SCLC is a highly malignant tumor characterized by rapid progression. The median survival time of affected patients is 17 months, while a 5-year survival rate for patients with the limited-stage disease is only 10% . At present, the treatment of SCLC is mainly based on chemoradiotherapy, while the role of surgical treatment remains controversial. In the last century, two prospective trials reported that surgery was not beneficial for SCLC [1, 2]. Consequently, surgery has not been recommended as a routine approach for treating SCLC for decades. However, in the past ten years, numerous retrospective analyses based on the SEER (the Surveillance, Epidemiology, and End Results) database and NCDB (National Cancer Database) have shown that surgery benefits stage I and II SCLC. Accordingly, the NCCN (National Comprehensive Cancer Network) guidelines recommended surgical treatment for T1 and T2N0 patients [3,4,5, 8,9,10,11,12]. ESMO (European Society for Medical Oncology) also proposed similar guideline practices for SCLC in 2021 .
Patients with early-stage SCLC have no significant symptoms. In our group, 60% of the patients were incidentally diagnosed during physical examination. On chest CT imaging, peripheral SCLC has a significantly higher proportion of smooth nodules than non-small cell lung cancer, which may be related to faster tumor cell growth and fewer stromal cells [1, 14,15,16]. Therefore, paying attention to the possibility of SCLC when encountering solitary pulmonary nodules with smooth edges on a chest CT scan is necessary. Also, the differential diagnosis needs to be differentiated from sclerosing hemangioma and inflammatory pseudotumor. SCLC tends to proliferate actively. The average SUV value in this group of patients who underwent PET/CT examination was 8.8, which was higher than that of non-small cell lung cancer . PET-CT also provides more accurate preoperative staging of SCLC [18, 19], which is important to make a clinical strategy.
Our results also showed that clinical early-stage SCLC (stage I-IIIA) achieved a better 5-year survival rate following surgical management. The survival analysis of this group showed that the mean OS was 44.8 months, and the 5-year survival rate was 46%, which is encouraging and consistent with the results of several previous retrospective analyses [3,4,5, 8,9,10,11, 20,21,22]. The 5-year survival rate of stage I was 52.1%, which was a favorable outcome as expected. Similarly, the very limited stage (T1-2N0M0) also obtained solid benefits from oncological resection, according to several retrospective studies [4, 8, 21, 23]. So, small peripheral tumors clinically staged as N0 are recommended for surgical resection rather than needle aspiration biopsy to exclude SCLC. Patients with stage IIIA SCLC were also found to have improved OS in the present study, which is consistent with a propensity score matching study reported by Gao et al.. The results indicate that patients with selected clinical stage IIIA SCLC whose lymph nodes could be completely dissected could be recommended for indications of surgery. In this cohort, there were seven cases with advanced stage, including five with IIIB and 2 with IV. The survival rate of the advanced stage was very poor, and the 5-year survival rate was zero even though these cases were treated with surgical resection and systemic chemoradiotherapy. The 5-year survival rate in the chemoradiotherapy group was better than that previously reported [21, 24], which might be due to the higher percentage of patients in the early stage of this study.
Lobectomy is still the preferred surgical approach for early-stage SCLC, and we found a significant difference in OS between the lobectomy group and the sublobar resection and pneumonectomy groups, which is also consistent with the results of previous studies [3, 22, 25]. In addition, although the incidence of mediastinal lymph node involvement in SCLC was high, the R0 resection rate in this group was still as high as 97%, which is related to strict preoperative evaluation.
In addition to surgical approach, age, surgical method, TNM stage, N stage, and vascular tumor thrombus were associated with survival time. Among them, multivariate analysis revealed lymph node involvement to as an independent survival risk factor. Therefore, preoperative lymph node biopsy should be considered when mediastinal lymph node involvement is suspected in preoperative imaging evaluation.
All incidentally confirmed SCLC should receive systemic adjuvant therapy after surgery . Although no survival benefit was observed following postoperative radiotherapy in this group, mediastinal radiotherapy and chemotherapy were recommended in patients with lymph node involvement [27, 28]. The lack of observable benefits from radiotherapy may be related to the low number of cases. Previous retrospective analyses also found no survival benefit from postoperative radiotherapy (including prophylactic whole cranial irradiation) or thoracic radiotherapy following postoperative chemotherapy . Prospective studies or larger retrospective analyses are expected to confirm this aspect in the future.
Recently, immune checkpoint inhibitors have been found to improve outcomes in patients with extensive-stage small-cell lung cancer in several randomized controlled trials (RCTs) [30, 31]. Anti–programmed cell death 1 (PD1) and anti-programmed death ligand 1 (PD-L1) monoclonal antibody checkpoint inhibitors are increasingly used in the adjuvant therapy of small cell lung cancer. Several RCTs have reported that antiangiogenic agents such as bevacizumab, an anti-VEGF monoclonal antibody, also led to improved PFS in small-cell lung cancer [32, 33]. Accordingly, immunotherapy and vascular targeted therapy were combined with traditional chemotherapy in 17 patients in two groups; however, they still cannot be considered standard care for SCLC.
The present study has several limitations. First of all, this was a retrospective analysis, with the relatively small number of cases, the large time span, the different characteristics of patients, and high heterogeneous postoperative treatment. Second, the study did not include patients with limited-stage SCLC without surgery as control during the same period. The subjects were patients with SCLC who were incidentally discovered after surgery, and the indications were different from those patients with SCLC confirmed by pathology before the operation. Also, neoadjuvant chemotherapy was not added. Neoadjuvant chemotherapy combined with surgery may be a reasonable option for clinical N2-stage patients . Despite these several limitations, the present study reflects the actual clinical outcomes of postoperative unsuspected SCLC patients.
In conclusion, this study shows that surgery and adjuvant therapy have encouraging outcomes in postoperative unsuspected SCLC. Patients with early-stage SCLC, including stage II and IIIA, can benefit from surgery, and standard lobectomy plus systematic lymph node dissection is recommended. Systemic therapy should be performed postoperatively. Future randomized controlled prospective studies are needed to confirm whether preoperative neoadjuvant chemotherapy or neoadjuvant chemotherapy plus immunotherapy can further prolong survival time and whether to perform thoracic radiotherapy after surgery.