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Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5.

ABSTRACT: Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine for which no effective preventative treatment has been definitively demonstrated. This trial was conducted on the basis of preliminary data that a urea/lactic acid-based topical keratolytic agent (ULABTKA) may prevent HFS.A randomized, double-blind phase III trial evaluated 137 patients receiving their first ever cycle of capecitabine at a dose of either 2,000 or 2,500 mg/m(2) per day for 14 days. Patients were randomly assigned to a ULABTKA versus a placebo cream, which was applied to the hands and feet twice per day for 21 days after the start of capecitabine. Patients completed an HFS diary (HFSD) daily. HFS toxicity grade (Common Terminology Criteria for Adverse Events [CTCAE] v3.0) was also collected at baseline and at the end of each cycle. The primary end point was the incidence of moderate/severe HFS symptoms in the first treatment cycle, based on the patient-reported HFSD.The percentage of patients with moderate/severe HFS symptoms was not different between groups, being 13.6% in the ULABTKA arm and 10.2% in the placebo arm (P = .768 by Fisher's exact test). The odds ratio was 1.37 (95% CI, 0.37 to 5.76). Cycle 1 CTCAE skin toxicity was higher in the ULABTKA arm but not significantly so (33% v 27%; P = .82). No significant differences were observed in other toxicities between groups.These data do not support the efficacy of a ULABTKA cream for preventing HFS symptoms in patients receiving capecitabine.

SUBMITTER: Wolf SL

PROVIDER: S-EPMC3020691 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5.

Wolf Sherry L SL Qin Rui R Menon Smitha P SP Rowland Kendrith M KM Thomas Sachdev S Delaune Robert R Christian Diana D Pajon Eduardo R ER Satele Daniel V DV Berenberg Jeffrey L JL Loprinzi Charles L CL

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20101108 35

<h4>Purpose</h4>Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine for which no effective preventative treatment has been definitively demonstrated. This trial was conducted on the basis of preliminary data that a urea/lactic acid-based topical keratolytic agent (ULABTKA) may prevent HFS.<h4>Patients and methods</h4>A randomized, double-blind phase III trial evaluated 137 patients receiving their first ever cycle of capecitabine at a dose of either 2,000 or 2,500 mg/m(2) per da ...[more]

PMID: 21060036

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Project description:Importance:Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. Objective:To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. Design, Setting, and Participants:This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Interventions:Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Main Outcomes and Measures:Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. Results:In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P?=?.38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P?=?.001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P?=?.001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P?=?.003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P?<?.001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P?=?.001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P?<?5?×?10-8), including a novel DPYD variant (rs75267292; P?=?1.57?×?10-10), and variants in the MACF1 (rs183324967, P?=?4.80?×?10-11; rs148221738, P?=?5.73?×?10-10) and SPRY2 (rs117876855, P?<?1.01?×?10-8; rs139544515, P?=?1.30?×?10-8) genes involved in wound healing. Conclusions and Relevance:Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. Trial Registration:clinicaltrials.gov Identifier: NCT00486213.

Project description:BACKGROUND:Breast cancer is a global problem, and a large number of new cases are diagnosed every year. Capecitabine is effective in patients with metastatic breast cancer (MBC). Hand-foot syndrome (HFS) is a common adverse effect of capecitabine. In this study, we investigated the association between single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers. METHODS:We selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes. We genotyped a total of 22 SNPs in the thymidylate synthase gene (TYMS), the methylene tetrahydrofolate reductase gene (MTHFR), and the ribonucleotide reductase M1 gene (RRM1) in 342 MBC patients treated with capecitabine-based chemotherapy. The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson's ?2 test, and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis. The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci (eQTL) browser online tools. RESULTS:We found 4 positive sites for HFS in the TYMS and MTHFR genes: TYMS rs2606241 (P?=?0.022), TYMS rs2853741 (P?=?0.019), MTHFR rs3737964 (P?=?0.029), and MTHFR rs4846048 (P?=?0.030). Logistic regression analyses showed that the genotype AG of MTHFR rs3737964 [odds ratio (OR)?=?0.54, 95% confidence interval (CI) 0.31-0.97, P?=?0.038] and MTHFR rs4846048 (OR?=?0.54, 95% CI 0.30-0.98, P?=?0.042) were protective factors of HFS, whereas the genotype CT of TYMS rs2853741 (OR?=?2.25, 95% CI 1.31-3.87, P?=?0.012) increased the risk of HFS. The association between the genotype GT of TYMS rs2606241 (OR?=?1.27, 95% CI 0.73-2.23, P?=?0.012) and HFS was uncertain. Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis. CONCLUSIONS:We have identified four potentially useful pharmacogenetic markers, TYMS rs2606241, TYMS rs2853741, MTHFR rs3737964, and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.

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: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.

Dataset Information

Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5.

Publications

Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5.

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