Weekly Cisplatin Plus Radiation for Postoperative Head and Neck Cancer (JCOG1008): A Multicenter, Noninferiority, Phase II/III Randomized Controlled Trial

Abstract

PURPOSE The standard treatment for postoperative high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (100 mg/m2). However, whether chemoradiotherapy with weekly cisplatin (40 mg/m2) yields comparable efficacy with 3-weekly cisplatin in postoperative high-risk LA-SCCHN is unknown. PATIENTS AND METHODS In this multi-institutional open-label phase II/III trial, patients with postoperative high-risk LA-SCCHN were randomly assigned to receive either chemoradiotherapy with 3-weekly cisplatin (100 mg/m2) or with weekly cisplatin (40 mg/m2) to confirm the noninferiority of weekly cisplatin. The primary end point of phase II was the proportion of treatment completion, and that of phase III was overall survival. A noninferiority margin of hazard ratio was set at 1.32. RESULTS Between October 2012 and December 2018, a total of 261 patients were enrolled (3-weekly cisplatin, 132 patients; weekly cisplatin, 129 patients). At the planned third interim analysis in the phase III part, after a median follow-up of 2.2 (interquartile range 1.19-3.56) years, chemoradiotherapy with weekly cisplatin was noninferior to 3-weekly cisplatin in terms of overall survival, with a hazard ratio of 0.69 (99.1% CI, 0.374 to 1.273 [< 1.32], one-sided P for noninferiority = .0027 < .0043). Grade 3 or more neutropenia and infection were less frequent in the weekly arm (3-weekly v weekly, 49% v 35% and 12% v 7%, respectively), as were renal impairment and hearing impairment. No treatment-related death was reported in the 3-weekly arm, and two (1.6%) in the weekly arm. CONCLUSION Chemoradiotherapy with weekly cisplatin is noninferior to 3-weekly cisplatin for patients with postoperative high-risk LA-SCCHN. These findings suggest that chemoradiotherapy with weekly cisplatin can be a possible treatment option for these patients.

Change in Pattern of Failure in Head and Neck Cancer

“…In the study by Kiyota et al, 1 the failure rates in both arms were predominantly distant, not locoregional. In the 3-weekly arm, of 51 recurrences, distant site–only recurrence was seen in 60.8% (n = 31) patients and distant site recurrence with locoregional failure was seen in another 9.8% (n = 5).…”

Acute toxicity in patients treated with concurrent chemoradiotherapy with proton versus intensity‐modulated radiation therapy for nonmetastatic head and neck cancers

“…[36][37][38] Furthermore, more patients in the IMRT group received cisplatin every 3 weeks (38.6% vs. 23.2%, p = 0.04), which has been shown to have greater toxicities compared to weekly cisplatin. 39,40 The proton group included more patients with HPV-positive tumors (65.6% vs. 58.0%, p = 0.049). However, our multivariable analyses were corrected for radiation timing, laterality of treatment, chemotherapy regimen, and HPV status to address these imbalances.…”

“…Patients undergoing trimodality treatment often experience increased morbidity and thus this baseline imbalance between the groups could cause bias 36–38 . Furthermore, more patients in the IMRT group received cisplatin every 3 weeks (38.6% vs. 23.2%, p = 0.04), which has been shown to have greater toxicities compared to weekly cisplatin 39,40 . The proton group included more patients with HPV‐positive tumors (65.6% vs. 58.0%, p = 0.049).…”

PROshot: Weekly Cisplatin Versus Every-3-Weeks Cisplatin, Screening Spine Magnetic Resonance Imaging in Prostate Cancer, Total Neoadjuvant Therapy for Rectal Cancer, and Omitting the Elective Low Neck in Nasopharyngeal Cancer

“…The multicenter, randomized, phase 2 and 3 Japan Clinical Oncology Group (JCOG) 1008 noninferiority trial enrolled patients with resected, stage III-IVB (Union for International Cancer Control (UICC) 7, which is similar to American Joint Committee on Cancer (AJCC) 7 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx who had positive margins and/or extranodal extension requiring adjuvant chemoradiation. 4 Of note, "microscopically positive margins" included those with margins <5 mm. The trial was designed around the rationale that a cumulative cisplatin dose of 200 mg/m 2 is necessary during radiation.…”