Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis

B. Lacas, J. Bourhis, J. Overgaard, Q. Zhang, V. Gregoire, M. Nankivell, B. Zackrisson, Z. Szutkowski, R. Suwinski, M. Poulsen, B. O'Sullivan, R. Corvo, S. G. Laskar, C. Fallai, H. Yamazaki, W. Dobrowsky, K. H. Cho, A. S. Garden, J. A. Langendijk, C. M. P. Viegas & 12 others J. Hay, M. Lotayef, M. K. B. Parmar, A. Auperin, C. van Herpen, P. Maingon, A. M. Trotti, C. Grau, J. P. Pignon, P. Blanchard, MARCH Collaborative Group, Giuseppe Sanguineti

Research output: Contribution to journalArticle

50 Citations (Scopus)

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updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered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.
Original languageEnglish
Pages (from-to)1221-1237
Number of pages17
JournalThe Lancet.Oncology
Volume18
Issue number9
DOIs
Publication statusPublished - Sep 1 2017

Fingerprint

Head and Neck Neoplasms
Meta-Analysis
Radiotherapy
Chemoradiotherapy
Survival
Drug Therapy
Squamous Cell Neoplasms
Hypopharynx
Oropharynx
Bibliography
Therapeutics
Standard of Care

Keywords

  • Carcinoma, Squamous Cell/mortality/pathology/radiotherapy
  • Dose Fractionation
  • Head and Neck Neoplasms/mortality/pathology/radiotherapy
  • Humans

Cite this

Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis. / Lacas, B.; Bourhis, J.; Overgaard, J.; Zhang, Q.; Gregoire, V.; Nankivell, M.; Zackrisson, B.; Szutkowski, Z.; Suwinski, R.; Poulsen, M.; O'Sullivan, B.; Corvo, R.; Laskar, S. G.; Fallai, C.; Yamazaki, H.; Dobrowsky, W.; Cho, K. H.; Garden, A. S.; Langendijk, J. A.; Viegas, C. M. P.; Hay, J.; Lotayef, M.; Parmar, M. K. B.; Auperin, A.; Herpen, C. van; Maingon, P.; Trotti, A. M.; Grau, C.; Pignon, J. P.; Blanchard, P.; Group, MARCH Collaborative; Sanguineti, Giuseppe.

In: The Lancet.Oncology, Vol. 18, No. 9, 01.09.2017, p. 1221-1237.

Research output: Contribution to journalArticle

Lacas, B, Bourhis, J, Overgaard, J, Zhang, Q, Gregoire, V, Nankivell, M, Zackrisson, B, Szutkowski, Z, Suwinski, R, Poulsen, M, O'Sullivan, B, Corvo, R, Laskar, SG, Fallai, C, Yamazaki, H, Dobrowsky, W, Cho, KH, Garden, AS, Langendijk, JA, Viegas, CMP, Hay, J, Lotayef, M, Parmar, MKB, Auperin, A, Herpen, CV, Maingon, P, Trotti, AM, Grau, C, Pignon, JP, Blanchard, P, Group, MARCHC & Sanguineti, G 2017, 'Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis', The Lancet.Oncology, vol. 18, no. 9, pp. 1221-1237. https://doi.org/S1470-2045(17)30458-8 [pii]
Lacas B, Bourhis J, Overgaard J, Zhang Q, Gregoire V, Nankivell M et al. Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis. The Lancet.Oncology. 2017 Sep 1;18(9):1221-1237. https://doi.org/S1470-2045(17)30458-8 [pii]
Lacas, B. ; Bourhis, J. ; Overgaard, J. ; Zhang, Q. ; Gregoire, V. ; Nankivell, M. ; Zackrisson, B. ; Szutkowski, Z. ; Suwinski, R. ; Poulsen, M. ; O'Sullivan, B. ; Corvo, R. ; Laskar, S. G. ; Fallai, C. ; Yamazaki, H. ; Dobrowsky, W. ; Cho, K. H. ; Garden, A. S. ; Langendijk, J. A. ; Viegas, C. M. P. ; Hay, J. ; Lotayef, M. ; Parmar, M. K. B. ; Auperin, A. ; Herpen, C. van ; Maingon, P. ; Trotti, A. M. ; Grau, C. ; Pignon, J. P. ; Blanchard, P. ; Group, MARCH Collaborative ; Sanguineti, Giuseppe. / Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis. In: The Lancet.Oncology. 2017 ; Vol. 18, No. 9. pp. 1221-1237.
@article{8a7942404046434da685c92fec811050,
title = "Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis",
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.",
keywords = "Carcinoma, Squamous Cell/mortality/pathology/radiotherapy, Dose Fractionation, Head and Neck Neoplasms/mortality/pathology/radiotherapy, Humans",
author = "B. Lacas and J. Bourhis and J. Overgaard and Q. Zhang and V. Gregoire and M. Nankivell and B. Zackrisson and Z. Szutkowski and R. Suwinski and M. Poulsen and B. O'Sullivan and R. Corvo and Laskar, {S. G.} and C. Fallai and H. Yamazaki and W. Dobrowsky and Cho, {K. H.} and Garden, {A. S.} and Langendijk, {J. A.} and Viegas, {C. M. P.} and J. Hay and M. Lotayef and Parmar, {M. K. B.} and A. Auperin and Herpen, {C. van} and P. Maingon and Trotti, {A. M.} and C. Grau and Pignon, {J. P.} and P. Blanchard and Group, {MARCH Collaborative} and Giuseppe Sanguineti",
note = "LR: 20170925; CI: Copyright (c) 2017; GR: U10 CA180822/CA/NCI NIH HHS/United States; GR: U10 CA180868/CA/NCI NIH HHS/United States; JID: 100957246; Carcinoma, squamous cell of head and neck; 2017/04/14 [received]; 2017/05/29 [revised]; 2017/05/31 [accepted]; ppublish",
year = "2017",
month = "9",
day = "1",
doi = "S1470-2045(17)30458-8 [pii]",
language = "English",
volume = "18",
pages = "1221--1237",
journal = "The Lancet.Oncology",
number = "9",

}

TY - JOUR

T1 - Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis

AU - Lacas, B.

AU - Bourhis, J.

AU - Overgaard, J.

AU - Zhang, Q.

AU - Gregoire, V.

AU - Nankivell, M.

AU - Zackrisson, B.

AU - Szutkowski, Z.

AU - Suwinski, R.

AU - Poulsen, M.

AU - O'Sullivan, B.

AU - Corvo, R.

AU - Laskar, S. G.

AU - Fallai, C.

AU - Yamazaki, H.

AU - Dobrowsky, W.

AU - Cho, K. H.

AU - Garden, A. S.

AU - Langendijk, J. A.

AU - Viegas, C. M. P.

AU - Hay, J.

AU - Lotayef, M.

AU - Parmar, M. K. B.

AU - Auperin, A.

AU - Herpen, C. van

AU - Maingon, P.

AU - Trotti, A. M.

AU - Grau, C.

AU - Pignon, J. P.

AU - Blanchard, P.

AU - Group, MARCH Collaborative

AU - Sanguineti, Giuseppe

N1 - LR: 20170925; CI: Copyright (c) 2017; GR: U10 CA180822/CA/NCI NIH HHS/United States; GR: U10 CA180868/CA/NCI NIH HHS/United States; JID: 100957246; Carcinoma, squamous cell of head and neck; 2017/04/14 [received]; 2017/05/29 [revised]; 2017/05/31 [accepted]; ppublish

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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.

AB - 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.

KW - Carcinoma, Squamous Cell/mortality/pathology/radiotherapy

KW - Dose Fractionation

KW - Head and Neck Neoplasms/mortality/pathology/radiotherapy

KW - Humans

U2 - S1470-2045(17)30458-8 [pii]

DO - S1470-2045(17)30458-8 [pii]

M3 - Article

VL - 18

SP - 1221

EP - 1237

JO - The Lancet.Oncology

JF - The Lancet.Oncology

IS - 9

ER -