Characteristics of studies based on the selection criteria, eleven studies with 768 patients were considered, 400 of whom (52.08%) were male and whose ages varied from 56 to 68 years [10–20]. Advanced GISTs patients would at least have undergone systemic antineoplastic therapy with imatinib and sunitinib. Two RCTs and nine prospective and retrospective studies with sample sizes ranging from 18 to 236 were found in this systematic review. The whole selection procedure was shown in Fig. 1. Regorafenib 160 mg/day was administered in four-week cycles with three weeks on and one week off, as the standard of care in all investigations. Demetri et al evaluated the regorafenib compared to the placebo for patients with advanced GISTs [11]. Another RCT performed by Kang et al evaluated the avapritinib versus regorafenib [19]. These studies were published between 2012 and 2022. More thorough research data are shown in Table 1.
Table 1
Basic characteristics of included literatures M male, F Female, CB clinical benefit, PR partial response, SD stable disease, mPFS median progression-free survival, mOS median overall survival, AEs adverse events, NA Not available
First author (year) | Country | Trial phase | Sample size | Sex (M/F) | Age (years) Median (rang) | Regorafenib does (mg/day) | Previous treatment | Outcoms |
George S, et al (2012) | Multicenter | phase II | 33 | 19/14 | 56(25–76) | 160mg,3-weeks-on, 1-week-off | imatinib sunitinib | CB, PR, SD, mPFS, AEs |
Demetri GD, et al (2012) | Multicenter | phase III | 133 | 85/48 | 60(51–67) | 160mg,3-weeks-on, 1-week-off | imatinib sunitinib | CB, SD, mPFS, AEs |
Kollàr A, et al (2014) | UK | retrospective study | 20 | 13/7 | 68(45–87) | 160mg,3-weeks-on, 1-week-off | imatinib sunitinib | CB, PR, SD, mPFS, OS, AEs |
Ben-Ami E, et al (2016) | Multicenter | phase II | 33 | 19/14 | 56(25–76) | 160mg,3-weeks-on, 1-week-off | imatinib sunitinib | CB, PR, SD, mPFS,OS, AEs |
Son MK, et al (2016) | Korea | prospective study | 57 | 34/23 | 56(50–62) | 160mg,3-weeks-on, 1-week-off | imatinib sunitinib | CB, SD, mPFS, OS, AEs |
Yeh CN et al (2017) | Taiwanese | phase II | 18 | 14/4 | 59(36–71) | 160mg,3-weeks-on, 1-week-off | imatinib sunitinib | CB, PR, SD, mPFS, AEs |
Kim JJ, et al (2019) | Korea | phase II | 25 | 21/4 | 60(42–74) | 100mg daily for 28 days | imatinib sunitinib | CB, PR, SD, mPFS, AEs |
Hu CH, et al (2020) | Taiwanese | prospective study | 28 | 20/8 | 61(36–71) | 160mg,3-weeks-on, 1-week-off | imatinib sunitinib | CB, PR, SD, mPFS, mOS AEs |
Nannini M, et al (2021) | Multicenter | retrospective study | 49 | NA | 58(19–78) | 160mg,3-weeks-on, 1-week-off | imatinib sunitinib | mPFS, OS |
103 | NA | personalized schedules | |
Kang YK, et al (2022) | Multicenter | phase III | 236 | 156/80 | 62(31–86) | 160mg,3-weeks-on, 1-week-off | imatinib sunitinib | PR, SD, mPFS, AEs |
Teranishi R, et al (2022) | Japanese | retrospective study | 33 | 19/14 | 62(26–81) | 160mg,3-weeks-on, 1-week-off | imatinib sunitinib | PR, SD, mPFS, mOS, AEs |
Risk Of Bias Assessment
The Cochrane Collaboration's tool classified the total bias risk of each study as "low" when more than four items classified as "low risk" were considered applicable, "moderate" when two to three items were considered applicable, and "high" when fewer than two "low risk" items or more than one "high risk" item were considered applicable. Two included RCTs were well designed and had a low bias risk by the Cochrane Collaboration’s tool (Fig. 2A). Except for Son's and Yeh's studies [14, 15], which had a high bias risk and a moderate bias risk, the other non-randomized studies contained trials that were carefully planned and had a low bias risk according to the ROBINS-I tool (Fig. 2B).
Sensitivity Analyses
Galbraith plot was performed the heterogeneity sources, we can observe that all points fall inside the interior of the confidence interval regression line in Galbraith plot (Fig. 3B-Fig. 9B). With the exception of SD and mPFS, where three studies [12, 14, 15] with conflicting directions of association were included, we conducted sensitive analysis by removing one study at a time and discovered that no study had significant effects on any of the major outcomes (Fig. 3C-Fig. 9C).
Efficacy Outcomes
The summary of pooled ORs for the efficacy of regorafenib in advanced GISTs after imatinib and sunitinib failure was reported in Fig. 3- Fig. 9. Among the studies, significant heterogeneity was observed for the CB rate (I2 = 85.81%, P = 0.00; Z = 9.59, p < 0.001) (Fig. 3A) and SD rate (I2 = 91.54%, P = 0.00; Z = 9.48, p < 0.001) (Fig. 5A); thus, the random-effects model was used for pooling data. Since there no significant heterogeneity (I2 = 20.47%, P = 0.27; Z = 6.54, p < 0.001) (Fig. 4A) was observed for the PR rate; hence, the fixed-effects model was used. The pooled results showed that approximately 67% (95%CI 53–80, Fig. 3A), 9% (95%CI 6–12, Fig. 4A), and 60% (95%CI 48–73, Fig. 5A) of patients with GISTs attained CB, PR, and SD rate respectively after regorafenib treatment, which was given after failure with imatinib and sunitinib treatments. Further study revealed that Kollàr’s study had effects on the major outcomes (Fig. 5C). When this study was deleted, the SD rate results showed that approximately 57% (95%CI 48–65, Fig. 8A). The mPFS was determined for all eleven studies, and significant heterogeneity (I2 = 97.9%, P = 0.00; Z = 5.27, p < 0.001) was observed among the studies. This meta-analysis revealed that the pooled mPFS was 8.59 months (95%CI 5.40-11.78, Fig. 6A) in patients after regorafenib treatment. Further study showed that Son’s and Yeh’s studies had an impact on the key results (Fig. 6C). When studies were deleted, the pooled mPFS results was 7.18 (95%CI 5.87–8.50, Z = 10.68, p < 0.001; Fig. 9A). The pooled mOS was determined for 4 studies, and significant heterogeneity (I2 = 98.9%, P = 0.00; Z = 4.61, p < 0.001) was observed among the studies also. This meta-analysis revealed that the pooled mOS was 19.67 months (95%CI 11.32–28.03; Fig. 7A) in patients after regorafenib treatment, which was given after failure with imatinib and sunitinib treatments.
Risk Of Aes
The pooled analysis of the studies revealed that the incidence of any grade toxicities related to the treatment of GISTs by regorafenib was 97% (OR = 0.97; 95%CI, 0.96–0.98; I2 = 0.00%, Z = 144.09, p < 0.001). Regarding specific AEs, hand-foot syndrome was the most common AE (77%, OR = 0.77; 95%CI, 0.66–0.88; I2 = 90.43%, Z = 14.00, p < 0.001), followed by fatigue (55%, OR = 0.55; 95%CI, 0.41–0.69; I2 = 90.90%, Z = 7.83, p < 0.001), hypertension (53%, OR = 0.53; 95%CI, 0.34–0.72; I2 = 96.35%, Z = 5.56, p < 0.001), anemia (53%, OR = 0.53; 95%CI, 0.03–1.03; I2 = 99.27%, Z = 2.06, p = 0.04), thrombocytopenia (53%,OR = 0.53; 95%CI, 0.02–1.04; I2 = 98.29%, Z = 2.02, p = 0.04), liver damage (52%, OR = 0.52; 95%CI, 0.30–0.74; I2 = 77.01%, Z = 4.64, p < 0.001), diarrhea (43%, OR = 0.43; 95%CI, 0.33–0.53; I2 = 83.34%, Z = 8.40, p < 0.001) and hypophosphatemia (42%, OR = 0.42; 95%CI, 0.30–0.54; I2 = 0.00%, Z = 6.98, p < 0.001), hoarseness (34%, OR = 0.34; 95%CI, 0.18–0.51; I2 = 95.84%, Z = 4.06, p < 0.001), oral mucositis (31%, OR = 0.31; 95%CI, 0.21–0.41; I2 = 85.01%, Z = 5.96, p < 0.001), hypothyroidism (30%, OR = 0.30; 95%CI, 0.12–0.48; I2 = 54.73%, Z = 3.22, p < 0.001), eta. The rate of specific AEs was listed in Table 2. In addition, the pooled analysis of the studies revealed that specific grade3-4 toxicities were 59% (OR = 0.59; 95%CI, 0.52–0.66; I2 = 62.91%, Z = 16.38, p < 0.001), among which the incidence of hand-foot syndrome, hypertension and hypophosphatemia was 20% (OR = 0.20; 95%CI, 0.16–0.24; I2 = 31.93%, Z = 13.22, p = 0.15), 16%(OR = 0.16; 95%CI, 0.10–0.22; I2 = 70.61%, Z = 30.62, p < 0.001) and 13%(OR = 0.13; 95%CI, 0.05–0.22; I2 = 0.00%, Z = 0.13, p = 0.72). It was common AEs of GISTs grade3-4 toxicities treated by regorafenib after the failure of imatinib and sunitinib. The rate of specific grade3-4 toxicities was listed in Table 3.
Table 2
Risk of specific adverse events AEs adverse events, OR odds ratio, CI confidence intervals
Any grade | No of study | Rate of AEs (%) | Pooled OR 95% CI | I 2 (%) | Z | p |
Hand-foot syndrome | 10 | 0.77 | 0.66–0.88 | 90.43 | 14.00 | < 0.001 |
Fatigue | 9 | 0.55 | 0.41–0.69 | 90.90 | 7.83 | < 0.001 |
Hypertension | 10 | 0.53 | 0.34–0.72 | 96.35 | 5.56 | < 0.001 |
Anemia | 4 | 0.53 | 0.03–1.03 | 99.27 | 2.06 | 0.04 |
Thrombocytopenia | 3 | 0.53 | 0.02–1.04 | 98.29 | 2.02 | 0.04 |
Liver damage | 3 | 0.52 | 0.30–0.74 | 77.01 | 4.64 | < 0.001 |
Diarrhea | 10 | 0.43 | 0.33–0.53 | 83.34 | 8.40 | < 0.001 |
Hypophosphatemia | 2 | 0.42 | 0.30–0.54 | 0.00 | 6.98 | < 0.001 |
Hoarseness | 8 | 0.34 | 0.18–0.51 | 95.84 | 4.06 | < 0.001 |
Oral mucositis | 9 | 0.31 | 0.21–0.41 | 85.01 | 5.96 | < 0.001 |
Hypothyroidism | 2 | 0.30 | 0.12–0.48 | 54.73 | 3.22 | < 0.001 |
Myalgia | 7 | 0.29 | 0.17–0.41 | 85.41 | 4.61 | < 0.001 |
Headache | 4 | 0.29 | 0.10–0.47 | 85.58 | 3.09 | < 0.001 |
Anorexia | 9 | 0.26 | 0.20–0.31 | 53.74 | 8.57 | < 0.001 |
Abdominal pain | 2 | 0.26 | 0.15–0.37 | 0.00 | 4.49 | < 0.001 |
Alopecia | 7 | 0.24 | 0.14–0.34 | 81.4 | 4.53 | < 0.001 |
Nausea | 6 | 0.22 | 0.14–0.29 | 70.75 | 5.80 | < 0.001 |
Rash, maculopapular | 5 | 0.20 | 0.15–0.24 | 11.75 | 8.13 | < 0.001 |
Constipation | 5 | 0.19 | 0.14–0.23 | 46.51 | 7.98 | < 0.001 |
Voice alteration | 2 | 0.19 | 0.00-0.41 | 74.71 | 1.75 | 0.08 |
Arthralgia | 2 | 0.18 | 0.06–0.30 | 34.68 | 2.88 | < 0.001 |
Hyperbilirubinemia | 2 | 0.17 | 0.12–0.22 | 0.00 | 7.28 | < 0.001 |
Decreased weight | 3 | 0.15 | 0.08–0.21 | 53.97 | 4.29 | < 0.001 |
Sensory neuropathy | 2 | 0.15 | 0.07–0.22 | 0.00 | 3.74 | < 0.001 |
Vomiting | 4 | 0.12 | 0.06–0.18 | 52.51 | 3.92 | < 0.001 |
Palpitation | 2 | 0.08 | 0.00-0.16 | 0.00 | 2.05 | 0.04 |
Hepatobiliary toxicity | 2 | 0.05 | 0.02–0.08 | 0.00 | 3.63 | < 0.001 |
Table 3
Risk of specific grade3-4 toxicities
Grade3-4 | No of study | Rate of AEs (%) | Pooled OR 95% CI | I 2 (%) | Z | p |
Hand-foot syndrome | 10 | 0.20 | 0.16–0.24 | 31.93 | 13.22 | 0.15 |
Hypertension | 10 | 0.16 | 0.10–0.22 | 70.61 | 30.62 | < 0.001 |
Hypophosphatemia | 2 | 0.13 | 0.05–0.22 | 0.00 | 0.13 | 0.72 |
Hepatobiliary toxicity | 4 | 0.09 | 0.03–0.15 | 11.67 | 3.40 | 0.33 |
Diarrhea | 5 | 0.06 | 0.04–0.09 | 0.00 | 3.49 | 0.48 |
Anemia | 3 | 0.05 | 0.00-0.11 | 36.23 | 3.14 | 0.21 |
Fatigue | 7 | 0.04 | 0.02–0.05 | 0.00 | 2.76 | 0.84 |
Rash, maculopapular | 5 | 0.04 | 0.01–0.07 | 12.58 | 4.58 | 0.33 |
Abdominal pain | 2 | 0.03 | 0.00-0.08 | 0.00 | 0.04 | 0.84 |
Anorexia | 2 | 0.02 | 0.00-0.05 | 0.00 | 0.14 | 0.71 |
Oral mucositis | 3 | 0.01 | 0.00-0.02 | 0.00 | 0.96 | 0.62 |
Myalgia | 3 | 0.01 | 0.00-0.02 | 0.00 | 0.76 | 0.68 |
Nausea | 3 | 0.01 | 0.00-0.01 | 0.00 | 0.85 | 0.65 |
Vomiting | 3 | 0.01 | 0.00-0.03 | 0.00 | 0.37 | 0.83 |
AEs adverse events, OR odds ratio, CI confidence intervals |