Abstract
In locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN), concurrent chemoradiotherapy is an integral part of multimodality management both in the adjuvant and in the definitive settings. Although de-intensification strategies have been propelled to the forefront of clinical research in human papillomavirus (HPV) positive oropharyngeal cancer, three cycles of 100 mg/m2 cisplatin given every 3 weeks concurrently with conventionally fractionated external beam radiotherapy represent a cost-effective and globally accessible treatment option for the majority of LA-SCCHN cases. Based on four large randomized trials, this regimen has become the non-surgical standard of care for cisplatin-eligible patients. Nevertheless, the outcomes in terms of efficacy, toxicity, and compliance have been rather disappointing. Therefore, there is an unmet need to find a better alternative. With limited support from randomized trials, weekly low-dose cisplatin regimens have replaced the standard high-dose schedule at some institutions. Four prospective trials exploring radiotherapy with and without weekly low-dose cisplatin have been published. Two of them were conducted in the 1980s, one of which had a negative outcome, the third study provided insufficient information on toxicity, and the fourth trial had to be prematurely terminated due to poor accrual. Moreover, the findings of two phase III trials comparing the two concurrent cisplatin regimens favored the high-dose protocol. We performed a composite meta-analysis of 59 prospective trials enrolling a total of 5,582 patients. The primary endpoint was overall survival. Reflecting different radiotherapy fractionation schemes and treatment intents, three meta-analyses were carried out, one for postoperative conventional chemoradiotherapy, one for definitive conventional chemoradiotherapy, and one for definitive altered fractionation chemoradiotherapy. In the former two settings, both high- and low-dose regimens yielded similar survival outcomes, thus, the primary objective was not met. When given concurrently with altered fractionation radiotherapy, patients treated with high-dose cisplatin had significantly longer overall survival than those who received low-dose cisplatin. In this article we provide a synthetic view of the results, discuss the issue of cumulative dose, compare two vs. three cycles of high-dose cisplatin, and present our three-step recommendations for use of the current standard of care, high-dose cisplatin, in clinical practice.
Highlights
EVIDENCE FROM CONTROLLED TRIALSIn squamous cell carcinomas of the head and neck (SCCHN), the prevailing clinical presentation is a locoregionally advanced (LA) disease stage, for which patients are usually offered a multimodality approach involving chemoradiotherapy [1, 2]
According to the inclusion criteria of our meta-analyses presented below, high-dose cisplatin was defined by a dose of 100 mg/m2 given once every 3–4 weeks for a total of three doses if combined with conventional radiotherapy or two doses if combined with altered fractionation radiotherapy
To the previously mentioned mortality outcomes, the only statistical difference was found in altered fractionation chemoradiotherapy, in severe late subcutaneous fibrosis, which was significantly more common in one trial of low-dose cisplatin compared with three studies on the high-dose regimen (p < 0.0001)
Summary
In squamous cell carcinomas of the head and neck (SCCHN), the prevailing clinical presentation is a locoregionally advanced (LA) disease stage, for which patients are usually offered a multimodality approach involving chemoradiotherapy [1, 2]. Individualization of chemoradiotherapy protocols in LA-SCCHN usually consists in tweaking radiotherapy parameters in terms of total dose, fractionation, and technique and chemotherapy parameters like the type of systemic agent, its peak dose, dose intensity, cumulative dose, and timing of its delivery In this scenario, despite a clear lack of convincing evidence from controlled trials, weekly concurrent chemotherapy based on low-dose cisplatin gained broader popularity. With conventional radiotherapy, a low-dose regimen was explored in 1 and 3 studies in the adjuvant and definitive settings, respectively, whereas the high-dose regimen was studied in 2 and 3 trials, respectively From this perspective, studies focusing on altered fractionation radiotherapy are lacking.
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