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A phase II trial of the effect of perindopril on hand-foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC.

ABSTRACT: PURPOSE:Regorafenib is an oral multi-kinase inhibitor that offers an OS benefit to patients with mCRC refractory to standard therapy (Grothey et al., in Lancet 381:303-312, 2013), but comes with potential significant toxicities including grade 3 hand-foot skin reaction (HFSR). The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. We hypothesized that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, indicated for the treatment of hypertension (Ceconi et al., in Cardiovasc Res 73:237-246, 2007), and which plays a role in preventing endothelial dysfunction, may help to prevent or reduce the severity of regorafenib-induced HFSR. PATIENTS AND METHODS:In this single-center phase II open-label trial, patients with refractory mCRC were treated with both regorafenib (160 mg/day) and perindopril (4 mg/day) for 21 days per 28-day cycle. The primary end point was to assess the proportion of patients with any grade HFSR toxicity. Secondary end points included time to development of worst (grade 3) HFSR, reduction of all grades of hypertension and all grade toxicities, as well as progression-free survival. All toxicities were evaluated using CTCAE v4.03. RESULTS:A planned interim analysis was performed after ten evaluable patients had completed their first cycle of study treatment. As 50% (5/10) experienced grade 3 HFSR, enrolment was stopped as the addition of perindopril did not lead to a reduced level of HFSR compared with regorafenib alone. Other grade 3 toxicities included hypertension (16.7%) and increased AST (16.7%). CONCLUSION:The addition of an ACE inhibitor perindopril to regorafenib did not reduce HFSR incidence or severity in patients with refractory mCRC.

SUBMITTER: Melosky BL

PROVIDER: S-EPMC6394486 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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A phase II trial of the effect of perindopril on hand-foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC.

Melosky Barbara L BL Lim Howard John HJ Davies Janine Marie JM Gill Sharlene S Kollmannsberger Christian K CK Ho Maria Yi MY Vandt Solomon A SA Renouf Daniel John DJ

Cancer chemotherapy and pharmacology 20181208 3

<h4>Purpose</h4>Regorafenib is an oral multi-kinase inhibitor that offers an OS benefit to patients with mCRC refractory to standard therapy (Grothey et al., in Lancet 381:303-312, 2013), but comes with potential significant toxicities including grade 3 hand-foot skin reaction (HFSR). The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. We hypothesized that perindopril, an angiotensin-converting enzyme (ACE) inhibit ...[more]

PMID: 30535909

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Project description:BackgroundRegorafenib is an orally available, small-molecule multikinase inhibitor with international marketing authorizations for use in colorectal cancer and gastrointestinal stromal tumors. In clinical trials, regorafenib showed a consistent and predictable adverse-event profile, with hand-foot skin reaction (HFSR) among the most clinically significant toxicities. This review summarizes the clinical characteristics of regorafenib-related HFSR and provides practical advice on HFSR management to enable health care professionals to recognize, pre-empt, and effectively manage the symptoms, thereby allowing patients to remain on active therapy for as long as possible.DesignThis review is based on a systematic literature search of the PubMed database (using synonyms of HFSR, regorafenib, and skin toxicities associated with targeted therapies or cytotoxic chemotherapy). However, as this search identified very few articles, the authors also use their clinical experience as oncologists and dermatologists managing patients with treatment-related HFSR to provide recommendations on recognition and management of HFSR in regorafenib-treated patients.ResultsRegorafenib-related HFSR is similar to that seen with other multikinase inhibitors (e.g. sorafenib, sunitinib, cabozantinib, axitinib, and pazopanib) but differs from the hand-foot syndrome seen with cytotoxic chemotherapies (e.g. fluoropyrimidines, anthracyclines, and taxanes). There have been no controlled trials of symptomatic management of regorafenib-related HFSR, and limited good-quality evidence from randomized clinical trials of effective interventions for HFSR associated with other targeted therapies. Recommendations on prevention and management of regorafenib-related HFSR in this review are therefore based on the expert opinion of the authors (dermatologists and oncologists with expertise in the management of treatment-related skin toxicities and oncologists involved in clinical trials of regorafenib) and tried-and-tested empirical experience with other multikinase inhibitors and cytotoxic chemotherapies.ConclusionsAs recommended in this review, treatment modifications and supportive measures to prevent, reduce, and manage HFSR can allow patients to continue regorafenib at the optimal dose to derive benefit from treatment.

Project description:BackgroundHand, foot, and mouth disease (HFMD) is an epidemic infectious disease in China. Relationship of neighborhood greenness with human health has been widely studied, yet its association with severe HFMD has not yet been established.MethodsIndividual HFMD cases that occurred in Guangdong province in 2010 were recruited and were categorised into mild and severe cases. Residential greenness was assessed using global land cover data. We used a case-control design (i.e., severe versus mild cases) with logistic regression models to assess the association between neighborhood greenness and HFMD severity. Effect modification was also examined.ResultsA total of 131,606 cases were included, of whom 130,840 were mild cases and 766 were severe cases. In an unadjusted model, HFMD severity increased with higher proportion of neighborhood greenness (odds ratio, OR = 1.029, 95%CI: 1.009-1.050). The greenness-HFMD severity association remained (OR = 1.031, 95%CI: 1.006-1.057) after adjusting for population density, demographic variables and climate variables. Both population density (Z = 4.148, P < 0.001) and relative humidity (Z = -4.297, P < 0.001) modified the association between neighborhood greenness and HFMD severity. In the stratified analyses, a protective effect (OR = 0.769, 95%CI: 0.687-0.860) of greenness on HFMD severity were found in the subgroup of population density being lower than and equal to 5 ln(no.)/km2. While in both the subgroups of population density being higher than 5, the greenness had hazard effects (subgroup of > 5 & ≤7: OR = 1.071, 95%CI: 1.024-1.120; subgroup of > 7: OR = 1.065, 95%CI: 1.034-1.097) on HFMD severity. As to relative humidity, statistically significant association between greenness and HFMD severity was only observed in the subgroup of being lower than and equal to 76% (OR = 1.059, 95%CI: 1.023-1.096).ConclusionsOur study found that HFMD severity is associated with the neighborhood greenness in Guangdong, China. This study provides evidence on developing a prevention strategy of discouraging the high-risk groups from going to the crowded green spaces during the epidemic period.

Project description:BackgroundHand-foot skin reaction (HFSR) is the most common regorafenib-induced adverse event and is in need of effective prevention and palliation.Materials and methodsThe Regorafenib Dose Optimization Study (ReDOS), a four-arm, previously published trial with a 1:1:1:1 randomization scheme, was analyzed in a manner in keeping with the original protocol to assess whether clobetasol 0.05% cream (a corticosteroid) applied to the palms and soles twice per day for 8 weeks was more effective when prescribed preemptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the first two cycles of regorafenib.ResultsSixty-one patients received preemptive clobetasol, and 55 received reactive clobetasol. Groups were balanced on demographics. Over the first two cycles, no evidence of HFSR occurred in 30% with preemptive clobetasol versus 13% with reactive clobetasol (p = .03). During the first cycle, 54% and 45% of patients had no HFSR with preemptive and reactive clobetasol, respectively (p = .35). During the second cycle, 33% and 15% had no HFSR with preemptive and reactive clobetasol, respectively (p = .02). During the second cycle, rates of grade 1, 2, and 3 HFSR were 30%, 8%, and 3%, respectively, with preemptive clobetasol and 43%, 18%, and 7%, respectively, with reactive clobetasol (p = .12). Patient-reported outcomes showed HFSR compromised nearly all activities of daily living with worse quality of life in patients who received reactive versus preemptive clobetasol. No clobetasol-induced adverse events were reported.ConclusionPreemptive clobetasol might lessen regorafenib-induced hand-foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort.Implications for practiceRegorafenib causes hand-foot skin reactions. Preemptive clobetasol, a high-potency topical corticosteroid, appears to lessen the severity of this adverse event. Although further study is needed, the favorable adverse event profile of this intervention might prompt clinicians to discuss this option with their patients.

Project description:Skin toxicity (hand-foot syndrome/hand-foot skin reaction, HFS/R) related to antineoplastic therapy is a significant issue in oncology practice, with potentially large impacts on health-related quality of life (HRQL).A patient-reported questionnaire, the hand-foot skin reaction and quality of life (HF-QoL) questionnaire was developed to measure the HFS/R symptoms associated with cancer therapeutic agents and their effect on daily activities. The validity and reliability of the HF-QoL questionnaire was tested in a randomized trial of capecitabine with sorafenib/placebo in 223 patients with locally advanced/metastatic breast cancer. Other measures completed included patient ratings of condition severity, the Functional Assessment of Cancer Therapy-Breast cancer (FACT-B), and the clinician-rated National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3.0, hand-foot skin reaction grade. The psychometric properties of the HF-QoL tested included structural validity, internal consistency, construct validity, discriminant validity, and responsiveness. Finally, the minimal clinically important difference (MCID) was estimated.The HF-QoL instrument comprises a 20-item symptom scale and an 18-item daily activity scale. Each scale demonstrated excellent measurement properties and discriminated between NCI-CTCAE grade and patient-rated condition severity with large effect sizes. The daily activity scale had excellent internal consistency and correlated with the FACT-B and HF-QoL symptom scores. Both HF-QoL scale scores increased linearly with increasing patient-rated condition severity. The MCIDs were estimated as 5 units for daily activities and 8 units for symptoms mean scores.The HF-QoL was sensitive to symptoms and HRQL issues associated with HFS/R among participants treated with capecitabine with and without sorafenib. The HF-QoL appears suitable for assessing the HRQL impairment associated with HFS/R to cancer therapies.Skin toxicity related to anticancer therapies is a significant issue in oncology practice. Several newer agents, as well as older therapies, are associated with the skin toxicity known as hand-foot skin reaction (HFSR) or hand-foot syndrome (HFS). This study describes the development and validation of a brief, patient-reported questionnaire (the hand-foot skin reaction and quality of life questionnaire) supporting its suitability for use in clinical research to aid in early recognition of symptoms, to evaluate the effectiveness of agents for HFS/R treatment within clinical trials, and to evaluate the impact of these treatments on HFS/R-associated patients' health-related quality of life.

Dataset Information

A phase II trial of the effect of perindopril on hand-foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC.

Publications

A phase II trial of the effect of perindopril on hand-foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC.

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