PMC:6909918 / 19589-30249 JSONTXT

{"project":"2_test","denotations":[{"id":"31790382-23177514-69134723","span":{"begin":228,"end":229},"obj":"23177514"},{"id":"31790382-25970050-69134723","span":{"begin":228,"end":229},"obj":"25970050"},{"id":"31790382-29215955-69134723","span":{"begin":228,"end":229},"obj":"29215955"},{"id":"31790382-29946728-69134723","span":{"begin":228,"end":229},"obj":"29946728"},{"id":"31790382-25981818-69134724","span":{"begin":232,"end":234},"obj":"25981818"},{"id":"31790382-23177514-69134725","span":{"begin":374,"end":375},"obj":"23177514"},{"id":"31790382-25970050-69134726","span":{"begin":430,"end":431},"obj":"25970050"},{"id":"31790382-29215955-69134727","span":{"begin":557,"end":558},"obj":"29215955"},{"id":"31790382-29946728-69134728","span":{"begin":698,"end":699},"obj":"29946728"},{"id":"31790382-25981818-69134729","span":{"begin":828,"end":830},"obj":"25981818"},{"id":"31790382-27932229-69134730","span":{"begin":2323,"end":2325},"obj":"27932229"},{"id":"31790382-23177515-69134731","span":{"begin":2378,"end":2380},"obj":"23177515"},{"id":"31790382-27325864-69134732","span":{"begin":2412,"end":2414},"obj":"27325864"},{"id":"31790382-23177514-69134733","span":{"begin":2918,"end":2919},"obj":"23177514"},{"id":"31790382-29946728-69134734","span":{"begin":2920,"end":2921},"obj":"29946728"},{"id":"31790382-23177514-69134735","span":{"begin":3421,"end":3422},"obj":"23177514"},{"id":"31790382-29946728-69134736","span":{"begin":3527,"end":3528},"obj":"29946728"},{"id":"31790382-17485136-69134737","span":{"begin":3675,"end":3677},"obj":"17485136"},{"id":"31790382-28740665-69134738","span":{"begin":3678,"end":3680},"obj":"28740665"},{"id":"31790382-29946728-69134739","span":{"begin":4385,"end":4386},"obj":"29946728"},{"id":"31790382-30950859-69134740","span":{"begin":4799,"end":4801},"obj":"30950859"},{"id":"31790382-30736738-69134741","span":{"begin":4984,"end":4986},"obj":"30736738"},{"id":"31790382-30736738-69134742","span":{"begin":5080,"end":5082},"obj":"30736738"},{"id":"31790382-29174481-69134743","span":{"begin":5808,"end":5809},"obj":"29174481"},{"id":"31790382-29215955-69134744","span":{"begin":5967,"end":5968},"obj":"29215955"},{"id":"31790382-25981818-69134745","span":{"begin":6087,"end":6089},"obj":"25981818"},{"id":"31790382-29174481-69134746","span":{"begin":6546,"end":6547},"obj":"29174481"},{"id":"31790382-29215955-69134747","span":{"begin":6821,"end":6822},"obj":"29215955"},{"id":"31790382-31278474-69134748","span":{"begin":6977,"end":6978},"obj":"31278474"},{"id":"31790382-31278474-69134749","span":{"begin":7219,"end":7220},"obj":"31278474"},{"id":"31790382-29174481-69134750","span":{"begin":7738,"end":7739},"obj":"29174481"},{"id":"31790382-31278474-69134751","span":{"begin":7740,"end":7741},"obj":"31278474"},{"id":"31790382-25970050-69134752","span":{"begin":7793,"end":7794},"obj":"25970050"},{"id":"31790382-29215955-69134753","span":{"begin":7817,"end":7818},"obj":"29215955"},{"id":"31790382-28894015-69134754","span":{"begin":8092,"end":8094},"obj":"28894015"},{"id":"31790382-28894015-69134755","span":{"begin":8388,"end":8390},"obj":"28894015"},{"id":"31790382-28894015-69134756","span":{"begin":8478,"end":8480},"obj":"28894015"},{"id":"31790382-25981818-69134757","span":{"begin":9649,"end":9651},"obj":"25981818"},{"id":"31790382-29215955-69134758","span":{"begin":9674,"end":9675},"obj":"29215955"},{"id":"31790382-29946728-69134759","span":{"begin":9762,"end":9763},"obj":"29946728"}],"text":"Discussion\nFollowing a systematic review of the literature, five published randomized placebo-controlled clinical trials (RCTs) were identified, which included 2,604 patients with refractory metastatic colorectal cancer (mCRC) [4–7,11]. The five published RCTs that underwent meta-analysis included the CORRECT Trial, of regorafenib monotherapy for previously treated mCRC [4], the RECOURSE Trial, of TAS-102 for refractory mCRC [5], the TERRA phase III trial, of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated mCRC [6], the FRESCO Trial, of the effect of fruquintinib compared with placebo on overall survival (OS) in patients with previously treated mCRC [7], and the CONCUR trial, of regorafenib plus best supportive care versus placebo in Asian patients with previously treated mCRC [11].\nThe results of the systematic review and network meta-analysis of the five identified RCTs showed that fruquintinib was associated with significant superiority for progression-free survival (PFS) and disease control rate (DCR) when compared with TAS-102 in patients with refractory mCRC. However, there was no significant difference from the indirect comparison of overall survival (OS) or the objective response rate (ORR) between regorafenib, fruquintinib, and TAS-102. Fruquintinib showed a significantly higher risk of serious adverse events (SAEs) when compared with TAS-102 or regorafenib. However, there were no significant differences in the risk in adverse events (AEs) at any grade, or fatal adverse events (FAEs) in the indirect comparison of fruquintinib, regorafenib, and TAS-102.\nIn previously treated patients with mCRC, drugs such as fruquintinib, regorafenib, and TAS-102 may be associated with different clinical outcomes due to their different molecular mechanisms. Fruquintinib is a potent, highly selective small-molecule inhibitor of vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, and VEGFR-3, and is an anti-angiogenic compound. However, regorafenib is a targeted pan-kinase inhibitor for the VEGFR family, and for fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), KIT, RET, and BRAF. Regorafenib was designed as salvage therapy in previously treated malignances, including hepatocellular carcinoma (HCC) [12], advanced gastrointestinal stromal tumors (GISTs) [13], and advanced gastric cancer [14]. TAS-102 is an orally administered combination of a thymidine-based nucleic acid analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride and is a chemotherapy agent. Although the mechanism of the anti-tumor effects in the three agents, fruquintinib, regorafenib, and TAS-102 is different, positive outcome data in patients with refractory mCRC was previously demonstrated in RCTs and provided the evidence to support their recommended use in current clinical guidelines [4,7].\nIn the present study, indirect comparisons of the three drugs showed that fruquintinib demonstrated a significant superiority for PFS when compared with TAS-102, with a similar finding also shown in the indirect comparison of DCR. These improved outcomes suggested that fruquintinb might be a better choice in selected pretreated patients with mCRC. Also, this study showed that the Eastern Cooperative Oncology Group Performance Status (ECOG PS) status of patients included in the CORRECT trial [4] (regorafenib, PS=0; 56.0%) was significantly improved when compared with patients in the FRESCO trial [7] (fruquintinib, PS=0; 27.4%).\nThe aim of this study was to independently determine the prognostic value of performance status in cancer patients [15,16], and apply this to patients with refractory mCRC. The findings from this study indicated that fruquintinib might be more effective in the control of refractory mCRC as a further treatment option. Although a significant improvement in OS was not shown from the indirect comparison of fruquintinib and TAS-102, the poorer performance status of patients treated with fruquintinib might have been responsible for this finding. However, definitive recommendations for the choice of treatment will only be determined by future head-to-head comparative clinical studies to compare fruquintinib and TAS-102.\nA finding of interest in this study was the finding that 30% of patients included in the FRESCO trial [7] had previously received anti-VEGFR treatment. The positive results from the effects of treatment with fruquintinib compared with placebo suggested that the further use of anti-VEGFR therapy in further lines of treatment may lead to increased benefits in patients with mCRC, which supports a previously reported finding [17]. The phenomenon was also observed in patients with non-small cell lung cancer (NSCLC) [18]. A similar finding was previously reported for the use of a tyrosine kinase inhibitor (TKI) in a patient with NSCLC who had been resistant to first-line treatment with an EGFR-TKI [19]. The patient subsequently had a positive response to TKI treatment in further-line therapy [19]. Therefore, re-challenge of previous treatment in the further-line therapy might be of value in selected patients with advanced or metastatic carcinomas, especially in patients with good ECOG PS (PS=0,1). Spatiotemporal heterogeneity of tumor proliferation and differentiation might have a role in this phenomenon. However, the specific mechanism of the positive results associated with drug re-challenge remains to be investigated.\nThe present study also included network meta-analysis of the indirect comparison between regorafenib and TAS-102. No significant differences were observed between regorafenib and TAS-102 in terms of OS. The results were consistent with the findings from a previously reported meta-analysis [8]. However, the present study was different from previous meta-analysis studies in several ways. Firstly, this study included an analysis of the TERRA trial [6], which investigated TAS-102 and was conducted in an Asian patient population with refractory mCRC. The CONCUR trial [11], which investigated regorafenib, was conducted in Asian patient population. Inclusion of both trials in the present study may have reduced any analysis bias in the indirect comparison. Secondly, the safety profiles of the indirect comparison of regorafenib and TAS-102 was different in this study and the previously published meta-analysis, which showed that regorafenib resulted in significantly higher toxicity at all grades when compared with TAS-102 [8]. The safety profile outcomes for regorafenib, fruquintinib, and TAS-102 in the present study showed no significant difference in AEs at any grade, SAEs, or FAEs between regorafenib and TAS-102 (Figure 9). This finding may have been due to the addition of the TERRA trial [6].\nA further and more recently published meta-analysis compared the efficacy and safety of regorafenib with fruquintinib in pretreated patients with mCRC [9]. The findings showed that fruquintinib showed no significant difference on OS compared with regorafenib, and there was a trend for superiority in PFS of fruquintinib compared with regorafenib, which did not reach statistical significance [9]. In the present study, there was no significant difference in PFS in the indirect comparison of fruquintinib and regorafenib. Also, there was no significant difference in OS in the indirect comparison of fruquintinib with regorafenib, of in PFS or OS in the indirect comparison between fruquintinib and regorafenib. Therefore, in the present meta-analysis, although the inclusion of four RCTs showed similar outcomes for regorafenib, and fruquintinib in patients with refractory mCRC to previous meta-analysis data [8,9], the addition of TAS-102 with the RECOURSE trial [5] and the TERRA trial [6] provided more comprehensive data and findings.\nIn 2018, the findings from a large, retrospective, multicenter, observational study compared the efficacy of regorafenib with fruquintinib (REGOTAS) in pretreated patients with mCRC, using subgroup propensity score analysis [20]. Although there were no differences in OS between regorafenib and TAS-102 (HR, 0.96; 95% CI, 0.78–1.18), adjusted analysis, using a propensity score, showed that regorafenib resulted in improved survival in patients aged \u003c65 years, and fruquintinib improved survival patients aged ≥65 years [20]. Also, the incidence of SAEs and FAEs were similar for regorafenib with fruquintinib [20]. The findings from this previous observational study were consistent with the findings from the present study, which also used an indirect comparison of fruquintinib and regorafenib and showed no significant difference in PFS or OS. However, the present study showed that the incidence of SAEs was reduced in patients treated with regorafenib when compared with fruquintinib, which might indicate that regorafenib may be safer in symptomatic patients with mCRC. The indirect comparison of AEs, SAEs, and FAEs for regorafenib, fruquintinib, and TAS-102 showed that the only significant difference was found for SAEs, and showed that the incidence of SAEs was more common in patients treated with fruquintinib compared with regorafenib, or TAS-102. This is an important finding for clinicians to be aware of who treat patients with mCRC. Otherwise, no differences were found from the indirect comparison in AEs at any grade or FAEs between fruquintinib, regorafenib, and TAS-102.\nThis study had several limitations. The network meta-analysis identified study heterogeneity, which might be explained by the racial differences in the study populations. The CONCUR trial [11] and the TERRA trial [6] were conducted in patients with mCRC from Asian populations, while the FRESCO trial [7] was conducted only in patients in China. Although a subgroup pooled analysis was performed to compare the efficacy of regorafenib, TAS-102, and fruquintinib in Asian patients with refractory mCRC, future global, multicenter, prospective, randomized studies may still be required. In addition, the type of AEs was not detailed in the presentation of the outcome data. Further studies should be considered to detail the comparisons of toxicities for fruquintinib, regorafenib, and TAS-102. Detailed clinicopathological data that included aspects of past medical history, comorbidities, and other drug treatments were not analyzed in the present study. These demographic and clinicopathological factors may be of interest in future studies. Finally, although there was no significant publication bias shown by the funnel plot, the existence of potential publication bias may not have been excluded."}