Pre-Emptive Treatment May Be Superior to Reactive Treatment of Hand–Foot Reactions in mCRC


A preplanned analysis of the Regorafenib Dose Optimization Study (ReDOS; NCT02368886) in patients with metastatic colorectal cancer (mCRC) showed using pre-emptive clobetasol to treat hand–foot skin reactions (HFSR) was more effective than treating this adverse event (AE) reactively.1

“Regorafenib [Stivarga] causes HFSR. Pre‐emptive clobetasol, a high‐potency topical corticosteroid, appears to lessen the severity of this AE,” wrote the authors led by Aminah Jatoi, MD of the Mayo Clinic, in the published manuscript. “Although further study is needed, the favorable AE profile of this intervention might prompt clinicians to discuss this option with their patients.”

Clobetasol 0.05% cream was given to 61 patients pre-emptively and 55 patients reactively. In the first 2 cycles of receiving regorafenib, 30% of patients had no evidence of HFSR with pre-emptive treatment versus 13% of patients who were treated with reactive clobetasol (P =.03). For the first cycle only, the investigators observed 54% of patients had no HFSR with pre-emptive treatment and 45% had no HFSR with reactive treatment (P =.35). There were 33% and 15% of patients who had no HFSR with pre-emptive and reactive clobetasol, respectively (P =.02), in the second cycle only.

With pre-emptive clobetasol, grade 1 HFSR was 30%, grade 2 was 8%, and grade 3 was 3% during the second cycle; these rates were 43%, 18%, and 7%, respectively, with reactive clobetasol (P =.12). There were no AEs due to the clobetasol cream.

HFSR compromised almost all daily living activities with worse quality of life according to patient-reported outcomes from those who received reactive treatment versus pre-emptive.

ReDOS, a phase 2 trial in refractory mCRC, randomized patients 1:1:1:1 to lower dose regorafenib with pre-emptive or reactive clobetasol compared with standard-dose regorafenib with pre-emptive or reactive clobetasol. Patients were directed to apply the clobetasol to their palms and soles twice a day for 8 weeks, which was demonstrated to be more effective before the development of HFSR than after.

“Pre‐emptive clobetasol might lessen regorafenib‐induced hand–foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort,” the authors concluded.

In the original publication of the trial results, the dose-escalation dosing strategy showed comparable activity and lower rates of AEs in patients with mCRC.2 Patients received regorafenib starting at 80 mg a day with weekly escalations of 40 mg, going up to 160 mg a day by the end of the escalation, or the standard dose of 160 mg a day for 21 days of a 28-day cycle. With a median follow-up of 1.18 years, the trial met its primary end point of the proportion of evaluable patients initiating cycle 3. Out of the 54 patients in the dose-escalation group, 23 (43%) initiated cycle 3 versus 16 (26%) of the 62 patients receiving the standard dose (one-sided P =.043).

The most common grade 3/4 AEs seen in this study were fatigue in 13% and 18% of the dose-escalation group and standard-dose group, respectively, HFSR in 15% and 16%, abdominal pain in 17% and 6%, and hypertension in 7% and 15%. There were 14 patients with at least 1 drug-related serious AE, 6 receiving dose escalation, and 8 receiving the standard dose. The standard-dose group had 1 probably treatment-related death due to myocardial infarction.

Jatoi et al noted that although these findings warrant further research in a larger cohort of patients, the results show that pre-emptive clobetasol can be offered by clinicians as an option for their patients with mCRC and hand–foot skin reactions.


1. Jatoi A, Ou FS, Ahn DH, et al. Pre-emptive versus reactive topical clobetasol for regorafenib-induced hand-foot reactions: a preplanned analysis of the ReDOS trial. Oncologist. Published February 18, 2021. Accessed February 24, 2021. doi:10.1002/onco.13730

2. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070-1082. doi:10.1016/S1470-2045(19)30272-4

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