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)
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.
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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
References (29)
- et al.
Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2010) - et al.
Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition)
Chest
(2007) - et al.
Phase II trial of postoperative adjuvant cisplatin and etoposide in patients with completely resected stage I–IIIa small cell lung cancer: the Japan Clinical Oncology Lung Cancer StudyGroup Trial (JCOG9101)
J Thorac Cardiovasc Surg
(2005) - et al.
Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan
Ann Oncol
(2007) - et al.
Results of operation without adjuvant therapy in the treatment of small cell lung cancer
Ann Thorac Surg
(1992) - et al.
1st ESMO consensus conference in lung cancer; Lugano 2010: small-cell lung cancer
Ann Oncol
(2011) - et al.
Prospective study of adjuvant chemotherapy for pulmonary large cell neuroendocrine carcinoma
Ann Thorac Surg
(2006) - et al.
A meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer
J Thorac Oncol
(2010) - et al.
Chemotherapy for pulmonary large cell neuroendocrine carcinoma: similar to that for small cell lung cancer or non-small cell lung cancer?
Lung Cancer
(2012) - et al.
Comparison of chemotherapy for unresectable pulmonary high-grade non-small cell neuroendocrine carcinoma and small-cell lung cancer
Lung Cancer
(2010)
Combination chemotherapy with irinotecan and cisplatin for large-cell neuroendocrine carcinoma of the lung: a multicenter phase II study
J Thorac Oncol
Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial
Lancet Oncol
Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases
Am J Surg Pathol
Neuroendocrine neoplasms of the lung
Am J Clin Pathol
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2015, Journal of Thoracic OncologyCitation Excerpt :More recently, a pilot adjuvant trial in HGNEC, including pulmonary LCNEC, enrolled patients to receive three to four cycles of cisplatin–irinotecan chemotherapy, after curative surgery. This study showed 3-year relapse-free survival of 74% and 3-year OS of 86%.37 On the basis of these studies, a phase III clinical trial of adjuvant cisplatin plus irinotecan versus etoposide has been designed and is still ongoing in Japan (Japan Clinical Oncology Group 1205/1206, UMIN000010298).38