Phase II/III trial of post-operative chemoradiotherapy comparing 3-weekly cisplatin with weekly cisplatin in high-risk patients with squamous cell carcinoma of head and neck (JCOG1008).

Abstract

6502 Background: The standard treatment for post-operative high-risk patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (CDDP) (100 mg/m2, q3wk, 66 Gy/33Fr; 3-weekly CDDP+RT). However, one concern with 3-weekly CDDP+RT is insufficient CDDP compliance due to high-dose-related toxicities. Weekly CDDP+RT (40 mg/m2, qwk, 66 Gy/33Fr; weekly CDDP+RT) is an alternative regimen with better compliance. Here, we conducted a phase II/III trial of weekly CDDP+RT in post-operative high-risk LA-SCCHN. Methods: This is a multi-institutional randomized phase II/III trial to confirm the non-inferiority of weekly CDDP+RT (Arm B) compared with 3-weekly CDDP+RT (Arm A). The trial enrolled pts aged 20-75 years with post-operative high-risk features (microscopically positive margin and/or extranodal extension) and ECOG-PS 0-1. Pts were randomized in a 1:1 ratio to Arm A or Arm B. Primary endpoint of phase II was the proportion of treatment completion and that of phase III was overall survival (OS). A non-inferiority margin of hazard ratio (HR) was set at 1.32. Results: Between Oct 2012 and Dec 2018, 261 pts were enrolled (Arm A 132 pts, Arm B 129 pts). At the planned second interim analysis in phase III with 76/161 events, the Data and Safety Monitoring Committee recommended terminating the trial and publishing the results because the statistical boundary for OS non-inferiority had met the pre-specified stop criteria. With a median follow-up of 2.2 years in all randomized pts, 3-year OS was 59.1% in Arm A and 71.6% in Arm B with a HR of 0.69 (99.1% CI, 0.374-1.273 [ < 1.32], one-sided p for non-inferiority = 0.00272 < 0.00433). 3-year RFS was 53.0% in Arm A and 64.5% in Arm B with a HR of 0.71 (95% CI, 0.48-1.06). Regarding acute adverse events, neutropenia (≥ grade 3), increased creatinine (≥ grade 2), hearing impairment (≥ grade 2) and mucositis (≥ grade 2) occurred in 48.8%, 8.5%, 7.8% and 55.0% in Arm A and 35.3%, 5.7%, 2.5% and 59.0% in Arm B, respectively. For compliance, median total dose of CDDP was 280 mg/m2 (IQR, 250-299) in Arm A and 239 mg/m2 (IQR, 199-277) in Arm B. Total radiation dose was 66 Gy (IQR, 66-66) in both arms. Proportion of treatment completion was 93.2% in Arm A and 86.8% in Arm B. Conclusions: Weekly CDDP+RT is non-inferior to 3-weekly CDDP+RT for post-operative high-risk LA-SCCHN pts and has a favorable toxicity profile. Weekly CDDP+RT should be considered the new standard treatment option for these pts. Clinical trial information: 000009125 .

Randomized Controlled Study Comparing Efficacy and Toxicity of Weekly vs. 3-Weekly Induction Chemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma

“…A retrospective study by Patil et al used induction chemotherapy with weekly paclitaxel and carboplatin in patients with LA-HNSCC and found that the above regimen was safe and effective even in elderly and those with poor performance status (16). Recently, the Japanese trial found that weekly cisplatin+RT is non-inferior to 3-weekly cisplatin+RT in LA-SCCHN pts and has a favorable toxicity profile, though this was reported in adjuvant setting (17). This formed the rationale for our study comparing standard 3-weekly with modified weekly TPF regimen using docetaxel at a dose of 30 mg/m 2 , Cisplatin 40 mg/m 2 and 5-FU 750 mg/m 2 , all administered weekly for 9 weeks followed by re-assessment.…”

Recent Advances and Future Directions in Clinical Management of Head and Neck Squamous Cell Carcinoma

“…However, due to the significant toxicities, a low-dose weekly cisplatin (30–40 mg/m 2 , administered intravenously every 7 days for the duration of radiation therapy) is frequently used in both definitive and adjuvant CRT settings, because the weekly regimen offers several advantages over the high-dose cisplatin including ease of administration and reduced toxicity [ 58 ]. A retrospective study as well as prospective Phase II/III studies comparing the efficacy of the 40 mg/m 2 cisplatin weekly and 100 mg/m 2 cisplatin every 3 weeks demonstrated non-inferiority of the weekly regimen for survival and locoregional control rates with fewer incidences of neutropenia, nephrotoxicity, and ototoxicity with low-dose cisplatin [ 59 , 60 , 61 ]. However, we need to wait for sufficient maturity of these data before suggesting changes to the current standard of care.…”

Systematic review of postoperative therapy for resected squamous cell carcinoma of the head and neck: Executive summary of the American Radium Society appropriate use criteria

“…At the time of this publication, the Japanese Clinical Oncology Group (JCOG) 1008 trial has been published in abstract form and showed non-inferiority of weekly cisplatin 40 mg/m 2 to three-weekly cisplatin in high-risk patients with microscopically positive margin and/or extranodal extension. 121…”

“…It is noteworthy that the 30 mg/m 2 is lower than the 40 mg/m 2 commonly employed in clinical practice and the 50 mg/m 2 weekly cisplatin dose that tested favorably in the RCT comparing it to PORT‐alone, 35 discussed above. At the time of this publication, the Japanese Clinical Oncology Group (JCOG) 1008 trial has been published in abstract form and showed non‐inferiority of weekly cisplatin 40 mg/m 2 to three‐weekly cisplatin in high‐risk patients with microscopically positive margin and/or extranodal extension 121 …”