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​Safe Dose of Regorafenib For Metastatic Colorectal Cancer

Colorectal cancer.

In patients with refractory metastatic colorectal cancer, regorafenib (Stivarga®, Bayer) provides a good overall survival benefit. Unfortunately, it also causes a lot of side effects, such as infection, severe bleeding, tears in the stomach or intestinal wall, hand-foot skin reaction, severe skin rash, high blood pressure, decreased blood flow to the heart, heart attack, reversible posterior leukoencephalopathy syndrome, and wound healing problems, all of which limit its usefulness. In order to find the appropriate balanced dose, researchers conducted a phase 2 trial evaluating two different dosing schedules of regorafenib and found that the dose-escalation strategy was most effective.

For this randomized, open-label, phase 2 study, published in The Lancet Oncology, 123 patients with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy were randomly assigned in a 1:1:1:1 ratio to receive either one of four regorafenib dosing strategies. All patients received clobetasol cream as either a pre-emptive or reactive measure at a dose of 0.05%. The dosing strategies for regorafenib included lower-dose regorafenib and pre-emptive clobetasol, lower-dose regorafenib and reactive clobetasol, standard-dose regorafenib and pre-emptive clobetasol, and standard-dose regorafenib and reactive clobetasol. Patients receiving a lower-dose dose-escalation strategy for regorafenib started with an oral administration of regorafenib 80 mg/day with weekly escalation in increments of 40 mg and continued all the way up to 160 mg/day if no significant treatment-related side effects occurred. The groups receiving a standard-dose strategy were administered 160 mg/day of regorafenib for 21 days of a 28-day cycle.

After a median follow-up of 1.18 years, 23 of the 54 patients in the dose-escalation group were able to initiate cycle 3, compared with 16 of 62 patients in the standard-dose group. Treatment-related adverse events of grade 3/4 included fatigue, hand-foot skin reaction, abdominal pain, and hypertension.

The study authors conclude, "The dose-escalation dosing strategy represents an alternative approach for optimizing regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data."

For More Information

Bekaii-Saab TS, Ou FS, Ahn, et al (2019). Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomized, multicentre, open-label, phase 2 study. Lancet Oncol. [Epub ahead of print] DOI:10.1016/S1470-2045(19)30272-4

Clinicaltrials.gov (2019). Lower or standard dose regorafenib in treating patients with refractory metastatic colorectal cancer. NLM Identifier: NCT02368886

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