Chemotherapy for pulmonary large cell neuroendocrine carcinoma: Similar to that for small cell lung cancer or non-small cell lung cancer?

Abstract

Background

There is controversy regarding palliative chemotherapy for large cell neuroendocrine carcinoma (LCNEC). We evaluated whether advanced LCNEC should be treated similarly to small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).

Patients and methods

The clinical reports and tumor specimens of 45 consecutive patients who were diagnosed with advanced LCNEC were reviewed. They were divided into SCLC (n = 11) and NSCLC regimen groups (n = 34) according to first-line chemotherapeutic regimens.

Results

Most patients were male (96%) and smokers (93%) with a median age of 64 years. Neuroendocrine differentiation was established in 42 (93%) tumors by immunohistochemical analyses. Regarding the efficacy of first-line chemotherapy in the SCLC and NSCLC regimen groups, the response rates were 73% and 50% (P = 0.19), and the median progression-free survival times were 6.1 and 4.9 months (P = 0.41), respectively. The difference in overall survival between the two treatment groups was 7.3 months (16.5 vs. 9.2 months, P = 0.10). There was also a considerable difference in the type and efficacy of salvage chemotherapeutic regimens between the two groups: salvage regimens with irinotecan, platinum, or taxanes were commonly used with relatively high objective responses in the SCLC regimen group, whereas frequently used agents in the NSCLC regimen group such as pemetrexed, gefitinib, or erlotinib were associated with no objective response.

Conclusion

Regarding palliative chemotherapy for advanced LCNEC, treatment similar to SCLC is more appropriate than NSCLC.

Introduction

Lung cancer can be divided into two large classes, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), and the pattern of treatment is different according to this classification. For SCLC, operation is controversial, and radiation therapy is more effective for SCLC than for NSCLC. In addition, the most effective chemotherapeutic drugs are different between the two classes [1], [2], [3], [4], [5], [6].

Large cell neuroendocrine carcinoma (LCNEC) is a type of neuroendocrine malignancy, which also includes low-grade typical carcinoid, intermediate-grade atypical carcinoid, and small cell carcinoma. LCNEC was first introduced as a variant type of large cell carcinoma in 1999 by the World Health Organization (WHO). Therefore, by definition, it is a subtype of NSCLC. However, LCNEC lacks any specific histologic features of NSCLC such as glandular or squamous differentiation, while displaying neuroendocrine differentiation similarly to SCLC. In addition to histologic similarities, Jones et al. previously reported comparable genetic alterations in LCNEC and SCLC which are difficult to differentiate [7]. LCNEC and SCLC also have common clinical characteristics including a preponderance of males and smokers and have aggressive clinical courses [8], [9], [10], [11], [12], [13]. Similar to SCLC, LCNEC recurs frequently after curative resection at an early stage, and can be fatal, which provides justification for the use of adjuvant chemotherapy even for early-stage LCNEC [10], [11], [13], [14].

However, it remains uncertain whether LCNEC has similar sensitivity to the chemotherapeutic regimens commonly used for SCLC. Although several studies have attempted to address this issue, the findings have been inconclusive because the studies were sparse and mostly performed in the adjuvant setting [10], [14], [15], [16], [17]. Until now, the largest study on chemotherapy for metastatic LCNEC was that of Rossi et al. [15]. They demonstrated that 12 LCNEC patients treated with SCLC-based chemotherapy outlived 15 patients who received common NSCLC regimens (51 vs. 21 months). Although this study included only previously operated advanced LNCEC, results indicate that SCLC-based regimens are more appropriate than NSCLC regimens for advanced LCNEC. However, one study recently proposed that LCNEC should continue to be classified and treated similarly as NSCLC because of their similarities in clinical and biologic features, which were primarily based on the epidemiologic database [18]. Cautious interpretation of the data is warranted, however, due to lack of histologically reviewed tissue specimens as well as its conflicting results when compared to previous studies.

Due to controversies regarding the classification and treatment of LCNEC, confusion exists among physicians, particularly among medical oncologists who are primarily responsible for the selection of appropriate chemotherapeutic agents. Therefore, it will be of significant interest to evaluate whether differences exist in survival and response rates between SCLC and NSCLC regimens in the treatment of advanced LCNEC. For such reasons, we retrospectively compared the clinical outcome of patients with LCNEC who had been treated with SCLC or NSCLC regimens as the first-line chemotherapy.