Patients with locally unresectable gastric cancer often lose the opportunity of optimal surgical treatment when the disease is diagnosed, and the prognosis is poor. For the clinical treatment of locally unresectable gastric cancer, chemotherapy is the main comprehensive treatment method. Chemotherapy can prolong the survival time of patients, but the adverse reactions brought by chemotherapy will affect the treatment effect and quality of life, which seriously limits the improvement of curative effect. The conversion therapy of locally unresectable gastric cancer is a treatment of great concern in recent years. Conversion therapy refers to the initial treatment of potentially resectable or unresectable advanced tumors, which can be cured by surgery after pre-operative treatment (Terashima 2016). Conversion therapy was first applied to the treatment of colorectal cancer with liver metastasis. In recent years, clinical studies have found that this treatment concept also has a good prospect in the treatment of gastric cancer. By selecting appropriate drugs to affect the biological characteristics of locally unresectable advanced gastric cancer, conversion therapy downgrades the tumor stage after treatment, bring radical surgery opportunities for locally unresectable advanced gastric cancer, improve the R0 resection rate, and prolong the survival time of patients. Through a retrospective study of 11 patients with unresectable gastric cancer, Fukuchi found that compared with chemotherapy alone, the prognosis of patients after transformation treatment was significantly improved (5-year OS rate 43% vs 1%, 5-year PFS rate 36% vs 0) (Fukuchi et al. 2015). The GYMSSA study compared conversion therapy for unresectable gastric cancer with chemotherapy alone in a prospective randomized controlled trial and found that conversion therapy can benefit some patients, with a median survival time increased from 4.3 months to 11.3 months (Rudloff et al. 2014).
At present, there is no consensus on chemotherapy scheme for the conversion treatment of locally unresectable advanced gastric cancer. The NCCN guidelines mainly recommend platinum combined with fluorouracil drugs for the preoperative treatment of gastric cancer, and SOX scheme is one of its representatives. Oxaliplatin is the third kind of platinum drugs, which has higher efficacy and safety than other platinum drugs such as cisplatin and lobaplatin (Jiang et al. 2015). S-1 is one of the most effective drugs in the monotherapy of advanced gastric cancer (Huang et al. 2016). Paclitaxel drugs can make the cell spindle lose its normal function, so as to kill tumor cells (Kurokawa et al. 2021). In recent years, paclitaxel has been increasingly used in the clinical treatment of advanced gastric cancer, and it has been gradually recommended from the original second-line drugs to the first-line use (Cascinu et al. 2004). A prospective phase II clinical study of AIO-FlOT3 in Germany observed the efficacy of FLOT scheme in the treatment of locally metastatic gastric cancer and esophageal gastric junction cancer. The results showed that the median survival time of patients who achieved R0 resection of lesions through conversion treatment was 31.3 months, which was significantly higher than that of patients who did not receive surgical treatment (Al-Batran et al. 2017). Sato et al reported the results of a multicenter retrospective analysis. After 100 cases of unresectable advanced gastric cancer were treated with DOS regimen (docetaxel, cisplatin, s-1), 28 cases (conversion rate 84.8%) underwent R0 surgical resection, and the median survival time of surgical patients was 47.8 months (Sato et al. 2017).
At present, there are few reports on the comparison of SOX chemotherapy and paclitaxel combined other two drugs regimen in the treatment of locally unresectable advanced gastric cancer. This study aims to explore the efficacy and safety of FLOT regimen in the treatment of locally unresectable advanced gastric cancer by comparing with the classic SOX regimen, and provide a theoretical basis for clinical application. The results of our study showed that the ORR in the FLOT group was significantly higher than that in the SOX group (80.8% vs 47.8%, P = 0.016), and there was no significant difference in DCR between the two groups (92.3 vs 82.6%, P = 0.550). The conversion rate in the FLOT group was significantly better than that in the SOX group (80.8% vs 52.2%, P = 0.033). At present, there are significant differences among the reports on the effectiveness of conversion therapy, and the conversion rate as its core indicators is generally 25% ~ 80%. Due to individual differences in conversion therapy, not all patients can benefit from conversion therapy (Kinoshita et al. 2015; Okabe et al. 2009; Sato et al. 2017). In our study, the overall survival time of patients in the FLOT group was significantly prolonged due to the high conversion rate, and the average survival time was 30 months (P = 0.045). By comparing the survival time of patients after surgical treatment in the two groups, it was found that there was no significant difference in the median survival time between the two groups (FLOT vs SOX: 34 months vs 30 months, P = 0.734). It can be supposed that the higher overall survival rate of the FLOT group is mainly contributed by the higher conversion rate of the group, while the conversion rate of the SOX group is significantly lower than that of the FLOT group, making its overall survival time less than that of the FLOT group. According to the postoperative pathological TRG grading, there were 4 patients (19.0%) with grade 1 TRG, 9 patients (42.9%) with grade 2 TRG and 5 patients (23.8%) with grade 3 TRG in the FLOT group; in Sox group, there were 1 (8.3%) patient with TRG grade 1, 2 (16.7%) patients with TRG grade 2, and 4 (33.3%) patients with TRG grade 3. The degree of tumor regression in FLOT group was significantly higher than that in SOX group (P = 0.041). In our study, the efficacy related indicators of patients in the FLOT group, such as the conversion rate, postoperative tumor TRG classification and postoperative survival time, are similar to the results of Sato and other studies. Compared with other conversion therapy regimens, the efficacy of FLOT is relatively ideal, indicating that the FLOT regimen can effectively reduce the clinical staging, improve the conversion rate, and prolong the overall survival time in the treatment of locally unresectable advanced gastric cancer. It is superior to the SOX regimen in terms of efficacy.
The toxicity of chemotherapy drugs is one of the important factors restricting the treatment of locally unresectable advanced gastric cancer. The SOX regimen has a recognized good tolerance due to the use of only two chemotherapy drugs. SYM et al. Used docetaxel + capecitabine + cisplatin in the treatment of unresectable gastric cancer and found that although the combination of three drugs had a high conversion rate (74%) and R0 resection rate (63%), its grade 3 and 4 adverse reactions reached 69%, showing a high toxicity (Sym et al. 2010). A prospective phase II study of 48 patients from Fukushima et al. showed that the incidence of grade 3–4 adverse reactions of docetaxel intraperitoneal injection, cisplatin intravenous injection and oral capecitabine for advanced gastric cancer with peritoneal metastasis was 42% (Ishigami et al. 2018). In our study, the most common hematological side effects in both groups were leukopenia, neutropenia and anemia, and the most common non hematological side effects were peripheral neuropathy, nausea, fatigue and elevated transaminase. The overall incidence of thrombocytopenia (P = 0.041) and fatigue (P = 0.032) in FLOT group was higher than that in SOX group. All kinds of toxic reactions of the two groups were mainly classified as grade I and grade II, and the patients were well tolerated. After clinical symptomatic treatment, the patients could complete the expected chemotherapy regimen. There was no significant difference in the overall incidence of grade III-IV toxicity between FLOT group and SOX group (34.8% vs 50%, p > 0.05). In this study, no patient withdrew from the study due to severe chemotherapy toxicity. It can be indicated that there is no significant difference in the severe toxicity of chemotherapy drugs between the FLOT group and the SOX group.
Local tissue edema and inflammatory reactions after conversion therapy may increase the difficulty of surgery for gastric cancer patients. As a result, the surgical time is prolonged, postoperative wound healing is affected and the incidence of postoperative complications are increased (Gan et al. 2017). ITO and other retrospective analysis showed that the incidence of postoperative complications was 21.4% in patients with stage IV gastric cancer who underwent surgery after conversion therapy (Ito et al. 2006). Liang Ping's study showed that the incidence of postoperative complications in patients with conversion therapy was 33.3% (Liang et al. 2017). In our study, the overall postoperative complications in the FLOT group were 38.1% and 41.7% in the SOX group, with no significant statistical difference between the two groups. We believe that the fibrosis of tumor tissue after conversion therapy leads to unclear space with surrounding organs, increased vascular brittleness and tissue edema, which are the main causes of postoperative complications. After chemotherapy, patients' immunity and nutritional status were reduced, which led to the reduction of postoperative anti infection ability and healing ability, and was also an important reason for postoperative complications.
There are still some limitations in our study. Firstly, because only 49 patients were included in our study, the sample size is small, and the selection bias cannot be well controlled; Secondly, although this study is a control study, it is still a retrospective study, which can only be used as low-level evidence to provide limited reference for the conversion therapy of advanced locally unresectable gastric cancer; Third, the follow-up time of this study is short, which can only evaluate the short-term safety and efficacy, and the long-term prognosis of patients, especially the overall survival time and disease-free survival time of patients in the two groups need to be further observed and compared.