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
Topic: Radiation/Chemotherapy

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Materials and methods: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT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.

Keywords: Chemotherapy; Head and Neck Cancer; Individual Patient Data; Meta-analysis; Radiotherapy; Randomised Clinical Trials.

PICO
Population: Patients with non-metastatic squamous cell carcinoma of the head and neck
Intervention: Concomitant chemotherapy (CT) with loco-regional treatment (LRT)
Comparison: Loco-regional treatment alone, or loco-regional treatment with induction or adjuvant chemotherapy, or different timing of chemotherapy (e.g., induction CT + radiotherapy vs. radiotherapy + concomitant or alternating CT)
Outcomes: Overall survival (OS)

Included studies:
title: 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
title: Longterm results of a phase III randomized trial of postoperative radiotherapy with or without carboplatin in patients with high-risk head and neck cancer
title: French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC)
title: Long-term update of the 24954 EORTC phase III trial on larynx preservation
title: 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
title: Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer
title: Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: A phase II randomized study
title: Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial
title: 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
title: 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
title: Radiotherapy alone or with concomitant daily low-dose carboplatin in locally advanced, unresectable head and neck cancer: definitive results of a phase III study with a follow-up period of up to ten years
title: Randomized clinical trial of post-operative radiotherapy versus concomitant carboplatin and radiotherapy for head and neck cancers with lymph node involvement
title: The use of cisplatin as radiosensitizing agent in advanced tumors of the head and neck. Randomized study
title: Comparison of concomitant radiotherapy and chemotherapy with radiotherapy alone in advanced cancers of the head and neck: results of a randomized trial
title: Conventional radiotherapy versus concurrent chemoradiotherapy versus accelerated radiotherapy in locoregionally advanced carcinoma of head and neck: Results of a prospective randomized trial
title: Simultaneous versus sequential combined technique therapy for squamous cell head and neck cancer
title: A randomized trial of combined multidrug chemotherapy and radiotherapy in advanced squamous cell carcinoma of the head and neck. An interim report from the SECOG participants
title: Chemo-radiotherapy in advanced head and neck tumors. Personal experience
title: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer
title: Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial
title: Intra-arterial methotrexate chemotherapy and telecobalt therapy in cancer of the oral cavity and oropharynx
title: Adjuvant intravenous methotrexate or definitive radiotherapy alone for advanced squamous cancers of the oral cavity, oropharynx, supraglottic larynx or hypopharynx. Concluding report of an RTOG randomized trial on 638 patients
title: A randomized EORTC study on the effect of preoperative polychemotherapy in pyriform sinus carcinoma treated by pharyngolaryngectomy and irradiation. Results from 5 to 10 years
title: A prospective study of preoperative chemotherapy and split-course irradiation for locally advanced or recurrent oral/pharyngeal squamous carcinoma
title: Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Final report of the Head and Neck Contracts Program
title: Randomised EORTC Head and Neck Cooperative Group trial of preoperative intra-arterial chemotherapy in oral cavity and oropharynx carcinoma
title: Randomized study of adjuvant chemotherapy for head and neck cancer
title: A randomized study of adjuvant chemotherapy for cancer of the upper aerodigestive tract
title: Preoperative chemotherapy in advanced resectable head and neck cancer: final report of the Southwest Oncology Group
title: Induction chemotherapy in head and neck cancer: Results of a phase III trial
title: Induction chemotherapy in advanced head and neck cancer. Preliminary results of a randomized study
title: A randomized trial of neoadjuvant vs concomitant chemotherapy vs radiotherapy alone in the treatment of stage IV head and neck squamous cell carcinoma
title: Induction chemotherapy in advanced head and neck tumors: Results of two randomized trials
title: Combination chemotherapy as induction therapy for advanced resectable head and neck cancer
title: Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer
title: The effects of delay in standard treatment due to induction chemotherapy in two randomized prospective studies
title: Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck: A randomized phase III study
title: Randomized study of 5 fluorouracil and cis platin as neoadjuvant therapy in head and neck cancer: A preliminary report
title: Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: A study by the Gruppo di Studio sui Tumori della Testa e del Collo
title: Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up
title: Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma
title: Induction chemotherapy with carboplatin and ftorafur in advanced head and neck cancer. A randomized study
title: Neoadjuvant combination of carboplatin and 5-FU in head and neck cancer: A randomized study
title: Neoadjuvant chemotherapy with carboplatin/5-fluorouracil in head and neck cancer
title: Induction chemotherapy in primary resectable head and neck tumors: A prospective randomized trial
title: Combined therapy in advanced head and neck cancer: hydroxyurea and radiotherapy
title: Ten-year results of randomized trial comparing radiotherapy and concomitant bleomycin to radiotherapy alone in epidermoid carcinomas of the oropharynx: experience of the European Organization for Research and Treatment of Cancer
title: Combined bleomycin treatment and radiation therapy in squamous cell carcinoma of the head and neck region
title: Bleomycin and radiation therapy in squamous cell carcinoma of the upper aero-digestive tract: A phase III clinical trial
title: Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer
title: A randomised clinical trial to contrast radiotherapy with radiotherapy and methotrexate given synchronously in head and neck cancer
title: Concomitant methotrexate and radiotherapy in advanced head and neck cancer: 15-year follow-up of a randomized clinical trial
title: Phase III study of radiation therapy with or without cis-platinum in patients with unresectable squamous or undifferentiated carcinoma of the head and neck: an intergroup trial of the Eastern Cooperative Oncology Group (E2382)
title: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer
title: Radiation therapy alone or with concurrent low-dose daily either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: A prospective randomized trial
title: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicenter study
title: Radiotherapy, combined with simultaneous chemotherapy with mitomycin C and bleomycin for inoperable head and neck cancer–preliminary report
title: Combined bleomycin and radiotherapy in oral cancer
title: Combined preoperative treatment with cobalt and bleomycin in patients with head and neck carcinoma–a controlled clinical study
title: Treatment of advanced head and neck cancer by means of radiation therapy plus chemotherapy–a randomised trial
title: Treatment of advanced head and neck cancer: multiple daily dose fractionated radiation therapy and sequential multimodal treatment approach
title: Randomized clinical trial of mitomycin C as an adjunct to radiotherapy in head and neck cancer
title: A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment for advanced laryngeal and hypopharyngeal squamous carcinoma
title: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: Final report of a randomized trial
title: Simultaneous chemoradiation in the treatment of advanced head and neck cancer
title: Mitomycin C as an adjunct to postoperative radiation therapy in squamous cell carcinoma of the head and neck: Results from two randomized clinical trials
title: Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy
title: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck
title: Feasibility of non-cisplatin-based induction chemotherapy and concurrent chemoradiotherapy in advanced head and neck cancer
title: Mature results of a Phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with Stage III and IV squamous cell carcinoma of the head and neck
title: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer
title: Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers
title: Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial
title: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial
title: An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer
title: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer
title: Long-term results of RTOG 91–11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer
title: Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy–a multicenter randomized trial
title: Final results of the 94–01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma
title: Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer
title: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer
title: Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy
title: Concomitant cisplatin and hyperfractionated radiotherapy in locally advanced head and neck cancer: 10-year follow-up of a randomized phase III trial (SAKK 10/94)
title: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy - Results of a multicentric randomized German trial in advanced head-and-neck cancer
title: Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer: A Hellenic Cooperative Oncology Group Phase III Study
title: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck
title: Long-term follow-up of the RTOG 9501/intergroup phase III trial: Postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck
title: Radiotherapy with or without mitomycin c in the treatment of locally advanced head and neck cancer: results of the IAEA multicentre randomised trial
title: Accelerated radiotherapy and concomitant high dose chemotherapy in non resectable stage IV locally advanced HNSCC: results of a GORTEC randomized trial
title: Patterns of failure in patients with locally advanced head and neck cancer treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin
title: Adjuvant treatment of tongue and floor of the mouth cancers