In 2020, esophageal carcinoma was the seventh most prevalent cancer and sixth leading cause of cancer-related death worldwide (1). The predominant esophageal cancer subtype in Asia is esophageal squamous cell carcinoma (ESCC) (2). ESCC accounts for over 84% of newly diagnosed esophageal cancers annually (3, 4). Surgical resection remains the gold standard for patients with locally advanced resectable ESCC. However, studies have shown that local recurrence and distant metastasis occur in approximately 33% of patients who receive surgery alone (5, 6). Thus, ESCC treatment is challenging and requires a multidisciplinary approach to improve the surgical therapeutic effect in locally advanced resectable disease.

Following the launch of a new era in immunotherapy (including programmed cell death-ligand 1 [PD-L1] and programmed cell death protein-1 [PD-1] inhibitors), further exploration of neoadjuvant immunotherapy alone or combined with chemotherapy or chemoradiotherapy is expected to further improve the therapeutic effect in locally advanced resectable ESCC. In a recent systematic review including 27 phase 2 or 3 clinical trials with 815 patients, the pooled pathological complete response (pCR) rate was 32.4% in ESCC after neoadjuvant chemoimmunotherapy(nCIT), with the pooled incidence of treatment-related severe adverse events of 26.9% (7). Zhu et al. reported that neoadjuvant immunochemoradiotherapy could not improve the pCR rate than neoadjuvant chemoradiotherapy (nCRT) for ESCC, but significantly increased the risk of severe adverse events (8). Another multicenter retrospective study that included 370 ESCC patients showed that the pCR rates of mono-immunotherapy, nCIT, and nCRT plus immunotherapy were 12.1%, 25.5%, and 42.3%, respectively (9). Hence, neoadjuvant PD-1/PD-L1 inhibitors in combination with chemotherapy or chemoradiotherapy are becoming a new therapeutic frontier for resectable ESCC with promising clinical outcomes. However, long-term follow-up are warranted to validate the survival benefits of nCIT or nCRT plus immunotherapy.

Camrelizumab is a PD-1 inhibitor produced in China by Jiangsu Hengrui Pharmaceuticals Co, Ltd. (Lianyungang, China). The ESCORT-1st study showed that first-line camrelizumab plus chemotherapy could achieve better disease control and long-term survival in advanced ESCC than chemotherapy alone (10). Several prospective phase-II clinical trials have also demonstrated that after neoadjuvant chemotherapy plus camrelizumab (nCIT) for ESCC, pCR rates ranged from 24.1% to 42.5%, with major pathological response (MPR) rates of between 45% and 68.8% (11–14). However, these sample sizes were small, and only a few studies reported survival results. Additionally, crucial details and technical know-how regarding the surgical techniques and perioperative challenges following nCIT are still poorly understood.

In the present study, we retrospectively reviewed the perioperative outcomes of esophagectomy following nCIT to compare it with surgery after nCT and nCRT. This study aimed to investigate the potential advantages and disadvantages of esophagectomy after nCIT.

This study described potential intraoperative technical challenges after nCIT and compared them with other neoadjuvant treatment modalities including nCT and nCRT. Compared with nCT, nCIT followed by esophagectomy achieved higher pCR and MPR rates, more resected lymph nodes during surgery, less intraoperative blood loss, and comparable results in other perioperative parameters. Compared with nCRT, nCIT achieved similar pCR and MPR rates, significantly more resected lymph nodes during surgery, shorter operation time, less intraoperative blood loss, and less frequent ICU stays after surgery. Regarding postoperative complications, no significant statistical difference was detected between the nCIT and the nCT or nCRT groups.

Over the past decade, there have been lingering controversies concerning the effects of neoadjuvant chemotherapy (nCT), chemoradiotherapy (nCRT), and immunotherapy for ESCC. There is still no convincing evidence to prove which neoadjuvant therapeutic modality is best for locally advanced resectable ESCC. Pathological responses including pCR and MPR have been considered as principal surrogate endpoints to evaluate the therapeutic efficacy of different neoadjuvant treatments. Previous large-scale randomized clinical trials have reported that nCRT could achieve higher pCR rates (43.2-49%) than nCT (3.8-10.7%) in ESCC, but nCRT might have more postoperative complications and higher postoperative mortality, with no identified overall survival differences (4, 17–24). Therefore, in Western countries, many institutions have adopted nCRT followed by esophagectomy, but globally, many other countries support nCT alone (4, 25).

In this study, the pCR rate for the primary tumor was 26.4%, and the MPR rate was 52.9% after nCIT, consistent with previous reports (9, 11, 12, 26–30). However, after nCT for ESCC, the pCR rate in previous studies is usually between 3.8% and 10.7% (23, 24, 31), which is close to the 4.1% for the primary tumor in this study and significantly lower than the results for nCIT. In contrast, the pCR rate for nCRT has reached approximately 28.9% to 49% in previous studies, which is slightly better than the 25.8% in this study (21, 24, 31–33). Xu et al. demonstrated that the pCR rate was comparable between nCIT and nCRT (29.8% vs 34.0%), with no significant differences in the incidence of postoperative complications and 30-day mortality (34). Thus, this study showed that ESCC might achieve better therapeutic efficacy from nCIT and nCRT on the basis of pCR and MPR results.

Although the pathological efficacy was better for nCIT and nCRT, controversies concerning the long-term survival results remained. Previous prospective trials on esophageal cancer, including JCOG9907, OEO2, CROSS, and NEOCRTEC5010 have demonstrated that nCT or nCRT can achieve better OS results than surgery alone or postoperative chemotherapy (20, 21, 32, 35). Nonetheless, survival differences between different neoadjuvant therapeutic modalities have not been clarified. Klevebro et al. and Wang et al. showed that nCRT could result in a higher pCR rate than nCT, but with no significant survival benefits (24, 31). Another study showed no significant differences in the 5-year OS or the 5-year relapse-free survival (RFS) rates between nCRT and nCT (36). Two separate meta-analyses also reported that nCRT did not show significant long-term survival benefits as nCT (37, 38). In this study, the 1-year OS rate in the nCIT group were 82.4%, consistent with the 1-year OS of between 87.6% and 92.8% in previous reports (29, 39), but not significantly different from nCT (77.3%) and nCRT (83.9%). In a few propensity score matching analyses, the 1-year OS rate in the nCIT group was 94.5-95.7%, slightly better than 84.8% in the nCT group and 86.2% in the nCRT group, but with no significant statistical differences (40, 41). Although no statistically significant difference was observed in our data, the 3-year OS after nCIT was 73.3%, slightly higher than 46.1% after nCT and 39.7% after nCRT. However, the sample size and follow-up time in the present study were too limited to report mature OS results. Therefore, the survival benefit after nCIT in locally advanced resectable ESCC still requires further investigation. Furthermore, as previously reported (4, 36, 42), our further analysis showed that radical esophagectomy, MPR, and ypN0 (no lymph node metastasis) were independent favorable prognostic factors for OS after neoadjuvant therapy. As to adjuvant therapy, approximately half of the patients received adjuvant therapy in each group, and no statistically significant difference was observed among the three groups. No survival difference was observed between patients received adjuvant therapy or not in our analysis.

This study also highlighted advantages for esophagectomy, as nCIT had more lymph nodes resected and less intraoperative blood loss compared with nCT. During our surgery, tumor and metastatic lymph nodes regression was more significant in the nCIT group than in the nCT group, facilitating lymph node clearance and reducing operation times. Qiao et al. also reported that patients who received nCIT had more lymph nodes cleared during surgery than those who received nCT (34 vs. 30, p<0.001), with comparable incidence of complications (23). Furthermore, when compared with nCRT, esophagectomy after nCIT also achieved more resected lymph nodes, shorter operation times, less intraoperative blood loss, and less frequent ICU stays after surgery. Based on our surgical experience, mild or moderate tissue adhesions were more frequently observed in the nCIT group compared to the nCRT group, which might help reduce the intraoperative difficulties. In certain propensity score matching analyses by Hong et al. and Xiao et al, esophagectomy after nCIT required shorter operative times, and dissected more lymph nodes than after nCRT (41, 43). Cheng et al. also reported that the nCIT group had minimal intraoperative blood loss, shorter operative times, and fewer perioperative complications than the nCRT group (37). However, the extent of lymph node resection and positive lymph node numbers after nCIT were similar to after nCT and nCRT in this study. Regarding other perioperative parameters such as radical resection rate and several postoperative recovery parameters, no significant differences were detected among the three groups.

Perioperative morbidity and mortality are the principal concerns in surgical treatment following neoadjuvant therapy. This study detected no significant statistical differences in the CTCAE grade related to neoadjuvant therapy and postoperative complication types among the three groups. Thus, the addition of camrelizumab to nCT did not increase morbidity or mortality. Additionally, another study by Qiao et al. showed that the total incidence of adverse events during nCIT was lower (77.1%) than nCT (91.7%, p=0.003) (23). As reported in previous studies (26, 30), pneumonia was the most prevalent major 30-day postoperative complication in this study. Other common complications included hoarseness, cardiac complication, and anastomotic leakage. Fortunately, no treatment- or surgery-related deaths were observed within 30 days after esophagectomy in this study, except for one sudden death in the nCT group, proving that esophagectomy following nCIT is safe and feasible.

Some limitations are apparent in this study. First, selection biases were inevitable between groups due to the limited sample size and the retrospective design. For example, the cT4 percentage in the nCIT group was 35.3%, which was significantly higher than in the nCT group. Second, the follow-up and recurrences data are insufficient to report mature OS and disease-free survival results. Third, each neoadjuvant therapy might have specific benefits for patient subgroups. The information on predictive biomarkers for therapeutic efficacy, such as PD-L1 expression, was absent in the present study. Therefore, the problem remains with selecting optimal patients who might benefit from different therapeutic modalities. Hence, more prospective phase III clinical trials with larger sample sizes and multiple centers should be conducted to identify the advantages and disadvantages of each neoadjuvant therapy in locally advanced resectable ESCC.

In conclusion, this real-world analysis showed that nCIT is safe and feasible, with satisfactory pCR and MPR rates. Esophagectomy following nCIT achieved several perioperative advantages over nCT and nCRT, with comparable perioperative morbidity and mortality. Although the 3-year OS after nCIT is slightly higher, the long-term survival benefits still require further investigation.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by The Ethics Committee of Hunan Cancer Hospital (No. 2022097). The patients/participants provided their written informed consent to participate in this study.

(I) Conception and design: BZ, QX, W, JW, XW, HZ. (II) Administrative support: BZ, QX. (III) Provision of study materials or patients: BZ, JW, DY, XL, WW, QX, XW, HZ, LG, XC, JL. (IV) Collection and assembly of data: BZ, JW, QX, XW, HZ, LG. (V) Data analysis and interpretation: BZ, QX. (VI) Manuscript writing: all authors. (VII) Final approval of manuscript: all authors. All authors contributed to the article and approved the submitted version.