Szturz Petr, Wouters Kristien, Kiyota Naomi, Tahara Makoto, Prabhash Kumar, Noronha Vanita, Adelstein David, Van Gestel Dirk, Vermorken Jan B
Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Scientific Coordination and Biostatistics, Antwerp University Hospital, Edegem, Belgium.
Front Oncol. 2019 Feb 21;9:86. doi: 10.3389/fonc.2019.00086. eCollection 2019.
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/m 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.
在局部晚期头颈部鳞状细胞癌(LA-SCCHN)中,同步放化疗是辅助治疗和根治性治疗多模式管理的重要组成部分。尽管去强化策略已成为人乳头瘤病毒(HPV)阳性口咽癌临床研究的前沿内容,但每3周给予100mg/m²顺铂,共三个周期,并与常规分割外照射放疗同步进行,对于大多数LA-SCCHN病例而言,是一种经济有效的且全球通用的治疗选择。基于四项大型随机试验,该方案已成为适合使用顺铂患者的非手术标准治疗方案。然而,在疗效、毒性和依从性方面的结果却相当令人失望。因此,迫切需要找到更好的替代方案。在随机试验的支持有限的情况下,一些机构采用每周低剂量顺铂方案取代了标准高剂量方案。四项探索放疗联合或不联合每周低剂量顺铂的前瞻性试验已发表。其中两项试验在20世纪80年代进行,一项结果为阴性,第三项研究提供的毒性信息不足,第四项试验因入组不佳而不得不提前终止。此外,两项比较两种同步顺铂方案的III期试验结果更倾向于高剂量方案。我们对59项共纳入5582例患者的前瞻性试验进行了综合荟萃分析。主要终点为总生存期。考虑到不同的放疗分割方案和治疗目的,我们进行了三项荟萃分析,一项针对术后常规同步放化疗,一项针对根治性常规同步放化疗,一项针对根治性分割方式改变的同步放化疗。在前两种情况下,高剂量和低剂量方案产生的生存结果相似,因此未达到主要目标。当与分割方式改变的放疗同步进行时,接受高剂量顺铂治疗的患者总生存期显著长于接受低剂量顺铂治疗的患者。在本文中,我们对结果进行了综合阐述,讨论了累积剂量问题,比较了两个周期与三个周期高剂量顺铂的情况,并针对在临床实践中使用当前标准治疗方案——高剂量顺铂,提出了我们的三步建议。