Background
Multicenter, open-label, phase II/III noninferiority RCT. 261 patients with postoperative high-risk (microscopically positive margin and/or extranodal extension) locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Tested whether weekly low-dose cisplatin chemoradiotherapy is noninferior to standard 3-weekly cisplatin (noninferiority margin HR 1.32).
Interventions and follow up
Arm A (3-weekly): Cisplatin 100 mg/m² q3wk × 3 cycles concurrent with radiotherapy (66 Gy in 33 fractions over 6.5 weeks, high-energy 4-10 MV photons)
Arm B (weekly): Cisplatin 40 mg/m² weekly × 7 cycles concurrent with the same radiotherapy
Primary endpoint: Phase II - proportion of treatment completion; Phase III - overall survival (OS)
mFollow up: 2.2 years
Arm B (weekly): Cisplatin 40 mg/m² weekly × 7 cycles concurrent with the same radiotherapy
Primary endpoint: Phase II - proportion of treatment completion; Phase III - overall survival (OS)
mFollow up: 2.2 years
Results
OS (weekly vs 3-weekly): HR 0.69, 99.1%CI 0.37-1.27 (upper limit below the prespecified noninferiority margin of 1.32; one-sided noninferiority P=.0027)
2-yr OS: 74.2% vs 77.7% (Arm A vs Arm B)
3-yr OS: 59.1% vs 71.6% (Arm A vs Arm B)
Median cumulative cisplatin dose: 280 vs 239 mg/m² (Arm A vs Arm B)
Actual/planned cisplatin delivery: 88.9% vs 84.1%
Treatment completion: 93.2% vs 86.8%
2-yr OS: 74.2% vs 77.7% (Arm A vs Arm B)
3-yr OS: 59.1% vs 71.6% (Arm A vs Arm B)
Median cumulative cisplatin dose: 280 vs 239 mg/m² (Arm A vs Arm B)
Actual/planned cisplatin delivery: 88.9% vs 84.1%
Treatment completion: 93.2% vs 86.8%
Adverse events
Overall (3-weekly vs weekly): any grade 4 18.6% vs 8.2%; any grade ≥3 79.8% vs 81.1%
Hematologic: grade ≥3 neutropenia 49% vs 35%; grade ≥3 thrombocytopenia 66% vs 84%; grade ≥3 infection 12% vs 7%
Renal/otologic: any-grade acute kidney injury 40% vs 30%; any-grade hearing impairment 17% vs 7%; any-grade tinnitus 35% vs 5%
Hematologic: grade ≥3 neutropenia 49% vs 35%; grade ≥3 thrombocytopenia 66% vs 84%; grade ≥3 infection 12% vs 7%
Renal/otologic: any-grade acute kidney injury 40% vs 30%; any-grade hearing impairment 17% vs 7%; any-grade tinnitus 35% vs 5%
Conclusions
Weekly cisplatin chemoradiotherapy was noninferior to standard 3-weekly cisplatin for OS in patients with postoperative high-risk LA-SCCHN, with less neutropenia, infection, renal and hearing toxicity, supporting weekly cisplatin as an acceptable alternative.
Key Limitations
Noninferiority design assessed at a planned interim analysis with relatively short 2.2-year median follow-up; longer-term OS and locoregional control remain to be confirmed. Conducted entirely in a Japanese population, which may limit generalizability. Restricted to the postoperative high-risk setting and does not address definitive (non-surgical) chemoradiation.
Clinical Context
JCOG1008 provides the first phase III evidence that weekly low-dose cisplatin (40 mg/m²) is noninferior to high-dose 3-weekly cisplatin (100 mg/m²) in postoperative high-risk SCCHN, complementing prior data favoring high-dose cisplatin in the definitive setting (where 3-weekly remains preferred). ESMO and ASCO recognize weekly cisplatin as a reasonable option in the adjuvant high-risk setting for patients unlikely to tolerate high-dose therapy.