the CR was 86% (CI 74%-93%) with grade 3–4 acute mucositis rate of 38% (CI 27%-50%) and acceptable late toxicity. In one of the studies employing such low DIs, survival data were provided showing a 3-year OS of 50%. Contrastingly, for DI ≥50mg/m²/week the CR was 71% (CI 55%-83%) with a significantly higher grade 3–4 acute mucositis rate of 74% (CI 62%-83%), often leading to treatment interruptions (survival data provided in 8 studies; 3-year OS: 27–63%). At those DIs (≥50mg/m²/week), we did not find any correlation between the cumulative dose of gemcitabine and the severity of acute local toxicity. Late toxicity comprising mainly mucosal and pharyngeal/esophageal toxicity was generally underreported, while information about xerostomia and skin fibrosis was scarce.

Conclusions: The presented review highlights the remarkable radiosensitizing properties of gemcitabine and indicates that even very low-doses (<50mg/m²/week) provide a sufficient therapeutic ratio and should be therefore further investigated. Moreover, to enhance the therapeutic index of low-dose gemcitabine, modifications in treatment schedules (e.g. alternating CRT), refinements in radiation techniques, including intensity-modulated radiotherapy, and novel drug combinations (e.g. with cetuximab) are currently being studied.

No conflict of interest.