Chemotherapy for Large Cell Neuroendocrine Carcinoma of the Lung: Should It Be Treated with the Same Strategy as Small Cell Lung Carcinoma?

Lung cancer is leading cause of cancer death in many advanced countries and one of the challenging malignancies because of poor prognosis. Lung cancer is traditionally divided into two major categories, so called small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) because of distinctive prognostic and treatment strategies between them. On the other hand, there is a spectrum of tumors called pulmonary neuroendocrine (NE) tumors that are thought to originate from neuroendocrine cells in the pulmonary and bronchial epithelium. Until recently, pulmonary NE tumors were classified into three categories, i.e., typical carcinoid (TC), atypical carcinoid (AC), and SCLC. Large cell neuroendocrine carcinoma (LCNEC) of the lung was officially identified by Travis et al. in 1991 as a fourth category, a unique higher grade NSCLC existing between TC and SCLC (Travis et al., 1991). It is often difficult to diagnose LCNEC with small biopsy specimens because accurate diagnosis needs morphological and immunohistochemical information. Although earlier reports mainly focused on prognosis after surgical procedures, several recent studies reported on the efficacy of chemotherapy for advanced LCNEC. Because of the limited numbers of cases (in surgical series, LCNEC represents ~3% of lung cancers), large scale prospective studies have not been reported. Standard treatment for LCNEC, especially if advanced, is not established although LCNEC is included in NSCLC in the treatment algorithm in many guidelines. However, accumulating data including recent retrospective studies have suggested that there is similarity in the prognosis and treatment response between LCNEC and SCLC. In this review, we will focus on the treatment of advanced LCNEC for the better selection of chemotherapeutic regimens for the patients with this relatively rare lung cancer.


Introduction
Lung cancer is leading cause of cancer death in many advanced countries and one of the challenging malignancies because of poor prognosis. Lung cancer is traditionally divided into two major categories, so called small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) because of distinctive prognostic and treatment strategies between them. On the other hand, there is a spectrum of tumors called pulmonary neuroendocrine (NE) tumors that are thought to originate from neuroendocrine cells in the pulmonary and bronchial epithelium. Until recently, pulmonary NE tumors were classified into three categories, i.e., typical carcinoid (TC), atypical carcinoid (AC), and SCLC. Large cell neuroendocrine carcinoma (LCNEC) of the lung was officially identified by Travis et al. in 1991 as a fourth category, a unique higher grade NSCLC existing between TC and SCLC (Travis et al., 1991). It is often difficult to diagnose LCNEC with small biopsy specimens because accurate diagnosis needs morphological and immunohistochemical information. Although earlier reports mainly focused on prognosis after surgical procedures, several recent studies reported on the efficacy of chemotherapy for advanced LCNEC. Because of the limited numbers of cases (in surgical series, LCNEC represents ~3% of lung cancers), large scale prospective studies have not been reported. Standard treatment for LCNEC, especially if advanced, is not established although LCNEC is included in NSCLC in the treatment algorithm in many guidelines. However, accumulating data including recent retrospective studies have suggested that there is similarity in the prognosis and treatment response between LCNEC and SCLC. In this review, we will focus on the treatment of advanced LCNEC for the better selection of chemotherapeutic regimens for the patients with this relatively rare lung cancer.

Large cell neuroendocrine carcinoma of the lung
LCNEC is classified as a variant of large cell carcinoma in NSCLC whilst LCNEC has neuroendocrine characteristics similar to SCLC such as morphology and the immunohistochemical staining pattern. This discrepancy raises the question as to what the best therapeutic modality is, that is, should we treat LCNEC as NSCLC or SCLC? T Abbreviations: LCNEC, large cell neuroendocrine carcinoma; HPF, high power field; NSCLC, non-small cell lung carcinoma; N/C, nuclear-cytoplasmic ratio; NE, neuroendocrine Table 1. Tumors with neuroendocrine morphology (Travis 2010, Gollard et al., 2010 Recently, Varlotto et al. reported survival analysis of resected cases with LCNEC and SCLC (Varlotto et al., 2011). They compared overall survival (OS) and lung cancer-specific survival (LCSS) of patients with LCNEC and SCLC or other large cell lung carcinomas (OLCs) using the US National Cancer Institute database (SEER program). Although, the survival rates tended to be better in LCNEC and OLCs compared to SCLC, multivariate analysis showed no statistical differences (4-year OS rates are 41 % in LCNEC, 42% in OLC, and 32% in SCLC; 4-year LCSS rates are 57 % in LCNEC, 54% in OLC, and 42% in SCLC). The SEER database does not include chemotherapy information, so that we do not know the impact of chemotherapy on survival. Other reports also noted that survival in the early stage LCNEC is similar to SCLC (Asamura et al., 2006, Sun et al., 2009 and not better than NSCLC (Iyoda et al., 2007).

Chemotherapy for advanced LCNEC
LCNEC is classified in the category of NSCLC pathologically (Brambilla et al., 2001), so that the guideline recommended treatment of advanced LCNEC as NSCLC (NCCN guideline TM 2011), and many trials have included this disease as a NSCLC. However, recent accumulating data have brought new insights regarding possibly better results with SCLC regimens. From the published literature, we found four major studies showing the treatment results with chemotherapy for advanced LCNEC (Igawa et al., 2010, Fujiwara et al., 2007, Yamazaki et al., 2005, Rossi et al., 2005 (Table 2). All studies were retrospective and a total of 83 patients were treated with first line systemic chemotherapy. Chemotherapy regimens can be classified into two groups: SCLC-based regimens (total n=44; platinum and etoposide n=27, platinum and irinotecan (CPT-11) n=16, CPT-11 only n=1) and NSCLC-based regimens (total n=39; platinum and paclitaxel (PTX) n=11, platinum and gemcitabine n=10, cisplatin with vindesine and mitomycin n=6, cisplatin and vindesine n=4, other platinum doublet n=2, other single agent n=6).
(Abbreviations are the same as in Table 1)  (Paez et al., 2004), and moreover c-MET is reported to be an important RTK in SCLC as well as NSCLC (Nakachi et al., 2010, Rossi et al., 2005, Schmid et al., 2010. RAD001 has limited but apparent antitumor activity against pretreated SCLC as a single agent (Tarhini et al., 2010). According to these results, targeting signaling pathways with cytotoxic agent might be the next challenge for SCLC and LCNEC. Because many of the current effort in NSCLC is searching for driver mutations (Paez et al., 2004, Naoki et al., 2002, such an effort is also important in SCLC and LCNEC.

Conclusion
Although there is an issue regarding accurate diagnosis with small biopsy specimens, accumulating retrospective data suggest that patients with advanced LCNEC will benefit from systemic chemotherapy. The current recommendation for the treatment of advanced LCNEC is similar to that of SCLC, i.e. platinum based combination chemotherapy, mainly with etoposide or CPT-11 and possibly with PTX. Further prospective data is needed to elucidate the best combination therapy. The developments in molecular medicine are transforming respiratory medicine. Leading clinicians and scientists in the world have brought their knowledge and experience in their contributions to this book. Clinicians and researchers will learn about the most recent advances in a variety of lung diseases that will better enable them to understand respiratory disorders. This treatise presents state of the art essays on airways disease, neoplastic diseases, and pediatric respiratory conditions. Additionally, aspects of immune regulation, respiratory infections, acute lung injury/ARDS, pulmonary edema, functional evaluation in respiratory disorders, and a variety of other conditions are also discussed. The book will be invaluable to clinicians who keep up with the current concepts, improve their diagnostic skills, and understand potential new therapeutic applications in lung diseases, while scientists can contemplate a plethora of new research avenues for exploration.