According to the WHO global cancer data, over one million new cases of gastric cancer worldwide have occurred annually in the recent years, ranking the sixth malignant tumors in the world in terms of morbidity and the second in terms of mortality (1). Although surgical resection remains the mainstream of gastric cancer treatment, chemotherapy offers additional survival benefit (2–4), and thus has been widely implemented in perioperative settings. Preoperative chemotherapy for gastric cancer, first pioneered by Schirren et al. and many other Western colleagues, has gained increasing popularity in the recent years (5). In addition to the survival benefit, the advantages of preoperative chemotherapy mainly include down staging, a better R0 resection rate, early control of micro-metastasis, better tolerance of adverse events, and better evaluation of therapy effect compared to postoperative settings (6).

With the accumulating evidence and guidelines suggestions, concerns remain with regard to its wide applications. For example, deterioration of physical conditions of patients caused by adverse events of preoperative chemotherapy may lead to the decrease of the ability of the patients to tolerate surgery and increase the occurrence of postoperative complications. Very high complication rates varying between 20 and 50% were reported in patients with preoperative chemotherapy, which seems disturbing for its further application because surgical complications may not only cause direct morbidity and even mortality after operation but also diminish the survival benefits of preoperative therapy (7–9). Moreover, with many international studies on neoadjuvant chemotherapy for gastric cancer, there is still no consensus with regard to the optimal regimens and therapy cycles. Although it is recommended by many Western guidelines, its application in East Asia, where most gastric cancer occurs, is still limited, partly due to lack of evidence. Our center is one of the leading centers attempting neoadjuvant chemotherapy (NACT) in China, and the oxaliplatin + S-1 (SOX) regimen is the most frequently used. To this end, we analyzed our prospectively maintained database to determine the influence of preoperative chemotherapy with SOX regimen on the perioperative safety. This study aims to determine whether preoperative SOX chemotherapy increases postoperative complications, and whether preoperative chemotherapy adverse events and its duration increase postoperative complications.

For surgeons, surgical safety prioritizes all surgical and therapeutic innovations. This analysis of our prospectively maintained database revealed that occurrence of postoperative complications was not influenced by preoperative chemotherapy with the SOX regimen but by preoperative comorbidity, tumor location, clinical stage, and resection range (including multiorgan excision). Neither the occurrence of chemotherapy adverse events nor the severity of them was associated with postoperative complications. However, our study also suggested that increased cycles of preoperative chemotherapy may lead to higher incidence of postoperative complications. We believe our data are suggestive to doctors during therapy selection for patients with gastric cancer.

The patient characteristics between the groups were imbalanced. There was no patient in the chemotherapy group, but 53 in the control group were in stage of T1N0M0. The percentage of T4a and T4b was accounted for 53.3% in the NACT group, significantly higher than that of 37.8% of the patients in the control group. Similar results were also found in the analysis of the preoperative N staging. These results were expected because NACT is only suggested to locally advanced cases, especially those in the stage of T3-4N+ as a therapeutic option in addition to the surgery-first strategy. The significant differences in clinical staging resulted in the subsequent differences in the resection range, duration of operation, and anastomotic methods. Many of the imbalanced factors, such as tumor location, operating time, and combined visceral resection, were identified as independent risk factors of complications, which are often reported in the literature as well (14–17). Given that, propensity score matching is necessary for our study to reduce the selection bias. Due to the retrospective nature of our study, these efforts were made to reach the best confidence of our conclusions (18).

After PSM, a higher rate of R0 resection was also found in the chemotherapy group, which was in accordance with the literature as one of the advantages of preoperative chemotherapy. However, longer duration of operation was still reported in the NACT group even after matching. Similar results had also been reported by Ramachandra (19) and Yuan (15), and there are at least two major reasons. First, due to lack of solid evidence in this regard, the surgical resection range, especially the lymphadenectomy resection range, is usually determined by the naïve clinical stage but not the yielded clinical stage even in cases with good remission (CR or PR) in our practice. This may cause longer surgical duration in the patients with NACT. Moreover, preoperative chemotherapy may lead to tissue adhesion, edema, and fibrosis, prolonging the surgical process. In general, the prolonged surgical process indicates higher incidence of postoperative complications. However, our results did not turn out that way, confirming the safety of preoperative chemotherapy. Our ongoing study is to further investigate whether there is a causal association between those tissue changes and complications.

The complication rate after gastrectomy was 34.1% in our study, most of which were categorized into Grade I/II (30.0%), while the rate of Grade III/IV was 4.1%. Such data are comparable to many prospective trials. After years of consecutively advocating early and strict registration of surgical complications, our center, together with many other major centers in China, reached reliable reported complication rates that are comparable to the literature (17, 20–22). The high rate of reported Grade I/II and the low rate of Grade III/IV complications indicate a good complication registration rate, and also suggest early detection, early diagnosis, and early intervention may improve the complication outcomes. In our study, postoperative complications were categorized according to the Expert Consensus on the Diagnostic Registration Criteria for Postoperative complications of Gastrointestinal Cancer surgery in China (2018 edition). It specifies how to register and grade complications, which was beneficial for the registration of early complications.

Similar rates of complications were found in the two groups regardless the preoperative therapy; our data confirm the safety of SOX as a choice of preoperative treatment strategy. Adverse events are very common, actually almost inevitable, during preoperative chemotherapy based on our data and the literature. The rate of severe adverse events reported in our study (28.6%) was lower than some previous reports and comparable to the others (23, 24). This is partially because the patients receiving preoperative chemotherapy are usually at better physical condition and better quality of life than those who receive after surgery, which may also lead to better tolerance of those adverse events. But more importantly, the SOX regimen has much less dose intensity when compared with the regimens applied in other trials, such as docetaxel, cisplatin, and S-1 (23), or docetaxel, oxaliplatin, and capecitabine (25). To this end, it is, therefore, important to emphasize that it is yet to conclude the influence of preoperative chemotherapy with much higher intensity to the surgical safety.

To date, the optimal cycles for gastric cancer preoperative chemotherapy are yet to be determined. Although, usually, two to three cycles are adopted nowadays, the COMPASS trial suggested the higher rate of pathological complete response in more cycles, which showed survival benefits in our previous analysis (26). It was unexpected to find more cycles of preoperative chemotherapy were associated with increased incidence of postoperative complications. The possible theory is the accumulation of chemotherapy toxicity due to the prolonged cycles. This is also partially supported by the higher rate of complications in the patients who underwent seven-to-eight-cycle preoperative chemotherapy. Of course, the incidence of complications in the patients with one to two cycles of chemotherapy was also slightly higher than that in the patients with three to four cycles of chemotherapy. But these patients are often the ones who were intolerant or had no response to preoperative chemotherapy. Although analysis with larger sample-sized database may further reveal the influence of preoperative chemotherapy to surgery, out data seem to indicate that the highest grade of adverse event may not properly represent the chemotherapy toxicity, and other parameters are still in request in this regard.

In conclusion, our data suggest that occurrence of postoperative complications was not influenced by preoperative chemotherapy with the SOX regimen but by preoperative comorbidity, tumor location, clinical TNM staging, and resection range (including multiorgan excision). Neither the occurrence of adverse events nor their severity during preoperative chemotherapy was associated with postoperative complications. However, increased cycles of preoperative chemotherapy may lead to a higher incidence of postoperative complications. We believe our data are suggestive to doctors during therapy selection for patients with advanced gastric cancer.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Peking University Cancer Hospital Ethics Committee (2016YJZ32). The patients/participants provided their written informed consent to participate in this study.

ZW and YW wrote the manuscript and researched the literature. ZW, YW, and SH contributed to performed bioinformatics analysis, material preparation, figures, and tables. SH, QW, BL, XY, and SL collected the clinical data and drafted the work. ZL and JJ supervised the study and contributed to the manuscript revision. All authors have read and approved the final manuscript.

This study was funded by the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (D171100006517004), Bethune Charitable Foundation (to ZW), and Beijing Municipal Administration of Hospitals' Youth Program (QML20191103).

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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