Benjamin Lacas, Jean Bourhis, Jens Overgaard, Qiang Zhang, Vincent Grégoire, Matthew Nankivell, Björn Zackrisson, Zbigniew Szutkowski, Rafał Suwiński, Michael Poulsen, Brian O'Sullivan, Renzo Corvò, Sarbani Ghosh Laskar, Carlo Fallai, Hideya Yamazaki, Werner Dobrowsky, Kwan Ho Cho, Beth Beadle, Johannes A Langendijk, Celia Maria Pais Viegas, John Hay, Mohamed Lotayef, Mahesh K B Parmar, Anne Aupérin, Carla van Herpen, Philippe Maingon, Andy M Trotti, Cai Grau, Jean-Pierre Pignon, Pierre Blanchard, Jean Pierre Pignon, Jacques Bernier, Quynh-Thu Le, Masheh KB Parmar, Andy Trotti, Jai Prakash Agarwal, Kian K Ang, Hassan K Awwad, Almalina Bacigalupo, Harry Bartelink, Ellen Benhamou, Wilfried Budach, Imjai Chitapanarux, Laurence Collette, Carla Dani, Stanley Dische, James W Denham, Chantal ML Driessen, Sushmita Ghoshal, Vincent Gregoire, John H Hay, Andrzej Hliniak, Jørgen Johansen, Claus Andrup Kristiansen, Valentina Krstevska, Johannes A. Langendijk, Michel Lapeyre, Boguslaw Maciejewski, Wojciech Michalski, Sung Ho Moon, Per Nilsson, Patrizia Olmi, Kinji Nishiyama, Mahesh KB Parmar, Michael G Poulsen, Kunnambath Ramadas, Anupam Rishi, David I. Rosenthal, Giuseppe Sanguineti, Michele I Saunders, Christian Sire, Krzysztof Skladowski, Luis Souhami, Rafal Suwinski, Nitin Tandon, Harm van Tinteren, Valter Torri, Lee Tripcony, John Waldron, Joachim Widder, Stuart Wong, Jonn S Wu, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
Item does not contain fulltext BACKGROUND: The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. METHODS: For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. FINDINGS: Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0.94, 95% CI 0.90-0.98; p=0.0033), with an absolute difference at 5 years of 3.1% (95% CI 1.3-4.9) and at 10 years of 1.2% (-0.8 to 3.2). We found a significant interaction (p=0.051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0.83, 0.74-0.92), with absolute differences at 5 years of 8.1% (3.4 to 12.8) and at 10 years of 3.9% (-0.6 to 8.4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1.22, 1.05-1.42; p=0.0098), with absolute differences at 5 years of -5.8% (-11.9 to 0.3) and at 10 years of -5.1% (-13.0 to 2.8). INTERPRETATION: This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested. FUNDING: Institut National du Cancer; and Ligue Nationale Contre le Cancer.