Background
Phase III noninferiority RCT (Tata Memorial) of 300 patients with locally advanced head and neck squamous cell carcinoma without distant metastases planned for curative chemoradiation. CRT was given in the adjuvant setting for ≥1 high-risk feature (extracapsular extension, close/positive margins, ≥2 LN+, T4 primary) or as definitive CRT for unresectable disease or organ preservation. Restaging imaging at 6-8 wk post-CRT; weekly assessment on CRT then q3mo for first 2 yrs.
Interventions and follow up
Arm A: cisplatin 100 mg/m2 q3wk with concurrent radiation
Arm B: cisplatin 30 mg/m2 weekly with concurrent radiation
Primary endpoint: locoregional control (LRC)*
Secondary endpoints: toxicity, compliance, response, PFS, OS
mFollow up: 22 months
Arm B: cisplatin 30 mg/m2 weekly with concurrent radiation
Primary endpoint: locoregional control (LRC)*
Secondary endpoints: toxicity, compliance, response, PFS, OS
mFollow up: 22 months
Results
2-yr LRC: 73.1% vs 58.5% (arm A vs B); delta 14.6% (95% CI 5.7%-23.5%); P=.014; HR 1.76 (95% CI 1.11-2.79)
mPFS: 28.6mo vs 17.7mo; HR 1.24, 95% CI 0.89-1.73; P=.21
mOS: not reached vs 39.5mo; HR 1.14, 95% CI 0.79-1.65; P=.48
Completed chemoRT: 94% vs 88.7%
Chemotherapy dose reduction: 8% vs 9.3%
Chemotherapy delayed >2 days: 28% vs 24.7%
Median cumulative cisplatin dose: 300 mg/m2 (IQR 200-300) vs 210 mg/m2 (IQR 180-210)
Median dose intensity: 42 mg/m2/wk (IQR 33.3-47.7) vs 30.7 mg/m2/wk (IQR 28.8-33.4)
mPFS: 28.6mo vs 17.7mo; HR 1.24, 95% CI 0.89-1.73; P=.21
mOS: not reached vs 39.5mo; HR 1.14, 95% CI 0.79-1.65; P=.48
Completed chemoRT: 94% vs 88.7%
Chemotherapy dose reduction: 8% vs 9.3%
Chemotherapy delayed >2 days: 28% vs 24.7%
Median cumulative cisplatin dose: 300 mg/m2 (IQR 200-300) vs 210 mg/m2 (IQR 180-210)
Median dose intensity: 42 mg/m2/wk (IQR 33.3-47.7) vs 30.7 mg/m2/wk (IQR 28.8-33.4)
Adverse events
Overall (arm A vs B): severe AEs 84.6% vs 71.6%, P=.006; hospitalization due to AEs 31.1% vs 13.3%, P<.001
Grade 3-4 (arm A vs B): mucositis 17.3% vs 18.1%; dysphagia 42% vs 38.9%; odynophagia 41.4% vs 51.7%; infection 19.5% vs 33.6%; hyponatremia 22.7% vs 52.4%; neutropenia 1.3% vs 12.7%
Grade 3-4 (arm A vs B): mucositis 17.3% vs 18.1%; dysphagia 42% vs 38.9%; odynophagia 41.4% vs 51.7%; infection 19.5% vs 33.6%; hyponatremia 22.7% vs 52.4%; neutropenia 1.3% vs 12.7%
Conclusions
Once-every-3-weeks cisplatin 100 mg/m2 produced superior locoregional control, albeit with more toxicity, than once-weekly cisplatin 30 mg/m2. Treatment compliance and cumulative cisplatin dose differed substantially between arms; the weekly 30 mg/m2 schedule yielded a lower cumulative dose.
Key Limitations
Open-label, single-institution; the weekly arm used 30 mg/m2 (lower cumulative dose) rather than the more common 40 mg/m2 schedule, limiting generalizability; the JCOG1008 trial used 40 mg/m2 weekly (cumulative ~239 mg/m2) and reached different conclusions. Mixed adjuvant and definitive populations. *LRC defined as absence of disease recurrence at the primary site or regional nodes 2 years after radiotherapy.
Clinical Context
High-dose 3-weekly cisplatin (100 mg/m2 x3, cumulative 300 mg/m2) remains the reference concurrent regimen with definitive RT. ESMO guidelines endorse high-dose 3-weekly cisplatin as standard; weekly schedules are accepted alternatives for patients unable to tolerate high-dose cisplatin, with the caveat that adequate cumulative dose (per JCOG1008, 40 mg/m2 weekly) is important.