Elsevier

Lung Cancer

Volume 84, Issue 3, June 2014, Pages 254-258
Lung Cancer

A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high-grade pulmonary neuroendocrine carcinoma (large cell neuroendocrine carcinoma and small cell lung cancer)

https://doi.org/10.1016/j.lungcan.2014.03.007Get rights and content

Abstract

Background

Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high-grade neuroendocrine carcinomas (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients.

Patients and methods

Patients with completely resected stage I–IIIA HGNEC received four cycles of irinotecan (60 mg/m2, day 1, 8, 15) plus cisplatin (60 mg/m2, day 1). This regimen was repeated every 4 weeks. The primary endpoint was the rate of completion of chemotherapy (defined as having undergone three or four cycles), and secondary endpoints were the rate of 3-year relapse-free survival (RFS), rate of 3-year survival and toxicities.

Results

Forty patients were enrolled between September 2007 and April 2010. Patients’ characteristics were: median age (range) 65 [45–73] years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90% C.I.; 71–90%). The rate of overall survival at 3 years was estimated at 81%, and that of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86 and 74% among 23 LCNEC patients, and 74 and 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutropenia, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and four patients (10%) had grade 3 nausea. No treatment-related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC by central pathological review.

Conclusions

The combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.

Introduction

In 1991, Travis et al. proposed the classification of neuroendocrine tumor of the lung, including typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC) [1]. In addition, LCNEC and SCLC are recognized as high-grade neuroendocrine carcinomas (HGNEC) of the lung. LCNEC and SCLC share several histological features, including rosette formation, molding of nuclei, and lack of apparent glandular formation and keratinization [2], [3].

LCNEC accounts for approximately 3% of all pulmonary malignancies, and SCLC accounts for 12%. In a large-scale, Japanese multi-institutional study of surgically resected pulmonary neuroendocrine tumors, there was no difference between LCNEC and SCLC in terms of overall survival. The survival curves were superimposed and the 5-year survival rates of surgically resected LCNEC and SCLC were 40.3 and 35.7%, respectively [4].

Retrospective analysis suggested that adjuvant chemotherapy using an SCLC-based standard regimen might be effective for LCNEC [5]. In patients with completely resected SCLC, platinum-based adjuvant chemotherapy may be considered [6], [7]. The combination of cisplatin and etoposide as adjuvant chemotherapy is reported to be a feasible regimen and results in a favorable profile for SCLC [8]. However, the optimum chemotherapy regimen has not been determined. Combination chemotherapy with cisplatin and irinotecan is a standard treatment in Japan for extensive SCLC, and has been demonstrated to yield significantly longer overall survival than cisplatin and etoposide in the Japan Clinical Oncology Group Study 9511 [9]. Although LCNEC is now classified as non-small cell lung cancer (NSCLC) in WHO criteria, this combination has also been reported to be active for NSCLC [10]. Therefore, we conducted a multicenter phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for completely resected HGNEC.

Section snippets

Study design

This prospective phase II trial was conducted at 12 centers in Japan. It was approved by the institutional review boards of all participating centers, and all patients provided written informed consent. This study was registered at the UMIN Clinical Trial Registry (UMIN000001319).

Patients

Eligible patients were aged 20–74 years and histologically confirmed LCNEC and SCLC, completely resected, pathological stage IA, IB, IIA, IIB and IIIA. Patients were also required to have: the ability to start

Results

Forty patients were enrolled between September 2007 and April 2010, and all patients were eligible. The clinical data cut-off date was May 2013 for the analysis of efficacy, including overall survival and RFS.

Discussion

Irinotecan and cisplatin showed acceptable toxicities and favorable feasibility as postoperative adjuvant chemotherapy for HGNEC of the lung. This study is the first prospective trial to evaluate the postoperative adjuvant chemotherapy of irinotecan and cisplatin for HGNEC. Although there have been no reports on a randomized trial of postoperative adjuvant chemotherapy for HGNEC, previous reports suggest the efficacy of postoperative adjuvant chemotherapy for very limited SCLC compared with

Funding

This work was supported in part by a National Cancer Center Research and Development Fund (23-A-18), a Grant-in-Aid for Cancer Research (17S-2) from the Ministry of Health, Labour and Welfare and a Grant from the Ministry of Health, Labour and Welfare for the Third-Term Comprehensive Strategy for Cancer Control, Japan.

Conflict of interest statement

The authors indicate no potential conflicts of interest.

Acknowledgments

We thank all the patients who participated in this study and their families. We also thank Ms. Fumiko Koh, Ms. Eriko Imai and Ms. Reiko Kashiwabara for data management, Dr. Toru Kameya (Shizuoka Cancer Center, Shizuoka), Dr. Koji Tsuta (National Cancer Center Hospital, Tokyo), Dr. Genichiro Ishii (National Cancer Center Hospital East, Chiba), Dr. Ken Inoue (Osaka City General Hospital, Osaka), and Dr. Shi-Xu Jaing (Kitasato University, Kanagawa) for central pathological review, and Dr. Makoto

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