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Abstract

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updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered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.​

Figure 2: Overall survival curves for trials comparing altered fractionation and conventional fractionation radiotherapy

(A) All types of altered fractionation radiotherapy. (B) Hyperfractionated radiotherapy. (C) Moderately accelerated radiotherapy. (D) Very accelerated radiotherapy.​ 

Collaborators (82)

Blanchard P, Bourhis J, Lacas B, Pignon JP, Bernier J, Le QT, Overgaard J, Parmar MK, Trotti A, Agarwal JP, Aupérin A, Ang KK, Awwad HK, Bacigalupo A, Bartelink H, Benhamou E, Bernier J, Blanchard P, Bourhis J, Budach W, Chitapanarux I, Cho KH, Collette L, Corvò R, Dani C, Dische S, Dobrowsky W, Denham JW, Driessen CM, Fallai C, Garden AS, Laskar SG, Ghoshal S, Grau C, Gregoire V, Hay JH, van Herpen C, Hliniak A, Johansen J, Kristiansen CA, Krstevska V, Lacas B, Langendijk JA, Lapeyre M, Le QT, Lotayef M, Maciejewski B, Maingon P, Michalski W, Moon SH, Nilsson P, Olmi P, Nankivell M, Nishiyama K, O'Sullivan B, Overgaard J, Parmar MK, Pignon JP, Poulsen MG, Ramadas K, Rishi A, Rosenthal DI, Sanguineti G, Saunders MI, Sire C, Skladowski K, Souhami L, Suwinski R, Szutkowski Z, Tandon N, van Tinteren H, Torri V, Tripcony L, Trotti A, Viegas CMP, Waldron J, Widder J, Wong S, Wu JS, Yamazaki H, Zackrisson B, Zhang Q.

Author information

​Lacas B1, Bourhis J2, Overgaard J3, Zhang Q4, Grégoire V5, Nankivell M6, Zackrisson B7, Szutkowski Z8, Suwiński R9, Poulsen M10, O'Sullivan B11, Corvò R12, Laskar SG13, Fallai C14, Yamazaki H15, Dobrowsky W16, Cho KH17, Garden AS18, Langendijk JA19, Viegas CMP20, Hay J21, Lotayef M22, Parmar MKB6, Aupérin A1, van Herpen C23, Maingon P24, Trotti AM25, Grau C3, Pignon JP26, Blanchard P27; MARCH Collaborative Group.​

1 Ligue Nationale Contre le Cancer Meta-Analysis Platform, Service de Biostatistique et d'Epidémiologie, Gustave Roussy Cancer Campus, INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.

2 Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

3 Department of Experimental Clinical Oncology, Aarhus, Denmark.

4 NRG Oncology Statistics and Data Management Center (formerly RTOG), Philadelphia, PA, USA.

5 Radiation Oncology Department, UCL-Cliniques Universitaires St-Luc, Brussels, Belgium.

6 Medical Research Council Clinical Trials Unit, University College London, London, UK.

7 Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.

8 Department of Radiotherapy, Cancer Center, Marie Curie-Sklodowska Memorial Institute, Warsaw, Poland.

9 Radiotherapy and Chemotherapy Clinic and Teaching Hospital, Marie Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland.

10 Radiation Oncology Services, Mater Centre, Brisbane, QLD, Australia.

11 Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.

12 IRCCS San Martino-IST, Genoa, Italy.

13 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India.

14 Department of Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

15 Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka, Japan.

16 Department of Clinical Oncology, Freeman Hospital, Newcastle, UK.

17 Proton Therapy Center, Research Institute and Hospital, National Cancer Center, Goyang, South Korea.

18 Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

19 Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

20 Radiation Oncology Department, Instituto Nacional de Cancer, Brasil National Cancer Institute, Rio de Janeiro, Brazil.

21 Division of Radiation Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.

22 Radiation Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt.

23 Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands.

24 European Organisation for Research and Treatment of Cancer, Radiation Oncology Group, Brussels, Belgium; Service d'Oncologie, Radiothérapie, Hôpitaux Universitaires Pitié Salpêtrière, Charles Foix, Paris, France.

25 Moffitt Cancer Center, Department of Radiation Oncology, Tampa, FL, USA.

26 Ligue Nationale Contre le Cancer Meta-Analysis Platform, Service de Biostatistique et d'Epidémiologie, Gustave Roussy Cancer Campus, INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. Electronic address: jean-pierre.pignon@gustaveroussy.fr.

27 Department of Radiation Therapy, Gustave Roussy Cancer Campus, INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.