Surgery is the most important treatment for GC. More than 60% of patients have reached advanced stage at the time of diagnosis, which led to low radical resection rate ,therefore an efficient method for increasing the radical resection rate is urgently needed in the clinic .
Previous studies have demonstrated that surgery was capable of inducing tumor cells to transform into drug-resistant clones and increasing the production of tumor growth stimulating factors which can promote tumor cell proliferation. In early stage, the number of tumor cells is small, cell proliferation and DNA replication are active, at this time, tumor cells are more sensitive to chemotherapeutic drugs . Therefore, chemotherapy drugs given before tumor resection can not only kill the primary tumor, but also inhibit the growth stimulating factors of cancer cells, which is also effective for micrometastases. The earlier chemotherapy, the fewer drug-resistant cell lines . Which highlights the importance of neoadjuvant chemotherapy.
Presently, increasing attention is being paid to preoperative chemotherapy. The role of NAC is to help surgeon in decreasing the primary tumor size and stage, eliminating micrometastasis, alleviating tumor related symptoms, improving curative resection rate and reducing postoperative recurrence. However, some patients who are not sensitive to chemotherapy drugs cannot benefit from NAC, resulting in tumor progression and the time delay of surgical resection. Studies have shown that nearly 15% of patients receiving preoperative neoadjuvant therapy have the risk of tumor progression . Moreover, patients often suffer from side effects of NAC including cardiotoxicity, hepatotoxic and nephrotoxicity, which increase the risk of complications and mortality when surgery is performed. Therefore, it is particularly important to predict the efficacy of NAC. Thus, we set up an exploratory study to identify pre-treatment parameters that can predict sensitivity to NAC, so as to provide basis for individualized treatment of gastric cancer patients. For patients with promising responsiveness to NAC, neoadjuvant chemotherapy should be considered, otherwise surgery or other comprehensive treatment should be performed as soon as possible.
Our data showed that the obvious response rate of NAC for advanced gastric cancer was 41.3%, which further indicated that only a portion of patients can benefit from NAC, thereby emphasizing the importance of predicting the responses to NAC. According to the results of the univariate and multivariate analysis, we found that tumor location, differentiation, depth of invasion and CA724 were significant influencing factors for predicting the response of NAC. By using the four factors, we constructed a nomogram for predicting the NAC response before performing gastrectomy with lymph node dissection.
A Germany retrospective cohort study including 410 patients indicated that tumor in the upper two-thirds of stomach tend to have a better response to NAT . Study by Li et al. also showed a similar finding , which was consistent with our result-the obvious response rate of NAC in patients with tumor locating in esophagogastric junction (63.86%) was higher than that in patients without tumor locating in esophagogastric junction tumor (28.57%), and the difference was statistically significant (P < 0.05).
There were many studies had explored that serum tumor markers were associated with diagnosis, prognosis and therapeutic effect of preoperative or postoperative chemotherapy in gastric cancer [28, 29]. Other studies had shown that, CA724 was an independent factor for efficacy of NAC in gastric cancer . Our study reached the same conclusion that the higher the level of CA724, the worse the response to NAC. However, another paper suggested that the sensitivity of CA724 was only approximately 45.0% , and in addition, CA724 was associated with H. pylori infection and environmental factors [32, 33]. These findings implied that there might be a bias to evaluate the patients' condition only depending on CA724, there are still many works that should be done to solve this problem.
Patients with well-differentiated had better survival than those with poorly differentiated in GC [34, 35], and previous studies suggested that differentiation is an important predictor of pathological response [36, 37], which is consistent with our study. However, different from the previous studies , our results show that patients with lower T stage (T2, T3) had better response to neoadjuvant chemotherapy than advanced T stage (T4). Because NAC regimens bring relatively serious toxic and side effects in patients, which damage hematological, digestive, and nervous systems . In this study, the overall incidence of NAC adverse reactions was 85.7%, the rate of grade 3/4 toxicity was 33.48%, therefore, it is important to select the optimal treatment options for different patients, we suggest that for these patients who are not sensitive to NAC, one solution is to apply other regimens of NAC, such as FLOT (fluorouracil plus leucovorin, oxaliplatin, and docetaxel), which resulted in superior OS compared with ECX . And the other is to implement surgery as soon as possible to avoid useless time interval of chemotherapy and surgery when radical resection is available.
In addition, it should be mentioned that in recent years, many studies have focused on the relationship between serum inflammatory factors and tumor, these findings suggest that, in the tumor microenvironment, platelets, neutrophils and lymphocytes take important parts in tumor progression and metastasis due to the production of inflammatory cytokines and chemokines [40–45]. The increase of the number of neutrophils and platelets and the decrease of lymphocytes usually indicate enhanced inflammatory response and impaired immune activity, which may promote tumor cell proliferation, invasion, lymph node metastasis and distant organ metastasis. However, our study suggests that inflammatory factors such as platelets, neutrophils and lymphocytes are not independent predictor of chemosensitivity.
Although a nomogram predicting the response of NAC had been established with C index of 0.767 , our study achieved a C-index of 0.806 which indicated a better performance on prediction than previously reported study.
At the same time, we have to admit that our study has some limitations. On the one hand, the results may be biased due to the retrospective design of our study. On the other hand, because most patients enrolled in the study were in the recent 2 years, there were insufficient survival events to analyze the impact of the predictor and chemosensitivity on overall survival rate. Therefore, a high-quality research with a larger cohort of patients is warranted to address this issue.