Surgery following neoadjuvant therapy has been proposed as one of the principal multidisciplinary treatments to achieve improved local and distant disease control in resectable non-small cell lung cancer (NSCLC). Emerging data from various ongoing phase II studies have indicated that the addition of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1(PD-L1) inhibitors alone or in combination with chemotherapy before surgery may significantly improve the survival of resectable NSCLC (1–5). Recently, the checkmate 816 trial, which was the only published phase III study on neoadjuvant chemoimmunotherapy until now, has shown a 24.0% pathological complete response (pCR) rate in patients treated with neoadjuvant Nivolumab combined with platinum doublets, approximately 10-fold higher than in patients receiving chemotherapy alone (2.2%) (6). These clinical trials have established the positive role of PD-1 inhibitors plus chemotherapy in the neoadjuvant treatment of NSCLC.

Surgical resection is still considered as the ultimate curative treatment for NSCLC when complete resection is feasible (7). However, as neoadjuvant chemoimmunotherapy becomes more widespread in clinical practice, there are increasing debates about the use of surgery. Considering that the hilar and mediastinal structure might be affected by neoadjuvant PD-1/PD-L1 inhibitors and chemotherapy, the preferable surgical approaches and surgical techniques require further clarification. But few studies have reported the details of surgical techniques and perioperative challenges following neoadjuvant chemoimmunotherapy until now.

Furthermore, video-assisted thoracic surgery (VATS) is superior to open thoracotomy for the resection of early stage NSCLC, with the advantages of less complications, less pain, faster recovery and equivalent long-term survival (8–11); however, several recent case series and anecdotal reports have suggested that VATS following neoadjuvant chemotherapy could also achieve satisfactory outcomes in locally advanced NSCLC patients (2, 12–14). But there was little evidence suggesting the feasibility and safety of VATS after neoadjuvant chemoimmunotherapy in NSCLC. It is widely acknowledged that neoadjuvant therapy might result in dense adhesions and fibrosis in the chest (1, 15, 16), particularly in cases with significant treatment response, which might increase the complexity of the surgical field. As down-staging rates are significantly increased after neoadjuvant PD-1 inhibitors plus chemotherapy, whether VATS remains suitable for patients with smaller down-staged tumors, and whether there will be increased rates of complications and conversion to thoracotomy remain to be clarified. Moreover, a comparative analysis between VATS and open thoracotomy following neoadjuvant PD-1 inhibitors plus chemotherapy in NSCLC has not yet been performed.

This study was conducted to investigate the perioperative outcomes of surgery following neoadjuvant PD-1 inhibitors plus chemotherapy in resectable NSCLC. The primary aim was to address the feasibility and safety of pulmonary resection after neoadjuvant chemoimmunotherapy via different surgical approaches, VATS and open thoracotomy. The advantages and disadvantages of VATS following neoadjuvant PD-1 inhibitors plus chemotherapy was also identified compared with open thoracotomy.

As the use of neoadjuvant chemoimmunotherapy is increasing rapidly in locally advanced NSCLC, it is incumbent on surgeons to cope with the new perioperative challenges under this novel treatment strategy. This study represents one of the largest experiences to date of neoadjuvant chemoimmunotherapy in resectable NSCLC from real-world observations. Our study has shown that neoadjuvant chemoimmunotherapy did not increase perioperative challenges. Only 21 patients (16.0%) received delayed surgery beyond 42 days after the final cycle of neoadjuvant therapy, and radical resection (R0) was achieved in 95.4% of the cohort. As previously reported (2, 5), lobectomy was the principal method of pulmonary resection (102 cases, 77.9%), and pneumonectomy was performed in 8.4% of the cohort (11 cases). There were 59 patients (45.0%) received bronchial sleeve resection/bronchoplasty, while vascular sleeve/angioplasty was performed in 20 patients (15.3%) in the present study. The MPR rate of the cohort was 53.4%, in accordance with several previous prospective studies (1–6).

In this study, postoperative complications within 30 days occurred in 28 patients (21.4%). The principal types of postoperative complications included pneumonia, prolonged air leak, and arrhythmia/heart failure, which were in accordance with previous reports (2, 5, 8, 15). Only two patients had immunological hepatitis within 30 days after surgery, and no mortality occurred in this study, proving that the addition of PD-1 inhibitors before surgery did not increase severe postoperative complications, in accordance with previous results (2, 5).

In the phase III checkmate 816 study (6), 30% and 22% of patients received VATS in the Nivolumab + chemotherapy and chemotherapy-only groups, respectively. In a systemic review by Cao et al (2), between 26% and 46% of patients received VATS after neoadjuvant immunotherapy, which was identical to the 40.5% of patients in our study, suggesting that VATS remains one of the principal surgical approaches for NSCLC patients after neoadjuvant chemoimmunotherapy. Our surgical data have shown that VATS tended to be performed in patients with smaller size and early-stage (cT1-3, cIB–IIB) NSCLC. VATS following neoadjuvant PD-1 inhibitors plus chemotherapy could also achieve similar definitive resection rates, postoperative recovery courses, and comparable morbidities, with the advantages of reduced operative time, less intraoperative blood loss, and fewer ICU stays after surgery compared with open thoracotomy, which was also in accordance with previous studies (5, 12, 19). However, there may be biases in the comparison because more patients in the thoracotomy group received bronchial sleeve resection/bronchoplasty and/or vascular sleeve resection/angioplasty. Therefore, a PSM analysis in order to balance the tumor stages, location and other characteristics between groups was performed, and VATS still has the advantage of fewer ICU stays after surgery in the present study.

However, the average number of total and N2 lymph nodes resected in the VATS group was both lower than in the open thoracotomy group. Retrospective multicenter studies (11, 20) have reported that although there is a reduced average number of resected lymph nodes during VATS, long-term survival is still better than open thoracotomy. Zhang et al (21). and Tian et al (22). reported that similar numbers of total and N2 lymph node stations could be harvested via VATS following neoadjuvant therapy. Fortunately, at least three N1 and three N2 lymph node stations including station 7 were resected in each patient in our study. Several studies have reported that VATS following neoadjuvant chemotherapy could achieve similar long-term survival results as open thoracotomy in locally advanced NSCLC patients (2, 12, 16, 19). In accordance, no significant difference was observed in tumor recurrence or RFS rates between VATS and open thoracotomy in this study.

One of the controversies that surrounds using VATS following neoadjuvant therapy is whether the rates of conversion from the minimally invasive approach to open thoracotomy and perioperative morbidities would be increased. According to analyses of the National Cancer Database by Krantz et al. (23) and Yang et al. (12), pulmonary resection was ultimately accomplished via a conversion approach in 5.3% to 25.7% of locally advanced NSCLC patients after neoadjuvant chemotherapy with comparable morbidity and mortality. In other previous reports (1, 5, 24), conversion surgery is required in 25% to 54% of patients initially operated on via a VATS or robotic approach after neoadjuvant immunotherapy, while that rate was 42% in this study. Our results identified that primary tumor invasion and dense adhesion and fibrosis after treatment were the principal causes leading to conversion surgery after neoadjuvant chemoimmunotherapy, similar to what was reported by Bott et al (1). Several previous reports have suggested that neoadjuvant PD-1/PD-L1 inhibitors generate significant adhesion and fibrosis or “pseudo-progression” in the chest that can increase surgical complexity (1–3, 5). The extent of this effect is heterogeneous and unpredictable from restaging imaging prior to surgery (2, 3). Unfortunately, no correlation between surgical approaches and radiographic tumor regression or pathological response was identified in this study, either. Moreover, most of bronchial sleeve resection/bronchoplasty and vascular sleeve resection/angioplasty were performed via thoracotomy in our study, indicating that more complicated pulmonary resections might also increase the conversion rate.

The frequency and severity of principal postoperative complications in the VATS group was also comparable with the open thoracotomy. Regarding postoperative recovery courses, including total drainage after operation, duration of chest tube, hospital stay after surgery, there were no significant differences between VATS and open thoracotomy, which is in accordance with the surgical results after neoadjuvant chemotherapy (5, 9, 19). Therefore, our results suggest a positive role of VATS in the surgical treatment of NSCLC after neoadjuvant chemoimmunotherapy with equivalent safety to thoracotomy.

There were several limitations to this study. First, due to the retrospective analysis, potential bias was inevitable. Second, because only small cohorts of retrospective data were available, full assessments of the perioperative risk and surgical approaches after neoadjuvant chemoimmunotherapy will require further surgical information from the ongoing phase III studies. Third, because of the short follow-up time, long-term survival and recurrence information are lacking. Moreover, the choice of surgical approaches is personalized, according to cancer characteristics, surgeons’ experience, and preference, et al. Candidates for VATS among NSCLC patients treated with neoadjuvant chemoimmunotherapy require careful selection by experienced surgeons, and the decision to convert to open thoracotomy should be made promptly to avoid possible morbidity.

In conclusion, the present study reported the details of surgical techniques and perioperative challenges following neoadjuvant chemoimmunotherapy. Our results confirmed that pulmonary resection following neoadjuvant PD-1 inhibitors plus chemotherapy was safe and feasible. VATS could achieve similar safety, definitive surgical resection, postoperative recovery, and equivalent oncological efficacy as open thoracotomy, with the advantages of fewer ICU stays after surgery. Therefore, both VATS and open thoracotomy should be recommended as principal surgical approaches for curative-intent resection in selected NSCLC patients. However, appropriate candidates to receive VATS should be carefully screened before surgery.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of Hunan Cancer Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

(I) Conception and design: BZ, HX, QX, WW; (II) Administrative support: BZ; (III) Provision of study materials or patients: BZ, JW, DY, JT, XL, ZW, YZ, WW; (IV) Collection and assembly of data: BZ, HX, QX; (V) Data analysis and interpretation: BZ, HX, QX; (VI) Manuscript writing: all authors; All authors contributed to the article and approved the submitted version.

This study was supported in part by the Natural Science Foundation of Hunan Province (2019JJ40179); Scientific Research Project of Hunan Provincial Health and Family Planning Commission (20201743); and Changsha Science and Technology Project (kq1901079).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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