Prophylactic Effect of Dexamethasone on Regorafenib-Related Fatigue and/or Malaise: A Randomized, Placebo-Controlled, Double-Blind Clinical Study in Patients with Unresectable Metastatic Colorectal Cancer (KSCC1402/HGCSG1402)

Abstract

Background: Regorafenib is an oral multikinase inhibitor with a proven survival benefit for metastatic colorectal cancer patients. The KSCC1402/HGCSG1402 study investigated the prophylactic effect of oral dexamethasone (DEX) on regorafenib-related fatigue and/or malaise. Patients and Methods: Patients who progressed after standard chemotherapy were randomized 1: 1 to a DEX group (2 mg/day; days 1–28) with regorafenib or a placebo group with regorafenib. The primary endpoint was the incidence of fatigue and/or malaise, based on version 4.0 of the National Cancer Institute’s CTCAE (Common Terminology Criteria for Adverse Events). One of the secondary endpoints was the in­cidence of fatigue and/or malaise based on the CTCAE assessed by patient-reported outcome (PRO). Results: The incidence of any grade of fatigue and/or malaise assessed by the investigators was 58.8% in the DEX group and 61.1% in the placebo group (p = 0.8101), and that assessed by PRO was 47.2 and 58.3%, respectively (p = 0.3450). The incidence of grade ≥2 fatigue and/or malaise, as assessed by the investigators, was 19.4% for the DEX group and 38.9% for the placebo group (p = 0.0695), and that assessed by PRO was 27.8 and 52.8%, respectively (p = 0.0306). Conclusion: Our results suggest that prophylactic oral DEX is clinically effective in improving regorafenib-related fatigue and/or malaise.

Fatigue in Cancer Patients in Palliative Care—A Review on Pharmacological Interventions

“…The result from this review showed that methylphenidate and corticosteroids may improve CRF in the palliative phase [14,34,35,39,46,48] but there is not enough evidence to propose use of modafinil, dexamphetamine, melatonin or testosterone in this setting. It should be noted that the studied cohorts are heterogeneous and include patients both in the early and late palliative phase.…”

“…Meta-analyses and group comparisons are therefore of little use at present, and instead we suggest that each study should be evaluated individually regarding generalizability of results. Unfortunately, characterization of disease severity in patients included in several studies in this review is scarce, and survival time is only accounted for in two trials [14,33]. Instead, inclusion and exclusion criteria, description of care facilities from which patients were recruited, assessed performance status at baseline and data on dropout rates and reasons for not completing intervention can be used to estimate general disease burden in studied cohorts.…”

“…Corticosteroids have in randomized trials showed to alleviate CRF. Patients with advanced colorectal cancer showed improved fatigue, receiving dexamethasone 2 mg/day for four weeks during chemotherapy in a randomized placebo-controlled study [14]. In addition, dexamethasone 8 mg/day for two weeks have also provided significant effect in alleviating fatigue in patients with advanced cancer (n = 84), in a randomized placebocontrolled trial [48].…”

“…There is a risk that patients suffering from fatigue underreport the symptom if assessment is not made or if health care personnel do not acknowledge the symptom and bring it up for discussion [13]. Patient reported outcome might differ from physician reported outcome [14], suggesting the importance of using validated assessment tools when measuring fatigue.…”

Treatment Outcomes in Patients Receiving Regorafenib for Metastatic Colon Cancer

“…For example, for treatment-related fatigue, one phase II study investigated the effect of dexamethasone on these patients but failed to show any improvement. 10 Currently there is no established marker to predict the treatment response towards regorafenib. In our study, patients with left-sided tumours enjoyed longer OS, which concurs with the findings of many other studies that left-sided tumours carry a better prognosis regardless of treatment, stage, race of patients, or length of study.…”