Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients With Advanced Neuroendocrine Carcinoma of the Digestive System
Authors: Morizane Chigusa , Machida Nozomu , Honma Yoshitaka , Okusaka Takuji , Boku Narikazu , Kato Ken , Nomura Shogo , Hiraoka Nobuyoshi , Sekine Shigeki , Taniguchi Hirokazu , Okano Naohiro , Yamaguchi Kensei , Sato Takuji , Ikeda Masafumi , Mizuno Nobumasa , Ozaka Masato , Kataoka Tomoko , Ueno Makoto , Kitagawa Yuko , Terashima Masanori , Furuse Junji ,   Japan Clinical Oncology Group (JCOG), Sano Yusuke , Hasegawa Kyoko , Sadachi Ryo , Nakamura Kenichi , Fukuda Haruhiko , Iwafuchi Mitsuya , Kushima Ryoji , Ushiku Tetsuo , Fukushima Noriyoshi , Ohike Nobuyuki , Katsuta Yuki , Okamura Keiya , Kawamoto Yasyuki , Shirakawa Hirofumi , Yamaguchi Hironori , Shimizu Satoshi , Matsubara Hisahiro , Kojima Yasushi , Sano Keiji , Umemoto Kumiko , Sakai Rika , Miwa Haruo , Shioji Kazuhiko , Kajiura Shinya , Terashima Takeshi , Ohkawa Kazuyoshi , Tsuda Masahiro , Asagi Akinori , Suzuki Toshiyuki , Fujimori Nao , Kawakami Kentaro , Akiyama Yuji , Murakawa Yasuko , Kawazoe Akihito , Kondoh Chihiro , Yabusaki Hiroshi , Tsuji Kunihiro , Maeda Atsuyuki , Yasuda Takushi , Hamakawa Takuya , Fujitani Kazumasa , Goto Masahiro , Kawabata Ryouhei , Kakeji Yoshihiro , Ohta Takashi , Shinohara Hisashi , Fukunaga Hiroki , Hirahara Noriyuki , Tanabe Kazuaki , Oono Satoshi , Yuasa Yasuhiro , Etoh Tsuyoshi , Takahashi Masanobu , Amanuma Yusuke , Nomura Motoo , Doki Yuichiro , Nagatani Yoshiaki , Ariyama Hiroshi 
Published: August 2022

ImportanceEtoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for advanced neuroendocrine carcinoma (NEC).ObjectiveTo identify whether EP or IP is a more effective regimen in terms of overall survival (OS) in patients with advanced NEC of the digestive system.Design, Setting, and ParticipantsThis open-label phase 3 randomized clinical trial enrolled chemotherapy-naive patients aged 20 to 75 years who had recurrent or unresectable NEC (according to the 2010 World Health Organization classification system) arising from the gastrointestinal tract, hepatobiliary system, or pancreas. Participants were enrolled across 50 institutions in Japan between August 8, 2014, and March 6, 2020.InterventionsIn the EP arm, etoposide (100 mg/m2/d on days 1, 2, and 3) and cisplatin (80 mg/m2/d on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m2/d on days 1, 8, and 15) and cisplatin (60 mg/m2/d on day 1) were administered every 4 weeks.Main Outcomes and MeasuresThe primary end point was OS. In total, data from 170 patients were analyzed to detect a hazard ratio (HR) of 0.67 (median OS of 8 and 12 months in inferior and superior arms, respectively) with a 2-sided α of 10% and power of 80%. The pathologic findings were centrally reviewed following treatment initiation.ResultsAmong the 170 patients included (median [range] age, 64 [29-75] years; 117 [68.8%] male), median OS was 12.5 months in the EP arm and 10.9 months in the IP arm (HR, 1.04; 90% CI, 0.79-1.37; P = .80). The median progression-free survival was 5.6 (95% CI, 4.1-6.9) months in the EP arm and 5.1 (95% CI, 3.3-5.7) months in the IP arm (HR, 1.06; 95% CI, 0.78-1.45). A subgroup analysis of OS demonstrated that EP produced more favorable OS in patients with poorly differentiated NEC of pancreatic origin (HR, 4.10; 95% CI, 1.26-13.31). The common grade 3 and 4 adverse events in the EP vs IP arms were neutropenia (75 of 82 [91.5%] patients vs 44 of 82 [53.7%] patients), leukocytopenia (50 of 82 [61.0%] patients vs 25 of 82 [30.5%] patients), and febrile neutropenia (FN) (22 of 82 [26.8%] patients vs 10 of 82 [12.2%] patients). While incidence of FN was initially high in the EP arm, primary prophylactic use of granulocyte colony-stimulating factor effectively reduced the incidence of FN.Conclusions and RelevanceResults of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although AEs were generally manageable, grade 3 and 4 AEs were more common in the EP arm.Trial RegistrationJapan Registry of Clinical Trials: jRCTs031180005; UMIN Clinical Trials Registry: UMIN000014795