Etoposide/Cisplatin vs Irinotecan/Cisplatin in Advanced Digestive System Neuroendocrine Carcinoma

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In a Japanese phase III trial (TOPIC-NEC) reported in JAMA Oncology, Morizane et al found no difference in overall survival with etoposide/cisplatin (EP) vs irinotecan/cisplatin (IP) in chemotherapy-naive patients with advanced digestive system neuroendocrine carcinoma.

Study Details

The open-label multicenter trial included 170 patients aged 20 to 75 years with recurrent or unresectable disease of the gastrointestinal tract, hepatobiliary system, or pancreas. They were randomly assigned between August 2014 and March 2020 to receive EP with etoposide at 100 mg/m2 on days 1, 2, and 3 and cisplatin at 80 mg/m2 on day 1 every 3 weeks (n = 84) or IP with irinotecan at 60 mg/m2 on days 1, 8, and 15 and cisplatin at 60 mg/m2 on day 1 every 4 weeks. The primary endpoint was overall survival.

Overall Survival

Median overall survival was 12.5 months (95% confidence interval [CI] =10.3–15.7 months) in the EP group vs 10.9 months (95% CI = 8.9–13.1 months) in the IP group (hazard ratio [HR] = 1.04, 90% CI = 0.79–1.37, P = .80); rates at 1 year were 52.1% vs 41.8%. In a post hoc analysis, median overall survival was better among 10 vs 13 patients with poorly differentiated disease of pancreatic origin (18.6 vs 7.9 months; HR = 4.10, 95% CI = 1.26–13.31).


  • No significant difference in overall survival was observed for EP vs IP.
  • No significant differences in progression-free survival or objective response rates were observed.

Median progression-free survival was 5.6 months (95% CI = 4.1–6.9 months) in the EP group vs 5.1 months (95% CI = 3.3–5.7 months) in the IP group (HR = 1.06, 95% CI = 0.78–1.45). Among 77 vs 80 patients with measureable lesions, objective response was observed in 54.5% vs 52.5% (P = .87).

Adverse Events

Grade 3 or 4 adverse events were more common in patients in the EP group, including neutropenia (91.5% vs 53.7%), leukocytopenia (61.0% vs 30.5%), and febrile neutropenia (26.8% vs 12.2%); the incidence of febrile neutropenia was reduced in the EP group after a protocol amendment permitted primary prophylactic use of granulocyte colony–stimulating factor. Any-grade diarrhea was more common in the IP group (47.6% vs 23.2%). One treatment-related death was reported due to hepatic failure in a patient in the IP group.

The investigators concluded, “Results of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although adverse events were generally manageable, grade 3 and 4 adverse events were more common in the EP arm.”

Chigusa Morizane, MD, PhD, of the National Cancer Center Hospital, Tokyo, is the corresponding author for the JAMA Oncology article.

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

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