Systematic review and network meta-analyses of third-line treatments for metastatic colorectal cancer

The present study is the first meta-analysis of SIRT, regorafenib, and TAS-102 for patients with chemotherapy-refractory or -intolerant mCRC. Previous meta-analyses have observed similar results for TAS-102 and regorafenib, at a starting dose of 160 mg/day, with no statistically significant difference in OS between the two drug regimens (Abrahao et al. 2018). Although both drugs are associated with increased incidence of treatment-emergent grade 3–4 AEs, the types of AEs associated with each drug are different. Regorafenib is frequently associated with AEs commonly reported for tyrosine kinase inhibitors, such as diarrhea, hand–foot skin reaction, or hypertension, while TAS-102 is more frequently associated with hematological abnormalities, as also evidenced in the present review. Regorafenib was reportedly associated with higher toxicity than TAS-102 overall (Abrahao et al. 2018).

The recently published ReDOS trial of regorafenib, comparing standard administration at a starting dose of 160 mg/day versus dose escalation at a starting dose of 80 mg/day, reported increased OS for the dose escalation strategy with lower incidence of grade 3 adverse events commonly associated with regorafenib (Bekaii-Saab et al. 2019). Based on published meta-analyses and outcomes of the present NMA, it is uncertain whether this OS increase would match the magnitude of clinical benefit observed for SIRT with Y-90 resin microspheres (Sonbol et al. 2019).

A key limitation of the present review was that the included studies of SIRT with Y-90 resin microspheres recruited exclusively subjects with colorectal metastases to the liver (with or without other extrahepatic disease), consistent with the liver-directed nature of the intervention, while studies of systemic treatment with regorafenib or TAS-102 included patients with any metastatic location. This difference in study design warrants caution when comparing median OS outcomes across the studies. This exploratory NMA was undertaken comparing HRs for OS, which are expected to capture differences in baseline characteristics across studies, as patients in the control group of each study of SIRT also have liver-dominant or liver-only metastatic disease. Nevertheless, it is worth noting that the median OS for patients receiving BSC was comparable in all studies, regardless of these differences in selection criteria, and that the lowest median OS was observed in the BSC group of the Seidensticker et al. 2012 study which only included patients with liver-dominant metastases (Seidensticker et al. 2012). This may reflect the prognostic importance of the liver and of liver metastases for patients with chemotherapy-refractory or -intolerant mCRC (Hendlisz et al. 2010).

Although the potential for confounding due to sample selection bias in the observational studies of SIRT included in this review should be noted, OS outcomes were consistent with those reported in large single-arm observational studies of regorafenib, TAS-102 and SIRT using Y-90 resin microspheres (de Groot J 2018; Andersen et al. 2019; Golfieri et al. 2015; Cosimelli et al. 2010; Kennedy et al. 2015; Saxena et al. 2015; Tohme et al. 2014; Lahti et al. 2015; Fendler et al. 2013; Maleux et al. 2016; Sofocleous et al. 2015; Nace et al. 2011). In ten identified studies of SIRT using Y-90 resin microspheres published between 2010 and 2019 which enrolled 50 or more patients with chemotherapy-refractory or -intolerant, liver-dominant colorectal metastases, median OS was between 6.9 and 13.8 months (median 10.2 months, pooled mean 9.9 months, and N = 1476). Sensitivity analysis also showed the findings to be insensitive to substantial increases in the modeled variance around the results from the non-randomized studies, with a fivefold increase in variance still associated with an average OS hazard ratio of 0.62 with SIRT relative to BSC. Other, more sophisticated techniques could have been employed to investigate the effect of including non-randomized studies in the analysis such as third-level hierarchical Bayesian modeling or utilizing data from randomized studies to modify the priors; (Efthimiou et al. 2017; Cameron et al. 2015); however, given that the non-randomized study data were confined to the single network edge comparing SIRT versus BSC, these techniques would have been unlikely to provide further insights into any bias arising from the non-randomized study designs.

Regorafenib and TAS-102 are recommended in ESMO, NCCN, French Intergroup, and Spanish consensus clinical guidelines for patients failing fluoropyrimidine-, oxaliplatin-, and irinotecan-based first- and second-line chemotherapy regimens (Van Cutsem et al. 2016; Benson et al. 2020; Phelip et al. 2019; Vera et al. 2019). SIRT using Y-90 resin microspheres is recommended in the ESMO and French guidelines in a similar setting, for patients with liver-only or liver-dominant colorectal metastases who are refractory or intolerant to chemotherapy, while NCCN guidelines are less specific about the recommended position for SIRT in the therapeutic strategy. These guidelines and the OS outcomes of the present review support offering patients presenting with colorectal liver metastases refractory to first- and second-line chemotherapy treatment with either systemic therapy options or SIRT with Y-90 resin microspheres depending on clinician and patient preference. In considering the mCRC armamentarium, it is worth mentioning the options available to specific sub-groups of patients with mCRC. Patients with BRAF V600E mutant mCRC (approximately 10% of mCRC cases) may be suitable for BRAF targeted therapies, such as encorafenib in combination with cetuximab, which received FDA in this indication after prior therapy in April 2020 (US Food and Drug Administration 2020; Kopetz et al. 2019). Numerous other BRAF pathway inhibitors, including dabrafenib, vemurafenib, and trametinib, are currently undergoing trials either alone or in combination with EGFR and/or MEK inhibitors in patients with BRAF V600E mutant mCRC (Ducreux et al. 2019). Moreover, patients with mismatch repair deficient (dMMR) and/or microsatellite instability-high (MSI-H) (approximately 3–5% of mCRC cases) may benefit from immune checkpoint inhibitors such as pembrolizumab, or nivolumab either alone or in combination with ipilimumab, all of which were approved by the FDA in 2017–2018 for use in patients with dMMR/MSI-H mCRC having progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan (Kamatham et al. 2019; Le et al. 2020; Overman et al. 2018). Enrollment of patients in trials of these and other agents may also be a viable option for patients with advanced mCRC refractory to multiple lines of chemotherapy, with the NCCN specifically noting in the CRC guidelines their belief that “the best management for any patient with cancer is in a clinical trial” (Benson et al. 2020).

With regard to the sequencing of locoregional therapy relative to systemic therapies, Jeyarajah et al. recently published the findings of a Delphi panel of experienced practitioners, including surgical oncologists, transplant surgeons, and hepatopancreatobiliary surgeons, concluding that SIRT with Y-90 microspheres may be effective at multiple points in the algorithm of liver-dominant mCRC management, including the complete treatment of small metastases, as first-line therapy for liver metastases either alone or in combination with chemotherapy, in combination with second- or third-line chemotherapy, and as salvage therapy for chemotherapy-refractory patients. The authors further recommended considering the various positions in therapy alongside the principle that SIRT should be introduced in the treatment algorithm to control liver tumor progression before the liver has been damaged severely by chemotherapy (Jeyarajah et al. 2020).

From a clinical perspective, the adverse event profiles of each agent, along with patient performance status, are likely to determine treatment choice (Argiles et al. 2019). While ECOG performance statuses 1–2 are considered negative prognostic factors for each intervention, the adverse event profile of SIRT using Y-90 resin microspheres is superior to both regorafenib and TAS-102, with a low incidence of all-grade or grade 3–4 AEs known to severely affect patient quality of life, such as diarrhea, hand–foot skin reaction, vomiting, or fatigue. The adverse event profile of SIRT is well established, and risk of complications from the procedure can be reduced with adequate treatment planning and patient selection (Sangro et al. 2017). SIRT may, therefore, be preferred in selected patients with colorectal liver metastases refractory to first- and second-line chemotherapy, especially when the AE profile of TAS-102 and regorafenib represents a disincentive for treatment with these agents. The incidence of the five potentially SIRT-related AEs recorded in the present study was low, with only grade 3+ REILD and grade 1–2 GI ulcer showing incidence rates above 5% in one study each.

Liver-related laboratory test abnormalities were not reported in a consistent manner across the included studies, and a meaningful analysis or presentation was not possible. A previous study of 606 patients with mCRC undergoing SIRT showed that a high proportion of patients had mild-to-moderate (mostly grade 1 or 2) baseline laboratory abnormalities prior to SIRT with Y-90 resin microspheres, including alkaline phosphatase, AST, albumin, and hemoglobin (Kennedy et al. 2015). While the study showed clinically significant increases in severe (grade 3 and 4) laboratory test values for total bilirubin, albumin, alkaline phosphatase, and aspartate aminotransferase after SIRT with Y-90 microspheres, all incidence rates were below 10% 90 days after treatment (Kennedy et al. 2015).

In indications such as mCRC in which patients are facing a poor prognosis with limited therapeutic options, the availability of locoregional options such as SIRT in addition to regorafenib and TAS-102 addresses a great unmet clinical need, especially in RAS mutant patients for whom anti-EGFR agents such as cetuximab or panitumumab are ineffective (Van Cutsem et al. 2015). Effective physician–patient communication is an essential element in ensuring appropriate treatment selection, and for setting expectations for treatment outcomes and adverse event incidence. As both regorafenib and TAS-102 are orally administered, patient adherence to the choice of treatment is also essential (Argiles et al. 2019). From the patient perspective, SIRT using Y-90 resin microspheres represents a relevant alternative with lower administration burden for the patient and no degradation of quality of life (Cosimelli et al. 2010). The adverse event profile of SIRT using Y-90 resin microspheres has also been established across the non-comparative evidence base in this indication for patients intolerant to chemotherapy and/or patients aged ≥ 70 years (Golfieri et al. 2015; Cosimelli et al. 2010; Kennedy et al. 2015; Saxena et al. 2015; Tohme et al. 2014; Lahti et al. 2015; Fendler et al. 2013; Maleux et al. 2016; Sofocleous et al. 2015; Nace et al. 2011).