Is neoadjuvant chemotherapy mandatory for limited-disease small-cell lung cancer?

Transcription

1 Interactive CardioVascular and Thoracic Surgery Advance Access published August 24, 2014 Interactive CardioVascular and Thoracic Surgery (2014) 1 7 doi: /icvts/ivu262 THORACIC Is neoadjuvant chemotherapy mandatory for limited-disease small-cell lung cancer? a b c Yong-jie Xu a,, Hui Zheng b,, Wen Gao b, Ge-ning Jiang b, Hui-kang Xie c, Chang Chen b, * and Ke Fei b, * Soochow University School of Medicine, Suzhou, Jiangsu, China Department of General Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China * Corresponding author. Zhengmin RD. 507, Shanghai , China. Tel: ; fax: ; changchenc@hotmail.com (C. Chen), ffeik126@126.com (K. Fei). Received 1 December 2013; received in revised form 16 April 2014; accepted 2 May 2014 Abstract OBJECTIVES: The present study attempted to evaluate the role of neoadjuvant chemotherapy combined with surgery in limited-disease small-cell lung cancer (LD-SCLC). METHODS: A retrospective analysis was performed on 106 LD-SCLC patients who underwent complete resections from February 2000 to February 2012 in Shanghai Pulmonary Hospital. Among these cases, two cycles of neoadjuvant chemotherapies were administered to all pathologically confirmed patients [Group Neoadjuvant (Group N)]. For those without pathology, operations followed by adjuvant chemotherapies were performed [Group Adjuvant (Group A)]. Prognostic features and overall survival (OS) were compared using the log-rank test and calculated using the Kaplan Meier method. RESULTS: Group N included 47 cases and Group A included 59 cases. A total of 57 patients were male and 49 were female, with a mean age of 56.1 ± 10.2 years. A total of 41 patients were at pathological stage (p-stage) IIIa, and 65 patients were at I or II. The overall 5-year survival rate (5-YS) was 28%. The 5-YS for p-stage I II (n = 65) was significantly better than that of p-stage III (n = 41) (35 vs 20%, P = 0.034). For p-stage IIIa (pn2 positive), the 5-YS of Group N was significantly better than that of Group A (34 vs 12%, P = 0.020). The median overall survival for Group N and Group A in IIIa (pn2 positive) LD-SCLC patients were 46 and 15 months (P = 0.009), respectively. Multivariate analysis for survival showed mediastinal lymph node involvement; surgery and histopathology of SCLC were both significant independent predictors of long-term survival. CONCLUSIONS: Neoadjuvant chemotherapy combined with surgery provided reasonable options for piiia-n2 LD-SCLC patients, which can give them a better chance of survival. Keywords: Small cell lung cancer Neoadjuvant chemotherapy Surgery INTRODUCTION Small-cell lung cancer (SCLC) accounts for about 14% of all lung cancers [1] and is particularly well known for its highly malignant nature and frequently occurring metastasis at an early stage [2]. Although chemotherapy has been the mainstay of treatment [3, 4] because of the extreme high sensitivity of these tumours, multimodality treatment combined with surgery provides additional survival benefits for surgically indicated SCLC cases. Eberhardt et al. [5] reported that the 5-year survival rate (5-YS) was 63% and the local control rate was 100% for 23 completely resected SCLC cases. Using chemotherapy alone, the local recurrence rate reached 50% [6, 7]. Therefore, an effective combination of chemotherapy and surgery is the key treatment for indicated SCLC candidates. A usual management of a newly diagnosed limited-disease SCLC (LD-SCLC) case is to treat the patient with immediate chemotherapy; however, operations are commonly performed Yong-jie Xu and Hui Zheng share the co-first authorship. after two or more cycles of chemotherapy. Fujimori et al. [8] reported experiences of induction chemotherapy with subsequent operations for LD-SCLC patients; the 3-year survival rate (3-YS) was 73%. However, few data exist regarding a contemporary survival comparison between LD-SCLC surgery patients who undertook neoadjuvant and adjuvant chemotherapy. In Hara s case series [9], for LD-SCLC patients, the 5-YS of induction chemotherapy with subsequent operations was 42%, whereas that of initial surgery combined with adjuvant chemotherapy was 33%; there was no significant difference between these groups(p >0.05). The report by the Japan Clinical Oncology Lung Cancer Study Group [10] showed that patients with LD-SCLC who were receiving adjuvant chemotherapy, four cycles of cisplatin and etoposide, followed by initial surgery yielded a 57% 5-YS. Brock et al. [11] reported a similar result that patients with LD-SCLC receiving surgery combined with adjuvant platinum chemotherapy yielded a 5-YS of 68%. However, according to the guideline [12], this result that initial surgery combined with adjuvant chemotherapy was performed for LD-SCLC surgery patients can be further discussed. The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 2 Y. Xu et al. / Interactive CardioVascular and Thoracic Surgery In this statement, for LD-SCLC cases, operations may be performed before chemotherapy. Therefore, a potentially conflicting circumstance may arise in managing a new LD-SCLC case: which should be the initial option, chemo or surgery? The present study attempted to evaluate whether the neochemotherapy option for patients with LD-SCLC yield long-term survival. PATIENTS AND METHODS Approval for the study was obtained from the Ethics Committee of the Hospital. Patients A total of 112 LD-SCLC patients underwent radical surgical resections in Shanghai Pulmonary Hospital, from February 2000 to February LD-SCLC was characterized by tumours confined to one hemithorax, with local involvement of ipsilateral and contralateral supraclavicular nodes, and ipsilateral and contralateral hilar or mediastinal nodes could be present [13]. Preoperative workup included chest CT, ultrasound scan of abdomen, brain MRI, whole-body bone scan and bronchoscopy, which aimed to exclude remote metastasis. Positron emission tomography was not commonly used. All 112 patients underwent exfoliative cell examination of sputum, bronchoscopic brush biopsy and traditional bronchoscopic biopsy. In addition, 13 patients received transthoracic needle pneumocentesis and 2 patients underwent mediastinoscopy. According to the SCLC management guideline in our department [14], in patients with a definite SCLC diagnosis obtained before surgery, neoadjuvant chemotherapy was performed, including an etoposide and cisplatin (EP) regimen (etoposide 25 mg/m 2 on Days 1 3; cisplatin 100 mg/m 2 on Day 1). The regimen was administered in 2 courses at an interval of 3 weeks. After neoadjuvant therapy, the tumour stage was re-evaluated by chest CT, ultrasound scan of abdomen, brain MRI, whole-body bone scan and bronchoscopy. Given that endobroncheal ultrasonography (E-BUS) was introduced to our hospital in 2004, it had been the standard procedure to perform tumour staging for patients between 2004 and However, before 2004, invasive mediastinal staging after neoadjuvant chemotherapy was not carried out and, so far, mediastinoscopy has not become universal. Patients underwent surgery when they were diagnosed as being partially in remission or when their tumour was stable after preoperative chemotherapy. However, patients who had indefinite pathological diagnosis of SCLC before surgery received initial surgery followed by postoperative adjuvant therapy. After neoadjuvant chemotherapy, patients in complete remission or those whose conditions had progressed were excluded from the study because surgery was not performed for these patients. In this study, cases were excluded because the results yielded incomplete follow-up data for 1 case and 5 patients did not receive postoperative chemotherapy; 2 of the patients underwent surgery alone because they refused postoperative adjuvant therapy and 3 patients only received postoperative radiotherapy for distant metastasis of tumour. R 0 resections with either neoadjuvant or adjuvant chemotherapy were administered to the remaining 106 patients, who were included in this study. Pathological diagnosis was based on the 2004 WHO classification of tumours. The pathological stage ( p-stage) was determined according to the 6th edition of Tumor, Node, Metastasis classification of lung cancer [15]. Grouping Two groups were assigned for further statistical analysis: Group Adjuvant (Group A), in which only postoperative chemotherapies were administered, and Group Neoadjuvant (Group N), in which surgery was combined with both 2 cycles of pre- and postoperative chemotherapy, respectively. Patients were assigned to Group A if they had an indefinite pathological diagnosis before surgery. Those with a definite SCLC diagnosis obtained before surgery were assigned to Group N. Adjuvant treatment and follow-up All 106 patients received postoperative adjuvant EP (cisplatin 80 mg/m 2 on Day 1, etoposide 100 mg/m 2 on Days 1 3)-based chemotherapy for at least 2 cycles. When relapse was apparent or lymph node fusion occurred during operation, postoperative radiotherapy was performed. All patients were followed up by telephone, letters or an out-clinic visit. Every follow-up assessment included a chest CT, ultrasound scan of abdomen, brain MRI and whole-body bone scan. Follow-up intervals were 1 month, 3 months, 6 months, within 2 years postoperatively and then every 1 year thereafter. Statistical analysis The survival rate and evaluation of the difference was calculated using the Kaplan Meier method and the log-rank test. Multivariate analysis of the prognostic factors was performed using Cox s regression model [16]. Categorical variables were compared using a χ 2 test. The differences between continuous variables were assessed using the Mann Whitney U-test. A P 0.05 was considered statistically significant. All statistical analyses were performed with SPSS RESULTS General information The current study included 57 males (54%) and 49 females. The mean age was 56.1 ± 10.2 years. A total of 25 cases were confirmed at p-stage Ia, 13 at pib, 13 at piia, 14 at piib and 41 at piiia. Pure SCLC was confirmed in 88 cases and 18 cases were of mixed SCLC type containing small-cell carcinoma and squamouscell carcinoma (Table 1). In addition to radical resection, 47 patients received neoadjuvant treatment as well as followed adjuvant chemotherapy (Group N); of these, 24 were proved to be SCLC before surgery by exfoliative cell examination of sputum and bronchoscopic brush biopsy, 12 patients by transthoracic needle pneumocentesis, 9 patients by E-BUS and 2 patients by mediastinoscopy. The remaining 59 patients only received adjuvant chemotherapy (Group A) because there was no pathological evidence of SCLC before surgery, although all of them underwent exfoliative cell examination (59), 5 of them E-BUS and 1 received transthoracic needle pneumocentesis. During the study period, a total of 7

3 Y. Xu et al. / Interactive CardioVascular and Thoracic Surgery 3 Table 1: General information of 106 enrolled cases Variables Group N Group A Total P-value Numbers of patients Age (mean ± SD) 55.2 ± ± ± years >60 years Sex (male/female) 25/22 32/27 57/ Histopathology Pure SCLC Mixed SCLC Pathological T-stage T T Pathological N-stage N N ptnm stage I II IIIa Surgery Lobectomy Pneumonectomy SCLC: small-cell lung carcinoma; SD: standard deviation; Mixed SCLC: small-cell carcinoma and squamous-cell carcinoma; Group N: Group Neoadjuvant; Group A: Group Adjuvant. patients experienced progression of disease after receiving neoadjuvant therapy and 3 of them died. Given that no surgery was performed, these 7 patients were not enrolled in our study. During our follow-up, prophylactic cranial irradiation (PCI) was performed in 36 patients with brain metastases. Thirteen patients received thoracic radiotherapy because of local recurrence and lung metastasis. Thoracic radiotherapy also was performed in 6 patients in whom lymph node fusion occurred during operation. In this study, recurrence was noted in 59 patients. Local failure was noted in 4 patients in Group N and 9 in Group A. Distant failure was found in 46 (43%) patients, including 19 in Group N and 27 in Group A. Furthermore, the study showed that distant failure was most frequently found in the brain (Group N: 14 patients; Group A: 22 patients) and the overall incidence rate of brain metastasis was 34% (36 patients). PCI was performed in all patients with brain metastases. Thirteen patients received thoracic radiotherapy because of local recurrence and lung metastasis (Group N: 4 patients; Group A: 9 patients). Ten patients did not complete radiotherapy, including 4 patients in Group N and 6 in Group A, because of progressive disease in 3 patients, adverse effects in 4 and refusal of radiotherapy in 3. Thoracic irradiation was performed at 2 Gy per day up to 45 Gy, whereas PCI was performed at 2.5 Gy per day up to 25 Gy. Table 2 gives the clinical and pathological staging. For the 106 (Group N: 47, Group A: 59) patients with both clinical and pathological staging, the number whose stage was considered better at pathological staging (down-staging) was 14 (30%) in Group N. The number of patients whose pathological staging was reported as worse than the clinical staging (up-staging) was 11 (19%) in Group A and 2 (4%) in Group N. In terms of Tumor and Node stage, 24 and 2% in Group N were regarded as having a lower N stage and the respective proportions for T stage after surgery. Table 2: Comparison of the clinical and pathological stage for the 2 groups Clinical stage (preoperative) Operations and postoperative complications As expected during chemotherapy, the severity of several symptoms among Group N diminished; there were no clear differences between the 2 groups. Both groups were occasionally reported as having continued cough, breathlessness, lethargy and chest pain. All 106 patients underwent radical resections and systematic sampling. Ninety-three patients underwent thoracotomy: 42 in Group N and 51 in Group A. Thirteen patients received Video Assisted Thoracic Surgery: 5 in Group N and 8 in Group A. The intraoperative mediastinal lymph node strategy was performed by the systematic sampling of L4, L5, L6, L7, L8, L9, L10 on the left side, and R2, R4, R7, R8, R9, R10 on the right side, if present. In addition, sleeve resections were performed in 12 patients. Lobectomy was performed in 54 patients, including right upper lobectomy (n = 17), right middle lobectomy (n = 3), right lower lobectomy (n = 11), left upper lobectomy (n = 17) and left lower lobectomy (n = 6). Bilobectomies were performed in 14 patients, included right middle and upper lobectomy (n = 1), and right middle and lower lobectomy (n = 13). Pneumonectomy was performed in 38 patients, including left side (n = 22) and right side (n =16). Postoperative complications were noted in 21 cases, which included prolonged air leaks in 10 cases with prolonged chest tube drainage under negative pressure (>2 weeks); pulmonary infections in 6 cases, which was cured after an additional 2 weeks of antibiotic therapy; respiratory failure in 1 case; arrhythmias in 3 cases; and chylothorax in 1 case. All patients were cured after symptomatic treatment. Follow-up information Pathological stage (postoperative) Group A Group N Group A Group N Patient data IA 22 (37%) 20 (43%) 15 (25%) 10 (21%) IB 12 (20%) 5 (11%) 7 (12%) 6 (13%) IIA 7 (12%) 8 (17%) 6 (10%) 7 (15%) IIB 5 (9%) 3 (6%) 5 (9%) 9 (19%) IIIA 13 (22%) 11 (23%) 26 (44%) 15 (32%) Group N: Group Neoadjuvant; Group A: Group Adjuvant. The follow-up ended on 1 June The follow-up rate was 89% and the mean follow-up time was 28.9 months. At the end of follow-up, 51 patients were alive, including 24 in Group N and 27 in Group A, whereas 55 patients had died (23 patients in Group N and 32 in Group A). Local regional recurrence was found in 6 patients who were alive, 2 in the bronchial stump and 4 in the mediastinal lymph nodes. Twenty-one patients died of distant metastasis. Remote metastasis was most frequently noted, which accounted for 38% overall.

4 4 Y. Xu et al. / Interactive CardioVascular and Thoracic Surgery Survival analysis The overall 5-YS was 28%. There was no statistical difference in 5-YS of Group N and Group A (32 and 25%, P = 0.63), respectively. However, the 5-YS of the 65 patients with p-stage I II was significantly better than that of the 41 patients with p-stage III (35 vs 20%, P = 0.034) (Fig. 1A). It was also revealed that the 5-YS of patients with lobectomy was better than that of those who underwent pneumonectomy, 33 vs 18% (P = 0.023, Fig. 1B). In p-stage I II (pn0 1), the 5-YS of 33 patients in Group A was 37% and that of the 32 patients in Group N was 33%; there was no statistical difference between the two groups (P = 0.19) (Fig. 2A). However, for patients with p-stage III, especially pn2 positive, neoadjuvant chemotherapy combined with surgery provided a better long-term survival than adjuvant chemotherapy combined with surgery. Interestingly, there was a significant difference in survival between the 2 groups for patients with p-stage III (pn2 positive). The median overall survival (OS) for Group N and Group A in IIIa (pn2 positive) LD-SCLC patients were 46 and 15 months (P = 0.009), respectively. The 5-YS of Group N was 34%, which was much higher than the 12% of Group A (P = 0.020) (Fig. 2B). Univariate survival analysis A univariate analysis for prognostic factors of survival was performed first by a log-rank test. Results showed that the survival of patients with p-stage III (pn2 positive) was worse than that of those with p-stage I II ( pn0 1) (P = 0.039). In addition, different histological types of SCLC (P = 0.022) and surgical types (P = 0.027) were statistically significant risk factors for survival (Table 3). Figure 1: (A) Survival of all 106 patients with p-stage I, II and III disease. The 5-YS of 65 patients with p-stage I II (pn0 1) disease was significantly better than that of the 41 patients with p-stage III (pn2 positive) disease (35 vs 20%, P = 0.034). (B) All 106 patients underwent radical surgery, the methods of which were lobectomy and pneumonectomy. The 5-YS of 68 patients who received lobectomy was 33%, whereas that of 38 patients who underwent pneumonectomy was 18%. This difference was statistically significant (P=0.023). Figure 2: (A) Postoperative survival of patients with p-stage I II (pn0 1) disease. The 5-YS of 33 patients in Group A was 37%, whereas that of 32 patients in Group N was 33% (P = 0.188). Group N: Group Neoadjuvant; Group A: Group Adjuvant. (B) Postoperative survival of patients with p-stage III (pn2 positive) disease. The 5-YS of 15 patients in Group N was 34%, which was obviously higher than the 12% of 26 patients in Group A. This difference was significant (P = 0.020). Group N: Group Neoadjuvant; Group A: Group Adjuvant.

5 Y. Xu et al. / Interactive CardioVascular and Thoracic Surgery 5 Table 3: survival Multivariate analysis of prognostic factors The results of the multivariate survival analysis showed that pathological mediastinal lymph node [P = 0.011; HR: 2.19; 95% confidence interval (CI): ], surgical methods (P = 0.005; HR: 2.36; 95% CI: ) and histology type of SCLC (P = 0.002; HR: 3.02; 95% CI: ) were independent factors affecting survival and prognosis for LD-SCLC. The neoadjuvant chemotherapy seemed not to be a significant factor, but yielded a strong tendency for survival (P = 0.052; HR: 1.85; 95% CI: ). For the pn2 SCLC cases, the analysis revealed that a significant benefit of 5-YS could be obtained after neoadjuvant chemotherapy was performed (P = 0.001; HR: 5.77; 95% CI: ) (Table 4). DISCUSSION Univariate analysis for factors associated with Variables HR 95% CI P-value Gender Male , Female Age (years) , >60 Histopathology Pure SCLC , Mixed SCLC Pathological T stage pt , pt2 ptnm stage I II (pn0 1) , III (pn2) Surgery Lobectomy , Pneumonectomy Neoadjuvant chemotherapy Group N , Group A HR: hazard ratio; 95% CI: confidence interval; Group N: Group Neoadjuvant; Group A: Group Adjuvant. Table 4: Multivariate analysis of prognostic factors for pn2 disease Variables HR 95% CI P-value T-stage Surgery Neoadjuvant chemotherapy Histological type HR: hazard ratio; 95% CI: confidence interval. In general, systemic chemotherapy using cisplatin/etoposide with concurrent thoracic irradiation is rational in the treatment of patients with LD-SCLC [17]. Unfortunately, local regional relapse is still frequent (26 63%) [18 20]. Some reports [5, 21, 22] have suggested that, in the multimodality approach of LD-SCLC, surgical resection reduces local relapse and improves the survival outcome of patients with LD-SCLC. Therefore, surgery combined with chemoradiotherapy has become a candidate treatment modality for patients with LD-SCLC. A survival benefit has also been shown in advanced and non-metastatic diseases [23]. A significant survival advantage can be obtained in patients with initially resectable NSCLC with neoadjuvant chemotherapy as well as after surgery as an adjuvant treatment. However, neoadjuvant chemotherapy is mandatory for patients with LD-SCLC, which has yet been indefinite. The results clearly showed that neoadjuvant chemotherapy is feasible; 47 of the patients in Group N who received 2 cycles of chemotherapy showed acceptable improvement of several symptoms. Furthermore, a comparison of prechemotherapy clinical staging and surgical pathological staging showed that, although 19% of Group A and 2% of Group N patients had their staging revised, a greater proportion, 30% in Group N, were reported as having a better pathological than clinical stage; this is presumably as a result of neoadjuvant chemotherapy. Surgery seemed unaffected by the delay of about 9 weeks taken to deliver the neoadjuvant chemotherapy, with similar proportions of patients proceeding to surgery. It is suggested that a small proportion of patients ( 5%) were able to have lobectomy rather than a pneumonectomy as a result of neoadjuvant chemotherapy, which is in line with surgical expectations and dependent on the position of the tumour and nodes. Similar proportions of patients were considered to have had a complete resection, and postoperative complications and time in hospital post-surgery were also similar in the 2 treatment arms. In addition, we did not observe any increase in treatment-related deaths after neoadjuvant chemotherapy and pneumonectomy. When surgery was combined with chemotherapy-treated LD-SCLC, the survival of Stage I II was better than that of Stage III. Ju et al. [24] reported that the 3-YS of p-stage I II was 84%, which was obviously better than the 13% 3-YS of p-stage III. In our study, the 5-YS of p-stage I II was 35% and that of p-stage III was 20%, which was significantly different (P = 0.034). In the multimodality treatment of patients with p-stage I II, initial surgery followed by adjuvant chemotherapy resulted in more favourable survival and prognosis, which was similar to that seen in neoadjuvant chemotherapy with surgery. Hara et al. [9] reported that the 5-YS of 14 patients with Stage I II who received surgery and postoperative chemotherapy was 54%, and that of 10 patients with Stage I II who received surgery combined with pre- and postoperative chemotherapy was 51%. In our study, during the treatment of p-stage I II, 5-YS of 33 patients in Group A was 37%, which was not significantly different from that of 32 patients in Group N (33%, P = 0.19). Similar benefits will be obtained by initial neoadjuvant chemotherapy combined with surgery as well as radical resection followed by postoperative chemotherapy for patients with Stage I and, probably, Stage II disease. There was an improvement of the OS for patients who received neoadjuvant chemotherapy before surgery for LD-SCLC. For resectable Stage III, particularly in patients with N2 disease, neoadjuvant chemotherapy after resection may be a favourable choice in the management of LD-SCLC because neoadjuvant chemotherapy provided a better survival than did surgery followed by adjuvant chemotherapy. Hara et al. [9] revealed that the median survival time of patients with Stage III who received initial chemotherapy was 29 months, which was significantly higher than the 17 months for who those received initial surgical resection. When

6 6 Y. Xu et al. / Interactive CardioVascular and Thoracic Surgery comparing our results, the 5-YS of 34% for 15 patients with p-stage III who received neoadjuvant chemotherapy combined with surgery was apparently higher than the 12% of 26 patients with p-stage III who did not receive preoperative chemotherapy; this difference was statistically significant (P = 0.020). It was revealed that neoadjuvant chemotherapy was not an independent prognostic factor, rather a strong tendency in the multivariate analysis for survival in all cohorts (P = 0.052; HR: 1.85; 95% CI: ). The probable reason for this finding might be that there was a large proportion of p-stage I II patients in our study, 61%. It is interesting that, in our further multivariate analysis of prognostic factors based on LD-SCLC patients with p-stage III ( pn2 positive) disease, the result showed that neoadjuvant chemotherapy was an independent factor that strongly affected survival and prognosis (P = 0.001; HR: 5.77; 95% CI: ). The present study supports the result that neoadjuvant chemotherapy combined with surgery is a reasonable option for LD-SCLC patients with p-stage III, especially pn2 positive disease because of the improved survival of these patients. We also considered the methods of surgery as another important predictive factor for long-term survival. Weksler et al. [16] reported that the median survival of patients who received lobectomy or pneumonectomy resection was significantly longer than that of patients who received wedge resection. This study revealed that the 5-YS of patients with lobectomy was better than that of those who underwent pneumonectomy: 33 vs 13% (P = 0.023, Fig. 1B). This result may be attributed to the effect of Stage T or N down-staging by neoadjuvant chemotherapy, which helps patients obtain more survival benefit from radical resection. Despite these positive results, several limitations of our study must be noted. First, this was a retrospective single-institution study. A retrospective analysis is susceptible to various sources of bias, which may not have been identified and controlled. Second, information of local recurrence and disease-free survival is limited because of the long time period of data collection (from 2000 to 2012). Third, because our study used a small series, additional prospective randomized, controlled trials with the same background are needed using a larger series. We concluded that neoadjuvant chemotherapy combined with surgery is a reasonable option for LD-SCLC patients with Stage III, especially pn2 positive disease because of the significant improvement in survival. In addition, down-staging induced by neoadjuvant chemotherapy helps diminish several symptoms, although there is no significant difference in the 5-YS for LD-SCLC patients with Stage I II disease. Finally, neoadjuvant chemotherapy combined with surgery might be recommended, especially for Stage III patients with LD-SCLC. ACKNOWLEDGEMENT The authors thank Li-ling Zou (Department of Statistics, Tongji University School of Medicine) for her assistance with statistical analysis. Funding This work was supported by Shanghai Municipal Committee of Science and Technology research projects (Nos and 11DZ ). Conflict of interest: none declared. REFERENCES [1] Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A 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: [2] David MJ, Bruce EJ. Small-cell lung cancer. Lancet 2005;366: [3] Kim HG, Lee GW, Kang JH, Kang MH, Hwang IG, Kim SH et al. Combination chemotherapy with irinotecan and cisplatin in elderly patients (>or= 65 years) with extensive-disease small-cell lung cancer. Lung Cancer 2008;61: [4] Lim E, Belcher E, Yap YK, Nicholson AG, Goldstraw P. The role of surgery in the treatment of limited disease small cell lung cancer: time to reevaluate. J Thorac Oncol 2008;3: [5] Eberhardt W, Stamatis G, Stuschke M, Wilke H, Müller MR, Kolks S et al. Prognostically orientated multimodality treatment including surgery for selected patients of small-cell lung cancer patients stages IB to IIIB: longterm results of a phase II trial. Br J Cancer 1999;81: [6] Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oatcelled carcinoma of bronchus. Ten-year Follow-up. Lancet 1973;2:63 5. [7] Turrisi AT, Kim K, Blum R, Sause WT, Livingston RB, Komaki R et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340: [8] Fujimori K, Yokoyama A, Kurita Y, Terashima M. A pilot phase 2 study of surgical treatment after induction chemotherapy for resectable stage I to IIIA small cell lung cancer. Chest 1997;111: [9] Hara N, Ohta M, Ichinose Y, Motohiro A, Kuda T, Asoh H et al.influence of surgical resection before and after chemotherapy on survival in small cell lung cancer. J Surg Oncol 1991;47: [10] Tsuchiya R, Suzuki K, Ichinose Y, Watanabe Y, Yasumitsu T, Ishizuka N 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 Study Group Trial ( JCOG9101). J Thorac Cardiovasc Surg 2005;129: [11] Brock MV, Hooker CM, Syphard JE, Westra W, Xu L, Alberg AJ et al. Surgical resection of limited disease small cell lung cancer in the new era of platinum chemotherapy: its time has come. J Thorac Cardiovasc Surg 2005;129: [12] NCCN Guidelines TM Version Panel Members Small cell Lung Cancer. [13] Stahel RA, Ginsberg RJ, Havemann K, Hirsch FR, Ihde DC, Jassem J. Staging and prognostic factors in small cell lung cancer: a consensus report. Lung Cancer 1989;5: [14] Saito H, Takada Y, Ichinose Y, Eguchi K, Kudoh S, Matsui K et al. West Japan Thoracic Oncology Group Phase II study of etoposide and cisplatin with concurrent twice-daily thoracic radiotherapy followed by irinotecan and cisplatin in patients with limited-disease small-cell lung cancer: West Japan Thoracic Oncology Group J Clin Oncol 2006;24: [15] Sobin LH, Wittekind C. TNM Classification of Malignant Tumours, 6th edn. New York: Wiley-Liss, [16] Weksler B, Nason KS, Shende M, Landreneau RJ, Pennathur A. Surgical resection should be considered for stage I and II small cell carcinoma of the lung. Ann Thorac Surg 2012;94: [17] Zimmermann FB, Bamberg M, Molls M, Jeremic B. Limited-disease smallcell lung cancer. Semin Surg Oncol 2003;21: [18] Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study J Clin Oncol 2002;20: [19] Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study. J Clin Oncol 1997;15: [20] Murray N, Coy P, Pater JL, Hodson I, Arnold A, Zee BC et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1993;11:

7 Y. Xu et al. / Interactive CardioVascular and Thoracic Surgery 7 [21] Elliott JA, Osterlind K, Hirsch FR, Hansen HH. Metastatic patterns in smallcell lung cancer: correlation of autopsy findings with clinical parameters in 537 patients. J Clin Oncol 1987;5: [22] Shepherd FA, Ginsberg RJ, Evans WK, Feld R, Cooper JD, Ilves R et al. Reduction in local recurrence and improved survival in surgically treated patients with small cell lung cancer. J Thorac Cardiovasc Surg 1983;86: [23] Song WA, Zhou NK, Wang W, Chu XY, Liang CY, Tian XD et al. Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: an updated meta-analysis of 13 randomized control trials. J Thorac Oncol 2010;5: [24] Ju MH, Kim HR, Kim JB, Kim YH, Kim DK, Park SI. Surgical outcomes in small cell lung cancer. Korean J Thorac Cardiovasc Surg 2012;45: 40 4.