Background
Updated individual-patient-data meta-analysis (MACH-NC) of 107 randomized trials, 19,805 treatment-naïve patients with resectable or unresectable squamous cell carcinoma of the head and neck (~90% stage III-IV) receiving definitive locoregional therapy with or without chemotherapy. Oral cavity, oropharynx, hypopharynx, larynx included; primary nasopharyngeal cancer excluded.
Interventions and follow up
Design: Individual-patient-data meta-analysis comparing chemotherapy (induction, concurrent, or adjuvant) added to locoregional treatment vs locoregional treatment alone
Comparisons: Induction (45 trials, 7,054 pts); concurrent chemoRT (71 trials, 10,680 pts); adjuvant (14 trials, 2,915 pts); concurrent vs induction (8 trials, 1,214 pts)
Primary endpoint: Overall survival
mFollow up: 6.5 years
Comparisons: Induction (45 trials, 7,054 pts); concurrent chemoRT (71 trials, 10,680 pts); adjuvant (14 trials, 2,915 pts); concurrent vs induction (8 trials, 1,214 pts)
Primary endpoint: Overall survival
mFollow up: 6.5 years
Results
Induction vs local alone OS: HR 0.96, 95%CI 0.90-1.01, P=.14 (NS)
Induction EFS: HR 0.96, 95%CI 0.90-1.02, P=.14 (NS); platinum polychemotherapy improved EFS (HR 0.74, 0.67-0.82)
Concurrent chemoRT OS: HR 0.83, 95%CI 0.79-0.86, P<.0001 (absolute +6.5% at 5yr, +3.6% at 10yr)
Concurrent chemoRT EFS: HR 0.80, 95%CI 0.77-0.84, P<.0001 (absolute +5.8% at 5yr)
Adjuvant OS: HR 1.02, 95%CI 0.92-1.13, P=.69 (NS)
Concurrent vs induction OS: HR 0.84, 95%CI 0.74-0.95, P=.005 (absolute +6.2% at 5yr); LRF HR 0.86, 95%CI 0.76-0.97, P=.01
No OS benefit of concurrent chemo if age >70 (HR 0.97, 0.81-1.16) or ECOG ≥2:
Induction EFS: HR 0.96, 95%CI 0.90-1.02, P=.14 (NS); platinum polychemotherapy improved EFS (HR 0.74, 0.67-0.82)
Concurrent chemoRT OS: HR 0.83, 95%CI 0.79-0.86, P<.0001 (absolute +6.5% at 5yr, +3.6% at 10yr)
Concurrent chemoRT EFS: HR 0.80, 95%CI 0.77-0.84, P<.0001 (absolute +5.8% at 5yr)
Adjuvant OS: HR 1.02, 95%CI 0.92-1.13, P=.69 (NS)
Concurrent vs induction OS: HR 0.84, 95%CI 0.74-0.95, P=.005 (absolute +6.2% at 5yr); LRF HR 0.86, 95%CI 0.76-0.97, P=.01
No OS benefit of concurrent chemo if age >70 (HR 0.97, 0.81-1.16) or ECOG ≥2:
Adverse events
Aggregated toxicity: Not formally pooled; this was a patient-level efficacy meta-analysis
Treatment-related mortality: Concurrent chemoRT increased early (120-day) mortality vs local alone (HR 1.89, 95%CI 1.33-2.68, P=.0003); concurrent regimens consistently raised acute mucosal, hematologic, and GI toxicity
Treatment-related mortality: Concurrent chemoRT increased early (120-day) mortality vs local alone (HR 1.89, 95%CI 1.33-2.68, P=.0003); concurrent regimens consistently raised acute mucosal, hematologic, and GI toxicity
Conclusions
MACH-NC confirmed the OS benefit of concurrent chemoradiotherapy for locally advanced head and neck SCC over locoregional therapy alone and over induction followed by locoregional treatment. Induction and adjuvant chemotherapy did not improve OS; benefit of concurrent chemo was absent in patients >70 years or ECOG ≥2.
Key Limitations
Pooled trials span decades with heterogeneous radiotherapy techniques (largely pre-IMRT) and chemotherapy regimens. Toxicity not systematically aggregated. HPV status unavailable for most oropharyngeal trials.
Clinical Context
Provides the foundational evidence underpinning ESMO recommendation of concurrent platinum-based chemoradiotherapy as standard definitive treatment for locally advanced head and neck SCC, and cautions against routine induction or adjuvant chemotherapy.