Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group

doi:10.1016/j.radonc.2021.01.013

Radiotherapy and Oncology

Volume 156, March 2021, Pages 281-293

https://doi.org/10.1016/j.radonc.2021.01.013 Get rights and content

Highlights

•
MACH-NC second update with 107 randomized trials (19805 patients) investigating chemotherapy (CT) in non-metastatic HNSCC.
•
Overall Survival (OS) improved by CT, benefit superior for concomitant CT (HR 0.83 [0.79; 0.86]) over induction or adjuvant CT.
•
Direct comparison confirmed the superiority of concomitant over induction CT on OS.

Abstract

Background and purpose

The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.

Materials and methods

Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.

Results

For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005).

Conclusion

The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.

Section snippets

Material and methods

The methods were pre-specified in a protocol (https://www.gustaveroussy.fr/fr/meta-analyses-protocoles-dessais-orl).

Results

The meta-analysis included 107 randomized trials (19805 patients). Sixteen new trials (2767 patients) [1], [2], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36] (Web-Fig. 1, Web-Appendix 6) and 2327 deaths (including death from updated previous trials) were added for this update. We were able to collect data from 725 of the 867 randomized patients who had been excluded from the original published analyses. Updated follow-up

Discussion

The present study provides the most comprehensive and robust analysis of the role of chemotherapy in combination with locoregional therapy for the treatment of non-metastatic HNSCC. It involved the individual data of 19,805 patients included in 107 randomized trials. Results were robust to multiple pre-specified sensitivity analyses. Given that the landscape of clinical trials has shifted from cytotoxic chemotherapy to targeted therapies and recently to immunotherapy, this analysis is likely to

Contributors

PB, JB, and JPP with the help of the steering committee members designed and supervised the study.

PB, and JPP obtained funding.

PB, JB, JPP and BL searched and selected the trials. Steering committee members contributed to the identification and selection of the trials.

PB, BL and JPP collected and checked data with the help of the investigators who validated the re-analysis of their trials.

AA, BL, PB and JPP did the statistical analyses and wrote the draft, with revisions from the other

Role of funding sources

The funding sources had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The submission of the paper for publication was decided by the MACH-NC collaborative group. AA, PB, BL, and J-PP had access to the raw data. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors have seen and approved the final version and, after consultation with the

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We thank the trialists and the collaborative groups who agreed to share their data. The contents of this publication and methods used are solely the responsibility of the authors and do not necessarily represent the official views of the ECOG-ACRIN Cancer Research Group, and NRG Oncology. This research was funded by grants from Institut National du Cancer (Programme Hospitalier de Recherche Clinique) and Ligue Nationale Contre le Cancer.

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Original ArticleMeta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group

Highlights

Abstract

Background and purpose

Materials and methods

Results

Conclusion

Section snippets

Material and methods

Results

Discussion

Contributors

Role of funding sources

Declaration of Competing Interest

Acknowledgements

Lancet

Radiother Oncol

Oral Oncol

Lancet

Lancet

Lancet Oncol

Control Clin Trials

Progr Cardiovasc Dis

J Clin Epidemiol

Ann Oncol

Ann Oncol

Ann Oncol

Radiother Oncol

Bull Cancer Radiother

Eur J Cancer

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Bull Cancer/Radiother

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clin Radiol

Clin Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Clin Radiol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Taxane-cisplatin-fluorouracil as induction chemotherapy in locally advanced head and neck cancers: an individual patient data meta-analysis of the Meta-Analysis of Chemotherapy in Head and Neck Cancer Group

J Clin Oncol

Practical methodology of meta-analyses (overviews) using updated individual patient data. Cochrane Working Group

Stat Med

Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement

JAMA

Quantifying heterogeneity in a meta-analysis

Stat Med

A proportional hazards model for the subdistribution of a competing risk

J Am Stat Assoc

A three-arm randomized trial comparing neo-adjuvant or concurrent weekly cisplatin to radiotherapy alone for locally advanced head and neck squamous cell cancer (HNSCC)

Eur J Cancer

Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial

Clin Transl Oncol

Long-term results of a phase III randomized trial of postoperative radiotherapy with or without carboplatin in patients with high-risk head and neck cancer

Laryngoscope

Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy

J Natl Cancer Inst

Docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by chemoradiotherapy or chemoradiotherapy alone in stage III-IV unresectable head and neck cancer: Results of a randomized phase II study

Strahlenther Onkol

Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer

J Clin Oncol

Long-term results of a randomized phase III trial of TPF induction chemotherapy followed by surgery and radiation in locally advanced oral squamous cell carcinoma

Oncotarget

Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma

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Original Article
Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group