Apatinib combined with SOX regimen for conversion therapy in advanced gastric cancer patients: a retrospective cohort study

Clinical factors of patients

By the end of the study, a total of 50 patients were enrolled in the study. Figure 2 shows the process of patient enrollment. Table 1 shows the baseline characteristics of these 50 patients. Of these patients, there were 31 males and 19 females, with a median age of 64 years. 21 of these patients were in SOX combined with apatinib conversion group, other 29 patients in SOX conversion group. The whole conversion chemotherapy lasted about 3–6 cycles, and the median treatment time was 4 cycles. Apatinib was generally stopped 4 or 6 weeks before operation.

Fig. 2figure 2

Flow diagram. SOX S-1/oxaliplatin

Table 1 Patient characteristicsClinical effects analysis of apatinib

We first evaluated apatinib combined with SOX regimen conversion group and SOX regimen conversion group to research the role of apatinib in conversion surgery and the effect of targeted therapy combined with chemotherapy on the prognosis of inoperable GC patients. In the SOX plus apatinib group, 15 patients achieved partial remission (PR) and 4 patients received stable disease (SD). Thus, the ORR were 71.4% (15/21), and the DCR was 90.5% (19/21). In the SOX group, 16 patients achieved PR and 9 patient was SD, the ORR was 55.2% (16/29), the DCR was 86.2% (25/29). Although the ORR and DCR of SOX combined with apatinib treatment group were higher than those of SOX alone group, the difference was not statistically significant (Table 2). We statistically analyzed all patients who received conversion therapy, whether combination therapy or chemotherapy alone. The ORR and DCR of the conversion therapy were 62% (31/50) and 88.0% (44/50), respectively.

Table 2 preoperative chemotherapy response of patients who accepted two kinds of conversion chemotherapy regimenConversion rate analysis of apatinib

Of all 50 patients, 33 underwent surgery, with an overall conversion rate of 66% (33/50). Among them, there were 16 patients in the SOX plus apatinib group, and the conversion rate was 76.2% (16/21), which was higher than 58.6% (17/29) in the SOX alone group. There was not significant difference between the two groups (p = 0.196). During the conversion operation, 13 patients in apatinib combined with SOX regimen conversion group achieved R0 resection of GC, 3 patients failed to achieve R0 resection, the R0 resection rates were 81.3% (13/16), while 17 patients in SOX regimen conversion group, R0 resection was achieved in 7 patients and 10 patients failed to achieve R0 resection, so the R0 resection rates were 41.2% (7/17). The R0 resection rate in SOX plus apatinib group was higher than that in SOX alone group, which was statistically significant (p = 0.032, Fig. 3).

Fig. 3figure 3

The R0 resection rates of patients who underwent conversion surgery (*p < 0.05)

In order to further analyze the curative efficacy of conversion therapy, we combined the patients who successfully underwent surgery after conversion therapy into the conversion therapy success group, and the patients who did not receive surgical treatment for various reasons were divided into the conversion therapy failure group. We analyzed the changes of tumor markers CEA and CA19-9 in conversion therapy success group and conversion therapy failure group respectively (Fig. 4). The results showed that after successful conversion therapy, compared with the baseline level, the level of CEA decreased significantly (p < 0.0001, Fig. 4a). Similarly, in conversion therapy success group, the CA199 level also decreased compared with the baseline level after conversion therapy (p = 0.045, Fig. 4a). However, in the conversion therapy failure group, compared with the baseline level, the tumor markers CEA and CA199 had an upward trend, but there was no statistical difference (p = 0.344; p = 0.242. Figure 4b).

Fig. 4figure 4

CEA and CA19-9 at different stages. a CEA and CA19-9 level change in the successful conversion group. A, B, and C represent the CEA level at baseline, before and after operation, respectively. F, G, and H represent the CA19-9 level at baseline, before and after operation, respectively. b CEA and CA19-9 level change in the failed group. D and E represent the CEA level at baseline and at the end of conversion therapy, respectively. I and J represent the CA19-9 level at baseline and at the end of conversion therapy, respectively. (***p < 0.001; ns, no significance)

Survival analysis

Overall survival curves are shown in Fig. 5. In the conversion therapy success group, 16 patients received SOX combined with apatinib, while 17 patients received SOX alone. The median PFS of patients treated with SOX plus apatinib and SOX were 25.5 months (95% CI 21.1–28.9) and 16 months (95% CI 8.4–23.6), respectively (p = 0.0455, Fig. 5A); the median OS was 34.0 (95% CI 25.2–40.8) versus 23.0 (95% CI 16.3–29.7) months (p = 0.0477, Fig. 5B). Among the 33 patients treated with surgery, the median OS and PFS of 20 patients who underwent R0 resection were 35.5 months (95% CI 28.4–41.6) and 27 months (95% CI 19.8–32.2), respectively. The median OS and PFS of 13 patients who received non-R0 resection were 19 months (95% CI 14.8–23.2) and 10 months (95% CI 7.5–12.3), respectively. R0 resection resulted in significantly longer OS and PFS than non R0 resection (p < 0.0001 Fig. 5C, D). In order to evaluate whether conversion therapy can really bring survival benefits, we contrasted the survival data of the conversion therapy success group and conversion therapy failure group. The results showed that the median OS and PFS of patients in the conversion therapy success group were significantly longer than those in the conversion therapy failure group (median OS, 29.0, 95% CI 24.3–33.7 vs 14.0, 95% CI 10.2–17.8 months; p < 0.0001; median PFS, 21.0, 95% CI 15.4–26.6 vs 4.6, 95% CI 3.9–5.3 months; p < 0.0001, Fig. 5E, F).

Fig. 5figure 5

Kaplan–Meier survival curves. A, B PFS and OS between patients received SOX plus apatinib and SOX in conversion therapy. C, D PFS and OS of R0 resection, non-R0 resection and conversion failure group. E, F PFS and OS of conversion success group and conversion failure group. PFS, progression-free survival; OS, overall survival; SOX, oxaliplatin/S-1

Safety

Adverse events (AEs) were assessed in 50 patients. All patients experienced different degrees of AEs. The common treatment-related side reaction in SOX combined with apatinib conversion group were vomiting (47.6%), neutropenia (42.9%), leucopenia (33.3%), and oral mucositis (23.8%), of which grade 3–4 adverse reactions accounted for 22.4% (11/49) of any grade adverse reactions. In the SOX conversion group, the common treatment-related AEs at any level were vomiting (48.3%), neutropenia (37.9%), leucopenia (31.0%), and 26.5% of patients suffered from 3–4 AEs. However, there was no significant difference between the two groups in the toxicity level of the conversion therapy regimen (Table 3). AEs associated with apatinib treatment include oral mucositis (23.8%), hypertension (19.0%) and hand-foot syndrome (19.0%), of which the incidence of serious AEs is low, including hypertension (n = 1, 4.8%) and hand-foot syndrome (n = 1, 4.8%).

Table 3 Incidence of treatment-related adverse events of two treatment regimens during preoperative treatment

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