Effect of Chemotherapy in Patients With Resected Small-Cell or Large-Cell Neuroendocrine Carcinoma

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1 ORIGINAL ARTICLE Effect of Chemotherapy in Patients With Resected Small-Cell or Large-Cell Neuroendocrine Carcinoma Nader Abedallaa, MD,* Lise Tremblay, MD, Charlotte Baey,* Dominique Fabre, MD, David Planchard, MD, PhD,* Jean Pierre Pignon, MD, PhD,* Joel Guigay, MD,* Cécile Le Pechoux, MD,* Jean Charles Soria, MD, PhD,* Vincent Thomas de Montpreville, MD, and Benjamin Besse, MD, PhD,* Introduction: Surgical resection of an undiagnosed lung lesion may lead to unintentional removal of small-cell lung cancer (SCLC). The benefit of perioperative chemotherapy in resected SCLC or large-cell neuroendocrine carcinomas (LCNEC) is not clear. Methods: This retrospective analysis included limited disease SCLC and LCNEC that had been surgically removed between 1979 and 2007 at a single institution. Perioperative treatments were analyzed, and survival followed up. Log rank tests were used to compare overall survival. Results: Among 74 patients who had a tumor resection, 45 received chemotherapy, four had preoperative radiotherapy, and 21 had postoperative radiotherapy. Eleven patients were women. The median age was 64 in the surgery group and 58 in the surgery plus chemotherapy group, and four and 11 patients in these groups, respectively, had LCNEC. There were 10 node positive tumors and only two incomplete resections in the surgery group versus 27 node positive tumors and three incomplete resections in the surgery plus chemotherapy group. The median follow-up was shorter in the group with surgery alone: 4.5 years (1.4 7) versus 5.8 years ( ). Among the patients with a survival or a follow-up of at least 6 months, the median survival was 2.3 and 6.1 years in the surgery (n = 20) and surgery plus chemotherapy (n = 39) groups, respectively, such that the hazard ratio for death was 0.48 (95% confidence interval, , p = 0.04). Conclusion: These results suggest that perioperative chemotherapy may be beneficial in patients with resected SCLC or LCNEC. Key Words: Perioperative chemotherapy, Small-cell lung cancer, Surgery. (J of Thorac Oncol. 2012;7: ) Small-cell lung cancer (SCLC) represents approximately 15% of new cases of lung cancer diagnosed annually. 1 It is an aggressive form of lung cancer that is associated in the vast *Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France; IUCPQ 2750 Chemin Sainte-Foy, Québec, Québec, Canada; and Department of Surgery, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France. Disclosure: The authors declare no conflict of interest. Address for correspondence: Benjamin Besse, MD, PhD, Department of Medicine, Institut Gustave Roussy, 114 rue Edouard Vaillant, Villejuif, France. address : besse@igr.fr ISSN: /12/ majority, approximately 95%, of cases with cigarette smoking. 2 The most important prognostic factors are disease stage, performance status, and extent of weight loss. Elevated lactate dehydrogenase level is also associated with a poorer prognosis. 3,4 At diagnosis, approximately 30% of patients with SCLC have limited disease (LD-SCLC). 5,6 Combined modality treatment involving chemotherapy and concurrent thoracic radiotherapy is the current standard of treatment for LD-SCLC, and is followed by prophylactic cranial irradiation for all patients who achieve complete remission The median survival is in the range 17 to 27 months, and the 5-year survival rate is 12% to 23%. 5,8,11 SCLC is classically considered a contraindication for surgery because radiotherapy is at least equivalent in terms of local control, and the rate of resectability in SCLC patients is poor. 12 However, some centers continue to support surgery for very LD patients because experience suggests that it is possible to achieve a long-term survival in these selected patients. 13,14 In daily practice, a small proportion of patients carrying resectable lung nodules receive a postoperative diagnosis of LD-SCLC. In screening programs, SCLC is diagnosed in 12.6% to 17.1% of patients undergoing nodule resection. 15,16 Among 12,620 cases of SCLC entered in the International Association for the Study of Lung Cancer (IASLC) data set used for the 7th edition of the classification of SCLC, surgically treated SCLC represented only 1.3% of all fully staged resected cases in the database and only 2.8% of all SCLC cases. 17 Some authors have reported 5-year survival rates of 30% to 40% for patients who underwent surgical resection before the histological diagnosis of SCLC and who were also given chemotherapy, chest radiotherapy, or both. 18,19 In the International Association for the Study of Lung Cancer (IASLC) data set (n = 339), the observed 5-year survival rate was 40% to 56% for patients with stage IIB disease or less, who were initially treated by surgical resection, and 12 % for stage IIIA. 17 The rate of adjuvant treatment in this data set of patients treated mostly between 1990 and 2000 is unknown. In the National Cancer Institute Surveillance Epidemiology and End Results, 247 patients underwent surgical resection for SCLC between 1988 and Of 205 patients with stage I SCLC who required only lobectomy, the 5-year survival rate was 50.3%. Surveillance Epidemiology and End Result does not provide chemotherapy details but it is assumed that Journal of Thoracic Oncology Volume 7, Number 7, July

2 Abedallaa et al. Journal of Thoracic Oncology Volume 7, Number 7, July 2012 most, if not all, of these patients received systemic therapy. Despite these reports, the role of surgery has not been established and the role of adjuvant treatment in resected patients is unknown. 21 Large-cell neuroendocrine carcinoma (LCNEC) is a subgroup of large-cell carcinoma and is a type of lung cancer showing neuroendocrine characteristics similar to that of SCLC. 22 A small number of studies suggest that after complete resection of pulmonary LCNEC, an adjuvant treatment combining etoposide and a platinum compound could be of value, but this needs to be confirmed. 23,24 In a retrospective study, we assessed the role of chemotherapy before or after a local treatment that in all cases included surgery, comparing the survival of two groups of patients diagnosed with LD-SCLC or early LCNEC: the first group was treated by surgery and chemotherapy combined, and the second by surgery alone. MATERIALS AND METHODS This retrospective study included LD-SCLC (according to the staging system of the Veterans Administration Lung Study Group) and early LCNEC surgically removed between 1979 and 2007 at the Surgical Centre Marie Lannelongue. We collected data on the patients characteristics (sex, age, and smoking status), the type of neuroendocrine tumor (SCLC or LCNEC), stage (according to the 6th edition of the tumor, node, metastasis (TNM) staging system based on the criteria established by the American Joint Committee for Cancer and IASLC), the type of surgery and its extent, the perioperative treatment (either systemic treatment or radiotherapy) and the outcome (recurrence, metastatic sites, second tumor, and cause of death). Tumors were classified according to the World Health Organization classification. 25,26 LCNEC fulfilled the following criteria: neuroendocrine morphology, mitotic rate greater than 10 per 10 high-power field, necrosis, cytologic features of non small-cell lung cancer (NSCLC), and positive immunohistochemical staining for one or more neuroendocrine markers. The neuroendocrine markers used were CD56, chromogranin, and synaptophysin. NSCLCs showing neuroendocrine differentiation (NSCLC-NE) were not included in our series because the relevance of immunohistochemichal neuroendocrine differentiation in NSCLC that does not show neuroendocrine morphology is controversial. 27 Statistical Analysis The χ 2 test, Fisher s exact test, t test, and the Wilcoxon test were used as appropriate to compare the patients who received or did not receive adjuvant treatment. Overall survival (OS) was calculated as the interval from the date of surgery until death from any cause or until the date of the last follow-up. Follow-up was assessed by the reverse Kaplan- Meier method. 28 OS curves were estimated by the Kaplan- Meier method and were compared with the log rank test. All p values were two-sided and p values of less than 0.05 were considered significant. Data were analyzed using SAS statistical software (SAS Institute, Cary, NC). RESULTS We identified 75 patients with resected SCLC and LCNEC: 42 patients had no preoperative pathological diagnosis (Table 1). One patient was excluded because of a definitive TABLE 1. Baseline Characteristics of the Patients Characteristic Surgery Alone (n = 29) Surgery Plus Perioperative Chemotherapy (n = 45) p Value Age at diagnosis median (range, year) 64 (49 78) 58 (33 78) 0.12 Male n (%) 25 (86) 38 (84) 0.87 Smoking status: n (%) 0.08 Never 3 (10) 0 (0) Current 16 (55) 32 (71) Former 10 (35) 13 (29) Number of packets 40 (6 100) 40 (10 80) 0.71 median (range) Preoperative diagnosis n (%) c Unknown 22 (76) 20 (45) SCLC 4 (14) 14 (31) LCNEC 2 (7) 6 (13) Other 1 (3) a 5 (11) b Clinical stage n (%) 0.36 d Stage I 15 (52) 19 (42) Stage II 6 (21) 13 (29) Stage III+IV 3 (10) 10 (22) Unknown 5 (17) 3 (7) ptumor category n (%) 0.63 e T1 5 (17) 9 (20) T2 15 (52) 20 (44) T3 2 (6) 11 (24) T4 3 (10) 1 (2) Unknown 4 (15) 4 (10) pnodal status n (%) 0.05 f N- 15 (52) 15 (33) N+ 10 (34) 27 (60) Unknown 4 (14) 3 (7) Type of surgery n (%) 1.00 g Lobectomy 19 (66) 26 (58) Pneumonectomy 8 (28) 13 (29) Bi-lobectomy 1 (3) 5 (11) Segmentectomy 1 (3) 1 (2) Type of resection n (%) 0.01 Complete resection 27 (93) 42 (93) Incomplete resection 2 (7) 3 (7) Postoperative diagnosis n (%) 0.38 SCLC 25 (86) 34 (76) LCNEC 4 (14) 11 (24) SCLC, small-cell lung cancer; LCNEC, large-cell neuroendocrine carcinomas. a Atypical carcinoid. b Non small-cell lung cancer n = 2, undifferentiated carcinoma n = 3. c Unknown vs. SCLC + LCNEC vs. other. d Stage I vs. stage II vs. stage III+IV. e T1 vs. T2 vs. T3-4. f N vs. N+. g Pneumonectomy vs. other. 1180

3 Journal of Thoracic Oncology Volume 7, Number 7, July 2012 Chemotherapy in Resected Neuroendocrine Carcinomas diagnosis of atypical carcinoid so that the analysis included the 74 remaining patients. Forty-five patients underwent surgery combined with perioperative chemotherapy, and 29 underwent surgery alone. Patients baseline characteristics are shown in Table 1. Among the 45 patients in the surgery-plusperioperative chemotherapy group, 10 received a preoperative treatment with chemotherapy alone (n = 6), concurrent chemoradiotherapy (n = 3), or radiotherapy alone (n = 1). In the same group, 37 patients received postoperative treatment with chemotherapy alone (n = 16), concurrent chemoradiotherapy (n = 19), or radiotherapy alone (n = 2). Three patients received both pre- and postoperative treatment: two had preoperative chemotherapy with either postoperative radiotherapy or concurrent chemoradiotherapy, and one had preoperative radiotherapy and postoperative chemotherapy. Most of the systemic therapies involved platinum-based drugs combined with either etoposide (62%) or another agent (13%; cyclophosphamide, doxorubicin, metotrexate, or ifosfamide). The remaining 25% patients received a platinum-free regimen. Seven patients received prophylactic cranial irradiation, all of them in the surgery-plus-perioperative chemotherapy group. The patients in the surgery-alone group were resected earlier during the study (median year of surgery 1998, range, ) compared with the chemotherapy group (median year of surgery 2001, range, ). Stage was unknown in eight cases (10.8%); 51% cases (n = 34) were at stage I, 29% at (n = 19) stage II, and 20% at (n = 13) stage III IV (Table 1). Clinical TNM (ctnm), in patients who did not receive preoperative chemotherapy, was compared with pathological TNM (ptnm). Seven values were missing, and 59 cases were assessable. In 30 patients (51%), there was no TNM change. The T-factor differed in 12 cases (20%) with underestimation of the ct versus pt in nine cases. The N-factor differed in 21 cases (36%) with underestimation of the cn versus pn in 17 cases. Only patients whose follow-up was 6 months or more (n = 59) were included in the survival analysis, such that patients who experienced postoperative death or rapidly growing metastatic disease refractory to chemotherapy were excluded. Thus, 15 patients (nine in the group without chemotherapy) were excluded from the survival analysis: (1) three patients were alive at the time of the last follow-up visit but the follow-up was shorter than 6 months (one in the group without chemotherapy and two in the group with chemotherapy), (2) four patients died within 1 month of surgery (considered to be postoperative death), including one patient who died from cancer (all in the group without chemotherapy), and (3) eight patients died between 1 and 6 months after surgery (four in the group without chemotherapy, including one death from cancer, two deaths from other causes, and one death of unknown cause; and four in the group with chemotherapy, including three deaths from cancer and one death of unknown cause). Among the 59 patients with a survival and a follow-up of at least 6 months, the median duration of follow-up was 5.8 years (range, years) and 33 died during follow-up. Follow-up was shorter for the surgery-alone group (4.5 years; range, years) than for the surgery-plusperioperative chemotherapy group (5.8 years; range, years). The median survival was 2.3 years ( ) for the surgery-alone group and 6.1 years ( ) for the group with perioperative chemotherapy (Fig. 1). The hazard ratio (HR) for death was 0.48 (95% confidence interval [CI], ; p = 0.04) for the perioperative chemotherapy group compared with the surgery-alone group. The OS rates at 1, 2, and 3 years were 92%, 79%, and 59%, respectively in the perioperative chemotherapy group, and 85%, 54%, and 48% in the surgery-alone group, respectively. A sensitivity analysis was performed by censoring follow-up at 3 years (Fig. 2). Thus, a patient who died 3.5 years after surgery was considered to be alive in this analysis. Similarly, a patient still alive after 5 years of follow-up was considered to be living with only 3 years of follow-up. The objective of this analysis was to mitigate the imbalance in the duration of follow-up between the two treatment groups: censoring follow-up at 3 years contributes to standardizing the follow-up between the two treatment groups (median followup was 3 years for each group). The median survival was not reached by 3 years in the group with chemotherapy, because less than 50% of the patients died. For the group without chemotherapy, the median survival was 2.3 years. The HR for 100% 80% 60% 40% 20% S S+C 0% At risk Years FIGURE 1. Overall survival according to treatment group: surgery (S) and surgery plus chemotherapy (S + C). FIGURE 2. Overall survival and sensitivity analysis censoring the follow-up after 3 years. 1181

4 Abedallaa et al. Journal of Thoracic Oncology Volume 7, Number 7, July 2012 death was 0.58 (95% CI, ; p = 0.18) for the group that received chemotherapy compared with the group with surgery alone. The OS rates at 1, 2, and 3 years were 85%, 54%, and 48% in the surgery-alone group and 92%, 79%, and 59% in the surgery-plus-perioperative chemotherapy group. We evaluated the impact of prophylactic cranial irradiation (PCI) on survival result. The sensitivity analysis for OS was performed for the population without the seven patients who received PCI (n = 52). The HR for death was 0.60 (95% CI, ; p = 0.22) for the group that received chemotherapy compared with the group with surgery alone. We used univariate analysis to study the prognostic value of three factors: the type of surgery (complete versus incomplete), the node status of the patient (pn- versus pn+), and type of cancer (SCLC versus LCNEC). As for the survival analysis, we restricted this analysis to the 59 patients whose follow-up was 6 months or longer. None of these three variables were significantly related to OS. DISCUSSION We report the first retrospective study to compare the benefit of the use of perioperative chemotherapy for survival in patients with resected SCLC and LCNEC. Our findings suggest that treatment involving surgery plus perioperative chemotherapy was associated with a significantly longer OS than surgery alone (6.1 years and 2.3 years, respectively) and the HR for death was 0.48 (95% CI, ; p = 0.04). However, follow-up was shorter for patients in the group without chemotherapy (4.5 versus 5.8), and this may introduce a bias in the analysis. We therefore conducted a sensitivity analysis by censoring the follow-up of patients at 3 years. This analysis in a limited population showed a nonsignificant improvement of OS, but the tendency for a benefit was still observed (HR: 0.58 (95% CI 0.26; 1.31, p = 0.18). The evidence for the benefits of surgery in LD-SCLC is poor. Three studies suggest that surgical resection plus chemotherapy in LD-SCLC is of more benefit than nonsurgical management. 13,29,30 A Japanese retrospective study investigated 91 patients who had undergone pulmonary resection for SCLC. 30 The subgroup of 40 patients with p-stage IA IIB, who received perioperative chemotherapy was compared with nine patients treated by surgery alone. The 5-year probability of survival for patients with perioperative chemotherapy was 54.9% as compared with 22.2% for patients without chemotherapy (p = 0.015). The poor survival rate of the surgery-alone group may have been because of an excess of comorbidities: when the authors censored patients whose cause of death was other than SCLC, the difference in the 5-year probability of survival did not persist. Lucchi et al. reported the OS of 127 patients who underwent radical resection of SCLC. 30 The 20 patients who were treated with surgery alone died within 2 years whereas the 5-year survival rates were 32% for the 92 patients treated with surgery and adjuvant chemotherapy, and 13% for the 15 patients treated with preoperative chemotherapy alone or in combination with adjuvant chemotherapy. Unfortunately, no formal comparison was reported of the survival in the arms with surgery alone and surgery plus perioperative chemotherapy. Moreover, the poor survival of the surgery arm can be explained by the higher rate of node-positive patients: 75% versus 48% in the surgery and adjuvant chemotherapy arm, respectively. In our study, the benefit of adjuvant chemotherapy was evidenced despite a higher rate of node-positive patients in the chemotherapy arm. In most published studies, the survival benefit associated with surgery is limited to stage I and II disease. 18,19,31,32,17,20,30 This is concordant with our observations. In our series, 80% of patients in the group surgery plus perioperative treatment (chemotherapy, radiotherapy, or both) were stage I or II. In various series of LD-SCLC managed by surgery plus perioperative chemotherapy, the 5-year OS ranged from 32% to 60%. 13,29,30,32,33 It may be difficult to compare these series because the rate of N2 disease or complete resection may differ among them. Timelines may also be of importance; in our cohort study, 82.5% of patients were operated between 1990 and 2007 with more than half after In recent years, the rate of lobectomy has increased, the use of platinum-based adjuvant chemotherapy has become more systematic, and workup is more extensive. These various factors may together explain the favorable median survival in our patients (6.1 years, Fig. 1). The use of adjuvant mediastinal radiotherapy may improve OS, as is the case for patients treated with combined chemoradiotherapy. 7,10,34 The use of PCI did not affect the results of our sensitivity analysis because results were similar if patients who received PCI were excluded from the analysis. We are aware that our study has limitations that make it difficult to interpret the results. We have no data on performance status (a major prognostic factor) or lactate dehydrogenase. The TNM-staging system according to the criteria established by the American Joint Committee for Cancer and IASLC is more accurate for classifying SCLC. 17,35 It has been recommended since 2002 but we began our retrospective study in We therefore had to use the staging system for SCLC introduced by the Veterans Administration Lung Study Group as an inclusion criterion to be consistent for all our patients. Preoperative workup was probably suboptimal, given the long inclusion period. This may explain the underestimation of the ctnm relative to the ptnm, as also observed by Inoue et al. 30 Improved imaging (including computed tomography scanning) and metabolic assessment (positron emission tomography scanning) may allow better selection of patients eligible for surgery. We do not have sufficient data concerning the surgery group to analyze and explain the decision for not using perioperative treatment. Of note, more patients had a node involvement in the chemotherapy group, indicating that physicians may have offered chemotherapy to patients with more advanced disease. No definitive conclusion can be made concerning this issue because of the small population examined in this study, its retrospective nature, the difference in follow-up between the two groups, and the heterogeneity of the combined treatments. Nevertheless, this study raises a very important question regarding the benefit of perioperative treatment for patients with surgically resected LD-SCLC. Histology (SCLC versus LCNEC) was not a prognostic factor in our study. Only 15 patients with LCNEC were included in the cohort, of which 11 received adjuvant chemotherapy. In a retrospective cohort of 83 patients with resected LCNEC, 1182

5 Journal of Thoracic Oncology Volume 7, Number 7, July 2012 Chemotherapy in Resected Neuroendocrine Carcinomas Rossi et al. 24 reported a better survival for the 38 patients who received adjuvant chemotherapy. Interestingly, the multivariate analyses showed a better outcome for patients receiving a SCLC-targeting regimen (platinum-etoposide) than a NSCLC-targeting regimen (response rate = 15.5 [ ], p = ). A Japanese study reported a 2-year survival of 88% (68 109) for 15 consecutive patients treated by complete resection followed by platinum-etoposide chemotherapy but only 65% (45 84) in a historical cohort of 23 patients treated by surgery alone. 36 These results are consistent with the benefit reported in our study. Our results suggest that surgical resection combined with adjuvant or neoadjuvant chemotherapy may be an appropriate option for patients with early disease SCLC or LCNEC. A prospective trial to address this issue would be useful, but may be difficult to run in this setting. ACKNOWLEDGMENTS We thank Benjamin Lacas for his help with statistical analysis. REFERENCES 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006;24: Brownson RC, Chang JC, Davis JR. Gender and histologic type variations in smoking-related risk of lung cancer. Epidemiology 1992;3: Paesmans M, Sculier JP, Lecomte J, et al. Prognostic factors for patients with small cell lung carcinoma: analysis of a series of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years. Cancer 2000;89: Wolf M, Holle R, Hans K, Drings P, Havemann K. Analysis of prognostic factors in 766 patients with small cell lung cancer (SCLC): the role of sex as a predictor for survival. 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