Impact of Adjuvant Therapy on Survival in Surgically Resected Limited-Stage Small Cell Lung Cancer

Background Data on efficacy of adjuvant therapy for surgically resected small cell lung cancer are scant. This study was determined to reveal the survival benefits of different adjuvant treatment modalities for limited-stage small cell lung cancer patients following surgical resection. Methods Data of patients with histologically confirmed small cell lung cancer after surgical resection were collected from November 2006 to June 2019. Survival analyses were calculated by Kaplan–Meier method, with log-rank test to evaluate statistical significance. Prognostic factors were identified by multivariate analysis using cox proportional hazards model. Further survival analysis and cox regression analysis stratified by clinicopathologic features were conducted to evaluate the survival benefits of different adjuvant treatment modalities. Results In total, 153 out of 157 patients were analyzed. Multivariate analysis showed male sex, lymph node metastasis, residual tumor, VPI and non-adjuvant therapy were independently associated with poor prognosis. Subgroup analyses revealed both adjuvant chemotherapy and adjuvant chemoradiotherapy were significantly associated with superior survival for stage pT2-4 (HR=0.176, 95%CI:0.053-0.578, p=0.004; and HR=0.115, 95%CI:0.033-0.405, p=0.001) and pure SCLC patients (HR=0.182, 95%CI:0.067-0.494, p=0.001; and HR=0.181, 95%CI:0.071-0.465, p<0.001). For pN0 patients, adjuvant chemotherapy was associated with better survival (HR=0.219, 95%CI:0.054-0.891, p=0.034), while adjuvant chemoradiotherapy was associated with improved survival for pN+ patients (HR=0.324, 95%CI:0.138-0.760, p=0.010). Conclusions For patients without pathologic lymph node metastasis, there is a survival benefit with adjuvant chemotherapy. However, for patients with pathologic lymph node metastasis, adjuvant chemoradiotherapy might achieve a significant survival benefit. Further prospective studies are needed to validate the results.


INTRODUCTION
Lung cancer accounts for 12% of new cases of cancer worldwide and is the leading cause of cancer-related deaths (1). Small cell lung cancer (SCLC) is increasing by more than 180,000 cases per year, accounting for approximately 15% of all newly diagnosed cases of lung cancer worldwide (2)(3)(4). Although rare cases have been reported among non-smokers, almost all SCLC patients are current or former smokers (5,6). In countries with high smoking rates, such as China, the incidence of SCLC is expected to remain elevated (3). SCLC progresses rapidly, and more than 70% of SCLC patients already have lymph nodes diseases or distant metastases at the time of diagnosis (7).
Platinum-based chemotherapy combined with radiotherapy remains the predominant treatment modality for SCLC patients (8)(9)(10)(11). According to the National Comprehensive Cancer Network guidelines, surgical resection is recommended for early-stage SCLC patients (cT1-2N0M0) (9,11). Nevertheless, due to the highly aggressive nature of SCLC, the number of operable SCLC patients is quite small. Consequently, data on efficacy of adjuvant therapy for resected SCLC are scarce. Previous studies have focused on the survival benefit of patients with SCLC after surgical resection, and the results have shown that patients with surgical resection have favorable survival (12)(13)(14)(15). In recent years, there have been several studies concerning the benefits of specific adjuvant treatment modalities (16)(17)(18)(19)(20)(21)(22). However, few studies have comprehensively analyzed the benefits of different adjuvant treatment modalities for patients with surgically resected SCLC.
In this study, therefore, we analyzed the survival of SCLC patients with surgical resection and investigated the prognostic factors of these patients. Furthermore, we evaluated the impact of adjuvant chemotherapy and adjuvant chemoradiotherapy on the overall survival stratified by clinicopathologic features.

Patients
From November 2006 to June 2019, patients who 1) had a preoperative diagnosis of lung cancer, 2) met the indications for surgery, 3) and with histologically confirmed SCLC after surgical resection were collected from the Department of Thoracic Surgery, Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. A total of 157 patients were enrolled. Following clinicopathologic characteristics were prospectively collected including gender, age, smoking history, ECOG scores, time of surgery, surgery procedures, pathology reports, and postoperative adjuvant therapy regimens. To minimize selection bias, four patients (2.5%) were excluded because they died within 30 days after surgery, as these patients would not have received adjuvant therapy (17). Ultimately, 153 patients were included in the analysis. This study was approved by the Ethics Committee and Institutional Review Boards, and all patients were exempt from an informed consent due to the retrospective nature of the study. Surgical resections were classified as sublobectomy, lobectomy and greater than lobectomy according to the extent of resection. All pathologic sections were re-reviewed by 2 pathologists. The clinical and pathological staging were reevaluated according to the American Joint Committee on Cancer (AJCC) eighth edition TNM and the Veterans Administration Lung Study Group (VALSG) staging systems (23,24).

Adjuvant Treatment Modalities
Etoposide with cisplatin for 4 to 6 cycles was the predominant adjuvant chemotherapy regimen. For patients with chest radiation, most of them received 50 Gy in 30 days. Patients with prophylactic cranial irradiation (PCI) most frequently received radiation dose of 25 Gy in 10 days. Since all patients in our cohort who underwent chest radiation or PCI had previously received adjuvant chemotherapy and no patients received radiotherapy alone, we divided the patients into nonadjuvant therapy group, adjuvant chemotherapy group and adjuvant chemoradiotherapy group according to the adjuvant treatment modalities. The adjuvant chemoradiotherapy was defined as receiving chemotherapy followed by radiotherapy after surgery, and radiotherapy including chest radiation, PCI or both.

Statistical Analysis
Overall survival (OS) was defined as the time from surgery to death from any cause or last follow-up. The overall survival was analyzed using the Kaplan-Meier method, with the log-rank test performed to evaluate survival variances. Cox proportional hazard model was used to identify the independent prognostic factors of surgically resected SCLC patients. To evaluate the survival benefits of different adjuvant treatment modalities, further survival analysis and multivariate analysis stratified by clinicopathologic features were conducted. For the multivariate model, all factors with a p<0.05 in the univariate analysis was included. All tests were bilateral, and statistical significance was set at p<0.05. All statistical analysis was performed using IBM SPSS 26.0 (IBM-SPS Inc, Armonk, NY) and RStudio software version 1.3.1093 (RStudio Inc, Boston, Mass).

Impact of Adjuvant Therapy on Overall Survival
To further investigate the impact of adjuvant therapy on survival, we conducted subgroup analyses to assess overall survival stratified by pathologic T stage, lymph node metastasis, and histologic subtypes. For stage pT1 or combined SCLC patients (Figure 2A and Figure 3B), survival analysis showed overall survival was not significantly different among non-adjuvant therapy, adjuvant chemotherapy, and adjuvant chemoradiotherapy group. However, both adjuvant chemotherapy and adjuvant chemoradiotherapy significantly improved survival for patients with stage pT2-4 (p<0.001 and p<0.001, Figure 2B) and pure SCLC (p=0.039 and p<0.001, Figure 3A). Meanwhile, survival analysis revealed adjuvant chemotherapy group and adjuvant chemoradiotherapy group had superior survival for pN0 and pN+ subgroups, respectively (p=0.017, Figure 2C and p<0.001, Figure 2D).
Cox multivariate regression analysis revealed consistent results with survival analysis. After multivariate analysis, both adjuvant chemotherapy and adjuvant chemoradiotherapy were associated with better survival for pT2-4 (HR=0. 176

DISCUSSION
Up to now, the treatment modality of SCLC is still dominated by platinum-based chemotherapy combined with radiotherapy (8-11). For early-stage SCLC, surgical resection is recommended (8,11 (18). These studies focused on the impact of the specific adjuvant treatment modalities on the survival at specific pathologic stages. In our cohort, 119 out of 153 patients underwent adjuvant chemotherapy. Of these patients, 59 patients only received adjuvant chemotherapy and 60 patients received adjuvant radiotherapy after chemotherapy. Using Cox multivariate regression analysis, we found both adjuvant chemotherapy (HR=0.303, 95%CI: 0.141-0.654, p=0.002) and adjuvant chemoradiotherapy (HR=0.267, 95%CI: 0.122-0.583, p=0.001) significantly improved the survival of SCLC patients after surgical resection. This mutually corroborates with the results of several previous studies. In addition, we found male sex, lymph node metastases, residual tumor, and VPI were associated with poor prognosis. Previous studies suggested that adjuvant chemotherapy has a survival benefit in relatively early-stage patients (17,19), and chest radiation and PCI tend to have a survival benefit in relatively advanced patients (18,21,22). In a previous study, Nicolas Zhou et al. performed a similar grouping, classifying patients into two subgroups, pN0 and pN+, to investigate the effects of adjuvant chemotherapy, PORT, and PCI on RFS in both groups, respectively, and multivariate analysis found that adjuvant chemotherapy significantly prolonged RFS in both groups (HR=0.49, 95%CI: 0.27-0.91, p=0.024 and HR=0.41, 95%CI: 0.18-0.94, p=0.035, respectively) (20). To further investigate the impact of different adjuvant treatment modalities on survival, we conducted subgroup analyses to assess overall survival stratified by pathologic T stage, lymph node metastasis, and histologic subtypes. Survival analysis showed both adjuvant chemotherapy and adjuvant chemoradiotherapy significantly improved survival for patients with stage pT2-4 and pure SCLC. Meanwhile, adjuvant chemotherapy group and adjuvant chemoradiotherapy group had superior survival for pN0 and pN+ subgroups, respectively. Multivariate analysis revealed consistent results with survival analysis. There was no statistically significant survival benefit of adjuvant therapy for patients with tumor diameters less than 3 cm (pT1) compared to greater than 3 cm (pT2-4), which suggested that the role of adjuvant therapy was limited in very early-stage SCLC. Due to its highly aggressive character, SCLC is more sensitive to adjuvant therapy than NSCLC. Therefore, for pure SCLC, there was a survival benefit of adjuvant therapy. In contrast, for combined SCLC with nonsmall cell component, the effect of adjuvant therapy was less pronounced. In terms of the results of lymph node metastasis status subgroup analysis, we speculate that SCLC is a very aggressive disease with the potential for metastasis in early stage, therefore, even for patients with R0 resection and pN0 disease, systemic chemotherapy is needed. Meanwhile, patients with pN+ disease have a higher degree of disease progression and are more probable to have local spread and distant metastases than patients with pN0 disease. Thus, pN+ patients are more likely to have a survival benefit from additional chest radiation around the resected lesion or PCI on the basis of adjuvant chemotherapy. Hence, the status of lymph node metastases has a significant impact on the selection of adjuvant treatment options for postoperative patients with SCLC.
This study has several limitations. As a single-center retrospective study, selection and institutional bias are inevitable. In our clinical work, to expand the study population, in addition to patients with early limited-stage SCLC (cT1-2N0M0), we also included patients who had a diagnosis of lung cancer before surgery but not suspected of SCLC and underwent surgery incidentally. This is both a strength and a weakness of our study. On the one hand, it allows our study to assist in the selection of adjuvant therapy for patients with postoperative proven advanced SCLC. On the other hand, it also affects the external veracity of this study to some extent and should be noted when generalizing the findings of this study. In addition, 34 patients in our cohort did not undergo any adjuvant therapy after surgery because of preference or the intolerance of side effects, and survival in this group might have been inherently poor, so there may be some bias. To try to address this issue, we further collated the patients' ECOG scores and compared them between groups receiving different adjuvant treatments and did not find any statistical difference among the groups (Supplementary Table 1). This may have avoided this bias to some extent. There were 11 patients with sublobectomy and 9 patients with residual tumor (R1), which may affect the results.
In conclusion, based on the analysis of 153 patients with SCLC after surgical resection, we investigated the effect of different adjuvant treatment modalities. There were survival benefits for adjuvant therapy, with a significant benefit in pT2-4 and pure SCLC patients compared to pT1 and combined SCLC patients, respectively. More importantly, for patients without pathologic lymph node metastasis, there was a survival benefit with adjuvant chemotherapy. However, for patients with pathologic lymph node metastasis, adjuvant chemoradiotherapy was required to achieve a survival benefit. Further prospective studies are needed to validate the results.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Ethics Committee and Institutional Review Board of Fudan University Shanghai Cancer Center. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.