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Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib.

ABSTRACT: Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes.Toxicities (> or = grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were evaluated. Toxicity incidence and VEGFR2 H472Q and V297I status were compared to clinical outcomes.Individuals experiencing HT had longer PFS following bevacizumab therapy than those without this toxicity in trials utilizing bevacizumab in patients with prostate cancer (31.5 vs 14.9 months, n = 60, P = 0.0009), and bevacizumab and sorafenib in patients with solid tumors (11.9 vs. 3.7 months, n = 27, P = 0.052). HT was also linked to a > 5-fold OS benefit after sorafenib and bevacizumab cotherapy (5.7 versus 29.0 months, P = 0.0068). HFSR was a marker for prolonged PFS during sorafenib therapy (6.1 versus 3.7 months respectively, n = 113, P = 0.0003). HT was a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib (OR(95%CI) = 3.2(1.5-6.8), P = 0.0024). Carriers of variant alleles at VEGFR2 H472Q experienced greater risk of developing HT (OR(95%CI) = 2.3(1.2 - 4.6), n = 170, P = 0.0154) and HFSR (OR(95%CI) = 2.7(1.3 - 5.6), n = 170, P = 0.0136).This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib.

SUBMITTER: Jain L

PROVIDER: S-EPMC2913951 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib.

Jain Lokesh L Sissung Tristan M TM Danesi Romano R Kohn Elise C EC Dahut William L WL Kummar Shivaani S Venzon David D Liewehr David D English Bevin C BC Baum Caitlin E CE Yarchoan Robert R Giaccone Giuseppe G Venitz Jürgen J Price Douglas K DK Figg William D WD

Journal of experimental & clinical cancer research : CR 20100714

<h4>Background</h4>Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes.<h4>Methods</h4>Toxicities (> or = grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were eva ...[more]

PMID: 20630084

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Project description:BACKGROUND: Hand-foot-skin reaction (HFSR) is an adverse event frequently observed during treatment with capecitabine (cape). In the present analysis, we sought to evaluate the potential association of HFSR and survival in German patients with metastatic colorectal cancer and locally advanced rectal cancer treated with cape in clinical trials. METHODS: Patients of the Arbeitsgemeinschaft für Internistische Onkologie (AIO) KRK-0104 and the Mannheim rectal cancer trial were evaluated. HFSR was graded according to NCI-CTC criteria in both trials. Time to first occurrence of HFSR was described per cycle and HFSR developing during cycles 1 and 2 was defined as 'early HFSR'. Baseline characteristics between the patient groups with or without HFSR were compared using Mann-Whitney-U, Fisher's exact or χ(2)-test, as appropriate. Haematological and non-haematological toxicities observed in both groups were compared using Fisher's exact test. Progression-free (PFS) or disease-free (DFS) as well as overall survival (OS) data from both trials were pooled and the HFSR group was compared with the non-HFSR using Kaplan-Meier analysis. RESULTS: A total of 374 patients were included, of whom 29.3% developed any HFSR. Of these, 51% had early HFSR. Baseline characteristics were comparable between both HFSR groups concerning age, gender, ECOG performance status and UICC stage. On multivariate analysis none of these factors had influence on the occurrence of HFSR. The percentage of all-grade (and grade 3-4) haematological toxicities did not differ between both the groups. By contrast, patients exhibiting HFSR had a significantly higher rate of all-grade (but not grade 3-4) diarrhoea, stomatitis/mucositis and fatigue (P<0.01, respectively). Patients with HFSR had improved PFS/DFS (29.0 vs 11.4 months; P=0.015, HR 0.69) and OS (75.8 vs 41.0 months; P=0.001, HR=0.56). Within the HFSR group, PFS/DFS and OS were comparable between patients with early vs late HFSR. INTERPRETATION: The present analysis provides evidence for the association of HFSR and survival in patients with colorectal cancer. Baseline characteristics, with the exception of UICC stage, older age and ECOG performance status, and the time of occurrence of HFSR had no impact on survival. Patients with HFSR had a higher probability of developing any-grade gastrointestinal toxicity and fatigue while no correlation with haematological toxicity was found.

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:BackgroundSkin 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).Materials and methodsA 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.ResultsThe 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.ConclusionThe 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.Implications for practiceSkin 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.

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Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib.

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Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib.

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