Discussion
toxicity, toxicities
SYNDROME
The STREAM study sought at evaluating regorafenib as a second-line therapy of Firstly, despite the short median PFS observed in the STREAM study, an encouraging OS of 18.9 months was reported, especially if compared to clinical outcomes reported in Moreover, despite the short PFS, regorafenib did not impair subsequent treatment outcomes. Overall, 37 patients (80.4%) received a third-line therapy, yielding a favorable median PFS2 of 13.3 months. In line with these results, preclinical data have suggested that regorafenib may play a role in chemosensitization. The observed synergy involves the proapoptotic protein PUMA and the modulation of drug transporters such as ABCB1, affecting the concentration of cytotoxic drugs in the tumor-associated microenvironment.Collectively, this evidence might not completely exclude the use of regorafenib in an earlier setting in patients with Secondly, as reported in previous studies, heterogeneous responses to regorafenib have been observed and have to be discussed. Patients who reported limited benefit are characterized by an overall worse prognosis, being associated with an unfavorable outcome across all lines of treatment, irrespective of regorafenib treatment. Indeed, patients with mCRC who experience early progression during first-line chemotherapy showed poor clinical outcomes in the second-line setting regardless of the use of antiangiogenic agents.Parallelly, the STREAM study showed that there is a subgroup of It is worthwhile to consider that long responder patients were associated with an overall more favorable prognosis, irrespective of the study drug, as observed by the outcomes reported in the first-line setting and in the subsequent lines of treatment. This population might benefit from a personalized approach, with less intensive treatment, in the context of a continuum-of-care strategy devoted to the maintenance of QOL and the prolongation of survival. Nevertheless, as demonstrated by GMI and by modified PFS ratio, an intrinsic effect of regorafenib was observed in long benefiter patients as well.Thirdly, treatment with regorafenib in the second-line setting was not associated with unexpected toxicities. Recent evidence from the ReDOS and CORRELATE studies suggest that dose optimization by using a dose-escalation strategy is noninferior from an efficacy standpoint, being associated to a decreased rate of toxicity within the first cycles and improving patients’ QOL.The STREAM study adopted a standard dosing schedule approach since it was developed before the dose-escalation evidences were available. However, the use of preemptive supportive measures, especially with regard to hand–foot syndrome reactions, and appropriate dose modifications were critical for patients’ compliance and treatment management. Therefore, early dose escalation and preemptive supportive measures should be routinely used during regorafenib therapy.The STREAM study also explored the role of [Indeed, baseline metabolic assessment, by using the highest or total SUVmax, might contribute to identifying patients with better prognosis and is more likely to benefit from less intensive treatment.Within the limitation of the small number of patients included in the metabolic assessment, the STREAM study suggests that the use of baseline [Treatment of A recent meta-analysis from 14 randomized trials reported that the survival benefit in the second-line setting with chemotherapy alone or in combination with antiangiogenic agents was significantly higher in patients with Despite several investigational efforts in the past decades, Despite recent advancements, developing novel therapeutic strategies for 