Abstract
Background: No standard chemotherapy has been established for patients with large-cell neuroendocrine carcinoma (LCNEC). Patients and Methods: Patients with LCNEC of the lung were treated with nedaplatin (NP) at 50 mg/m2 and irinotecan at 50 mg/m2 on days 1 and 8 every four weeks for four cycles. Results: Data for 18 of the LCNEC patients were retrospectively analyzed. All patients were male, with a performance status 0 or 1, and the median age was 68 (range 58-80) years. Nine patients received adjuvant chemotherapy after undergoing complete surgical resection. Fourteen patients were able to receive four cycles of nedaplatin and irinotecan. Grade 4 leukopenia and neutropenia occurred in 5.6% and 16.7%, respectively. Four patients experienced grade 3 non-hematologic toxicities, such as diarrhea, enterocolitis, duodenal perforation and myocardial infarction. There were no treatment-related deaths. Two patients achieved complete response and four achieved partial response, and the median survival time was 12.3 months for the nine patients with advanced disease. Conclusion: Nedaplatin plus irinotecan is effective and safe for patients with LCNEC of the lung.
Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a rare tumor accounting for approximately 3% of all pulmonary malignancies (1). It belongs to the family of neuroendocrine tumors, together with typical carcinoid, atypical carcinoid, and small-cell lung cancer (SCLC). Its distinctive pathological features include high-grade proliferation, large areas of necrosis, a neuroendocrine architecture, and cytologic features of non-SCLC (NSCLC), as well as immunohistochemical expression of at least one neuroendocrine marker other than neuron-specific enolase (2). LCNEC shares many similarities with SCLC in terms not only of morphology, immunohistochemistry, and molecular biology, but also of treatment (3); several studies have shown that LCNEC responds to cisplatin-based chemotherapeutic regimens similar to those used for SCLC (4, 5). However, as LCNEC is a poorly recognized and underdiagnosed entity, it is frequently mistaken for poorly differentiated NSCLC, atypical carcinoid, or intermediate cell-type SCLC (6-8). In one previous study that included 75 patients, only 44 (53%) were correctly diagnosed as having LCNEC at the outset, whereas 31 (47%) were misdiagnosed as having other NSCLCs (9). Such difficulty is attributable to the obscure morphology of neuroendocrine tumors at the light microscopy level, especially in the case of cytology or small biopsy samples (7). As a result, no optimal treatment for patients with LCNEC has yet been indicated, and there is no evidence to suggest whether affected patients might benefit from chemotherapeutic protocols designed for NSCLC or SCLC.
Cisplatin plus irinotecan is effective for not only SCLC (10) but also for NSCLC (11), and this regimen is one of the standard treatments for both cancers in Japan. Nedaplatin is an analogue of cisplatin, with relatively low neurotoxicity and nephrotoxicity, and high in vivo bioavailability, ensuring its position as a primary chemotherapeutic agent for the treatment of patients with advanced lung cancer (12). Three-dimensional analysis models have demonstrated a remarkable synergistic interaction of concurrent platinum with irinotecan (13). This synergistic interaction was also observed even when nedaplatin and irinotecan were combined over a wide concentration range for each drug. However, for the cisplatin and irinotacan combination, the drug interaction pattern was biphasic and dependent on the drug concentrations; a synergistic interaction was observed at lower drug concentrations, whereas an antagonistic effect was observed at higher concentrations. These data suggest that the nedaplatin plus irinotecan combination is more active than the one of cisplatin plus irinotecan. We therefore conducted studies to investigate the effect of nedaplatin plus irinotecan chemotherapy on NSCLC. Our results demonstrated that this combination was feasible and active for locally advanced and metastatic NSCLC (14-16). Therefore, we are now undertaking two studies of nedaplatin and irinotecan for NSCLC patients after complete tumor resection, and for chemonaïve patients with SCLC. Some patients with LCNEC practically received nedaplatin and irinotecan, and we retrospectively analyzed the backgrounds and outcomes of these patients.
Patients and Methods
Patients. The patients whose data were analyzed had cytologically or histologically confirmed LCNEC, an Eastern Cooperative Oncology Group performance status (PS) of 0, 1, or 2, and were 20 years of age or more. All patients had adequate organ function, as indicated by a leukocyte count of >4000/μl, a platelet count of >100,000/μl, a hemoglobin level of >10.0 g/dl, a total bilirubin level of <1.5 mg/dl, aspartate aminotransferase and alanine aminotransferase levels of <90 IU/l, and a serum creatinine level of <1.5 mg/dl. We did not attempt any geriatric assessment in the present study.
Treatment assignment and drug administration. The regimen of consisted of four 4-week cycles of 50 mg/m2 irinotecan on days 1 and 8 and 50 mg/m2 nedaplatin on days 1 and 8. Patients received serotonin 5-HT3 antagonist iv and 8 mg of dexamethasone iv before administration of the anticancer drugs. Both drugs were administered on day 8 when the following criteria were satisfied: leukocyte count ≥3000/μl, neutrophil count ≥1,500/μl, platelet count ≥75,000/μl, non-hematological toxicity less than grade 2 except for alopecia, and leukocyte or neutrophil count greater than 1,000/μl or 500/μl, respectively, during the period between day 2 and day 8. Subcutaneous administration of recombinant human granulocyte colony-stimulating factor (G-CSF) at 50 mg/m2/day or 2 μg/kg/day, once a day, was permitted when the patient's leukocyte and neutrophil counts were below 1,000/μl and 500/μl, respectively.
Evaluation of response and toxicities. Tumor response was evaluated according to the RECIST criteria (17) and the toxicities were evaluated according to the NCI-CTC v.3 criteria (18). Overall survival was estimated using the method of Kaplan and Meier.
Results
Patient characteristics. Between August 2006 and August 2011, 18 patients diagnosed as having LCNEC received the nedaplatin and irinotecan chemotherapy (Table I). All the patients were male, with a median age of 68 (range 58-80) years. All of them were current or former smokers. Eight patients had a PS of 0 and 10 had a PS of 1. Clinical stage was I in four, stage II in three, stage III in four, and stage IV in five, and two patients had postsurgical recurrence. Nine patients received adjuvant chemotherapy after undergoing complete surgical resection.
Treatment delivery. Fourteen patients received the full four cycles of chemotherapy, and the median number of chemotherapy cycles was four. Two patients ended chemotherapy after the first cycle because of grade 3 diarrhea and acute myocardial infarction, respectively. The reasons for discontinuing the chemotherapy after the second cycle were patient refusal in one case and lack of tumor response in one patient, respectively.
Toxicities and outcomes. Adverse effects and events are summarized in Table II. Grade 4 leukopenia and neutropenia occurred in 5.6% (1/18) and 16.7% (3/18) of patients, respectively. Grade 3 non-hematological toxicities, such as diarrhea, enterocolitis, duodenal perforation and myocardial infarction, were observed in four patients. Acute myocardial infarction was observed when a grade 3 increase of alkaline phosphatase occurred in the first cycle. Another patient who suffered from duodenal perforation in the third cycle was treated surgically and resumed chemotherapy after a two-month interval. Grade 3 enterocolitis without neutropenia occurred in another patient, and was cured with antibiotics. Each of these toxicities was improved with adequate treatment, and there were no treatment-related deaths. Two patients achieved complete response and four achieved partial response. The objective response rate was 66.7% (6/9), and the median progression-free and overall survival periods were 10.9 and 12.3 months, respectively, in nine patients with unresectable advanced LCNEC.
Discussion
Some studies have suggested that survival after resection of LCNEC is substantially worse than that for other forms of NSCLC, and in fact is similar to that for SCLC (8, 19, 20). No standard chemotherapy regimen has yet been established for LCNEC, mainly because of the relative infrequency of LCNEC and the difficulty in accurate pathological diagnosis using cytology and small biopsy specimens. Two retrospective studies of chemotherapy for unresectable LCNEC using platinum-based regimens demonstrated objective response rates of 50% and 59% (5, 21). Considering these results, the response of LCNEC to platinum-based chemotherapy may be comparable to that of SCLC, and better than the response of NSCLC. Otherwise, some retrospective studies have demonstrated that patients with LCNEC have significantly improved outcomes if they receive adjuvant chemotherapy with cisplatin plus etoposide (4, 9, 22).
The present study of nedaplatin and irinotecan demonstrated some moderate toxicities such as myocardial infarction and duodenal perforation, but these were considered sporadic events because other studies of nedaplatin and irinotecan did not demonstrate such toxicities (14-16). In fact, 14 out of 18 patients were able to receive the full four cycles of chemotherapy. Every patient who developed grade 3 or 4 toxicity was successfully managed by full supportive care and appropriate treatment, and no treatment-related death occurred. Six out of nine patients with unresectable advanced LCNEC in the present study achieved an objective response. These data suggest that this treatment regimen is promising for future chemotherapy. Combination chemotherapy with cisplatin and irinotecan is a standard treatment for metastatic SCLC in Japan, and has been demonstrated to yield significantly longer overall survival than cisplatin and etoposide in the Japan Clinical Oncology Goup 9511 study (10). The mechanism of drug sensitivity in LCNEC is believed to be similar to that in SCLC, and a phase II study of adjuvant cisplatin and irinotecan for LCNEC has been performed in Japan. Forty patients were registered, and 31 (77.5%) of them were able to receive the full number of chemotherapy cycles. Grade 4 neutropenia and grade 3 diarrhea were observed in 4% and 2% of patients, respectively, and no severe toxicities were observed (23). These results suggested that cisplatin and irinotecan is a feasible and safe treatment regimen, and a comparative study of cisplatin plus irinotecan with cisplatin plus etoposide as adjuvant chemotherapy after complete resection is now planned in Japan. Considering these data and current plans, combination therapy of nedaplatin and irinotecan appears to be one of the most promising candidate treatments for chemonaïve patients with advanced LCNEC, for which a prospective study will be required.
Acknowledgements
This work was supported in part by the Kanagawa Prefectural Hospitals Cancer Research Fund and Kanagawa Health Foundation.
Footnotes
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Conflict of Interest Statement
All Authors indicate they have no conflicts of interest, including any financial, personal or other relationships with other people or organizations within 3 years of beginning our submitted work that could have inappropriately influenced our conclusions.
- Received February 20, 2012.
- Revision received March 12, 2012.
- Accepted March 13, 2012.
- Copyright© 2012 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved