Adjuvant Irinotecan/Cisplatin vs Etoposide/Cisplatin for Resected High-Grade Neuroendocrine Carcinoma of the Lung

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In a Japanese phase III trial reported in the Journal of Clinical Oncology, Kenmotsu et al found that adjuvant irinotecan/cisplatin did not improve relapse-free survival vs etoposide/cisplatin in patients with completely resected, pathologic stage I–IIIA, high-grade neuroendocrine carcinoma of the lung.

Study Details

In the multicenter trial, 221 patients were randomly assigned between April 2013 and October 2018 to receive etoposide at 100 mg/m2 on days 1 to 3 plus cisplatin at 80 mg/m2 on day 1 every 3 weeks for up to four cycles (n = 111) or irinotecan at 60 mg/m2 on days 1, 8, and 15 plus cisplatin at 60 mg/m2 on day 1 every 4 weeks for up to four cycles (n = 110). The primary endpoint was relapse-free survival in the intention-to-treat population.

Relapse-Free Survival

At the second interim analysis, early termination of the trial was recommended due to futility. At median follow-up of 24.1 months, 3-year relapse-free survival was 65.4% in the etoposide/cisplatin group vs 69.0% in the irinotecan/cisplatin group (hazard ratio [HR] = 1.076, 95% confidence interval [CI] =0.666–1.738, P = .619).


  • Adjuvant irinotecan/cisplatin did not improve relapse-free survival vs etoposide/cisplatin.
  • The trial was ended early due to futility.

No significant difference in 3-year recurrence-free survival was observed between 59 vs 58 patients with histology of small cell lung cancer (SCLC) or combined SCLC (65.2% vs 66.5%, HR = 1.029, 95% CI = 0544–1.944) or between 52 vs 52 patient with large-cell neuroendocrine carcinoma or combined large-cell neuroendocrine carcinoma (66.5% vs 72.0%, HR = 1.072, 95% CI = 0.517–2.222). No significant differences were observed according to pathologic disease stage.

No significant difference in overall survival was observed. Overall, 13 patients in the etoposide/cisplatin group vs 19 in the irinotecan/cisplatin group had died at time of analysis; at 3 years, overall survival was 84.1% vs 79.0%.

Adverse Events

Grade 3 or 4 adverse events were more common in the etoposide/cisplatin group vs the irinotecan/cisplatin group, including neutropenia (97% vs 36%), leukopenia (60% vs 14%), and febrile neutropenia (20% vs 4%). Grade 3 or 4 nonhematologic adverse events occurred in 40.4% vs 31.2% of patients. Grade 3 or 4 anorexia (6% vs 11%) and diarrhea (1% vs 8%) were more common in the irinotecan/cisplatin group.

The investigators concluded, “Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving relapse-free survival in patients with completely resected high-grade neuroendocrine carcinoma of the lung; thus, etoposide plus cisplatin remains the standard treatment.”

Hirotsugu Kenmotsu, MD, PhD, of the Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Japan Agency for Medical Research and Development and National Cancer Center Research and Development Funds. For full disclosures of the study authors, visit

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