Discussion
diarrhoea, tumour, long-term disease, fatigue
EVENTS, TUMOUR
This study showed that even when regorafenib treatment was initiated with a reduced dose of 120 mg, it was still possible to achieve a DCR similar to that obtained using a starting dose of 160 mg. The lower limit of the 90% CI of the DCR exceeded the 27% value that was previously set, indicating that the primary endpoint was achieved in this study. The median PFS was approximately the same duration or even longer than that of the CORRECT studyThe DCR threshold was set to 27%, based on the actual clinical patient group (various clinical parameters, such as PS, tend to be worse overall than in the patient group that can participate in clinical trials). We assumed that regorafenib would be clinically significant if the DCR value did not decrease to below 70% of the DCR value (40%) in the Japanese subsetIn addition, although the treatment starting dose was reduced to 120 mg, the dose intensity was at the same level as that of the CORRECT study. This observation suggests that because the starting doses differed between the two studies, the actual daily dose in the present study was lower than that in the CORRECT study. Prior to initiating our study, we predicted that setting a low starting dose would reduce the incidence rate of serious AEs (caused by a high dose, such as 160 mg). In addition, we predicted that the dose intensity in this study would be higher than that in the CORRECT study (78.9%) because the final treatment dose would achieve the same level of efficacy regardless of whether the starting dose was 160 mg or 120 mg.However, this was not our finding, as the dose intensity in the present study was 71.0%. In the CORRECT study, 75.6% of patients needed a dose modification, and the present study showed similar but not lower values, with 75.9% of patients needing dose modifications. The incidence rate of AEs ≥ grade 3 in the present study, which was 55%, may seem comparable to that reported in the CORRECT study (51%) at first glance; however, it is necessary to note that while the present study did not collect TRAE data but treatment-emergent AEs (TEAEs) data, the CORRECT study findings were based on TRAEs.The CORRECT and CONSIGNIt is also important to note that while a certain number of ≥ grade 3 fatigue and diarrhoea events occurred in the CORRECT and CONSIGN studies, none were observed in the present study. In salvage treatments where the quality of life (QOL) is considered important, having only a few AEs ≥ grade 3 with subjective symptoms may be more significant than prolongation of OS. Moreover, supportive care has become important in recent years suggesting the effectiveness of using corticosteroids for fatigueOur study did not show a clear reduction in the frequency of AEs by lowering the starting dose to 120 mg. However, recently, the importance of adjusting the dose of regorafenib and surviving the first two cycles immediately after the start of treatment, during which time the frequency of incidence of side effects is high, has been emphasisedInterestingly, one patient exhibited long-term disease control even after the regorafenib dose was reduced to 40 mg. Unfortunately, there are no data on whether doses below 80 mg/day provide a tumour shrinkage effectThe OS in this study was 10 months, which is long for a salvage therapy. Moreover, 12-month survival was observed in 40.0% of patients, which was higher than the 24.3% in the CORRECT study. Of all 60 patients, 23 either could not or did not want to change to the subsequent treatment, but 36 did undergo some subsequent treatment. Of those administered subsequent treatments, 29 patients had used TFTD at some point, and 10 patients showed post-progression survival for 12 months or more; all of these patients had a history of TFTD use. The period of this study differed from that of the CORRECT study, and the increase in TFTD use was thought to have extended the survival post-progression and ultimately prolonged the OS in our study. Using fluoropyrimidine, oxaliplatin, and irinotecan is known to prolong survivalCurrently, no conclusion has been reached on whether the optimum starting dose of regorafenib should be 160 mg for all patients, and several outstanding issues need to be resolved, including relevant biomarkers, for this drug to be used most effectively. However, we hope that the results of this study will facilitate the establishment of the most effective administration strategy for regorafenib.