Gastric cancer is one of the most common malignancies worldwide, which affects ~990,000 people and causes around 738,000 deaths every year (1–3). In China, the incidence of gastric cancer is ~30.64 per 100,000 populations per year (4). In all gastric cancer, locally advanced gastric cancer (LAGC) is a special type since the prognosis of patients with LAGC is dramatically different between resectable and unresectable ones (5–7); therefore, creating surgery opportunities for the patients with unresectable LAGC by neoadjuvant chemotherapy is necessary (8–11). Meanwhile, it is also critical to optimize surgical conditions for the patients with resectable LAGC by neoadjuvant chemotherapy, which reduces postoperative recurrence, thus further improving survival in these patients (12–14). Among the regimens of neoadjuvant chemotherapy, docetaxel, cisplatin, and capecitabine (DCC), chemotherapy is tolerable and brings promising efficacy with a 5-year survival rate of 54% in R0 patients with resected LAGC (15).

Bevacizumab (BEV), an angiogenesis inhibitor, binds to vascular endothelial growth factor (VEGF)-A to prevent the interaction of VEGF-A with the VEGF receptor, then suppresses the VEGF signaling pathway, thereby inhibiting neovascularization (16, 17). Nowadays, BEV plus chemotherapy as a neoadjuvant regimen is used in patients with locally advanced cancers (14, 18, 19). For instance, neoadjuvant BEV plus oxaliplatin, leucovorin, and 5-fluorouracil realize a pathological downstaging rate of 65% in locally advanced rectal cancer patients (14); moreover, another research illustrates that BEV plus paclitaxel and carboplatin as a neoadjuvant regimen achieves 100% objective response rate (ORR) and an optimal pathological response of 38% in patients with locally advanced cervical cancer (18); besides, as for unresectable stage III lung adenocarcinoma patients, neoadjuvant BEV plus pemetrexed and carboplatin induces pathologic downstaging rate of 73.8% and 1-year event-free survival rate of 56.1% (19). Based on the above-mentioned information, we hypothesized that BEV plus chemotherapy as neoadjuvant therapy might be a promising regimen in LAGC, while it is rarely applied in LAGC.

The current pilot study aimed to investigate the efficacy and safety of neoadjuvant BEV plus DCC in patients with resectable LAGC.

Neoadjuvant chemotherapy has been extensively applied in patients with LAGC (25, 26). For instance, neoadjuvant DCC shows an R0 resection rate of 86.7% and R1 resection rate of 4.5% in patients with resectable gastric cancer (25); in patients with LAGC, neoadjuvant docetaxel, cisplatin, and S-1 realizes a partial response rate of 57% and an SD rate of 43%; meanwhile, it also facilitates a pathological response grade 1a in 17% patients, grade 1b in 30% patients, grade 2 in 37% patients and grade 3 in 17% patients (26). Recently, a trial reports that BEV plus DCC as neoadjuvant regimen presents pleasing treatment response in previous patients with unresectable LAGC or paraaortic lymph node metastatic gastric cancer, and the data shows that the ORR is 64.3%; meanwhile, the pathological complete regression rate is 12.9% (22), which indicates that neoadjuvant BEV plus DCC may improve treatment response in patients with gastric cancer. Thus, our study further explored the role of neoadjuvant BEV plus DCC in patients with LAGC and discovered that BEV plus DCC as neoadjuvant therapy presented a good clinical response, with an ORR of 55.0% and a pathological response grade 2 in 40.0% of patients and grade 3 in 15.0% patients, which was numerically better than DCC chemotherapy alone as neoadjuvant therapy (25). The explanations might be that (1) BEV could inhibit the neovascularization and induce the regression of tumor blood vessels (16), meanwhile, chemotherapy exhibited the ability of anti-cancer cytotoxicity (27), therefore, BEV plus DCC might present a better anti-tumor effect; (2) BEV might enhance the chemosensitivity of gastric cancer cells via suppressing the VEGF- phosphatidylinositol 3 kinase/protein kinase B-survivin signaling cascade (28); thus, it combined with DCC could induce favorable outcomes.

Neoadjuvant chemotherapy has been reported to improve survival in patients with LAGC. For example, neoadjuvant DCC chemotherapy displays acceptable survival with the median progression-free survival (PFS) and OS of 12.1 months (range 9.5–14.6 months) and 22.9 months (range 14.3–31.5 months) in patients with unresectable LAGC (15); docetaxel plus S-1 as neoadjuvant regimen shows a high 3-year PFS rate compared with surgery alone (80.0 vs. 58.7%) in patients with LAGC (29); patients with LAGC receiving neoadjuvant epirubicin, oxaliplatin, and capecitabine chemotherapy present PFS rate of 40% and OS rate of 64.4% over a 3-year follow-up (30). In our study, BEV plus DCC as a neoadjuvant regimen for patients with LAGC displayed that the 1-, 2-, and 3-year DFS rates were 88.8, 80.7, and 67.3%, and the 1-, 2-, and 3-year OS were 100.0, 75.8, and 75.8%, which was numerically better than previous study using DCC alone as the neoadjuvant regimen (15). The results might be because BEV plus DCC presented more effective on tumor downstaging and pathological response than DCC chemotherapy alone (mentioned above), which directly reduced the recurrence risk to improve their prognosis.

The safety of BEV and DCC in patients with cancer has been reported. The main toxicities related to BEV are hypertension, proteinuria, and hemorrhage which can limit therapy and lead to other complications (31, 32). The most common adverse events after DCC treatment are neutropenia, anorexia, and febrile neutropenia (33). In the present study, the common hematological adverse events were anemia, leukopenia, and neutropenia, and the non-hematological adverse events were alopecia, anorexia, and fatigue. The incidences of adverse events were generally similar compared with a previous study (33). Besides, the adverse events were manageable, and most of them were of grades 1 and 2, which revealed that BEV plus DCC chemotherapy as neoadjuvant therapy was a tolerable option for patients with LAGC. However, further studies should be conducted to further verify the safety of BEV plus DCC as neoadjuvant therapy in patients with LAGC.

Some limitations still existed in our study: (1) we did not enroll patients with LAGC receiving neoadjuvant DCC chemotherapy as control, therefore, further randomized controlled trial could be performed; (2) the sample size of this study was only 20 patients because the usage of BEV as neoadjuvant therapy in patients with LAGC remained in exploring stage, thus, a subsequent study with larger sample size was needed to verify our conclusion; (3) the follow-up time was relatively short, which might affect the DFS and OS evaluation in statistics; (4) the effect of other anti-angiogenesis agents (such as apatinib) combining with chemotherapy as a neoadjuvant regimen in LAGC could be investigated further.

In conclusion, neoadjuvant BEV plus DCC presents a favorable pathological response and survival profile with acceptable safety in patients with LAGC. The results of this study highlight that BEV plus DCC is a potentially neoadjuvant regimen that may achieve survival benefits in patients with LAGC.

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 Institutional Review Board of the People's Hospital of XiaJin Affiliated to Shandong First Medical University. The patients/participants provided their written informed consent to participate in this study.

DY and TH contributed to the study design and manuscript writing. DY, ZW, TH, and LY conducted literature research and clinical practice. DY, ZW, and TH contributed to the data acquisition and analysis. DY and TH reviewed the manuscript and made revisions. All authors read and approved the final manuscript. The figures were made by the authors' own work. All authors contributed to the article and approved the submitted version.

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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