Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial.

PURPOSE: Hand-foot syndrome (HFS) is a dose-limiting side effect of capecitabine. Celecoxib prevents HFS by inhibiting cyclooxygenase-2 (COX-2) that is upregulated because of the underlying associated inflammation. However, systemic side effects of celecoxib have limited routine prescription. Topical diclofenac inhibits COX-2 locally with minimal risk of systemic adverse events. Therefore, we conducted this study to assess the efficacy of topical diclofenac in the prevention of capecitabine-induced HFS. METHODS: In this single-site phase III randomized double-blind trial, we enrolled patients with breast or GI cancer who were planned to receive capecitabine-based treatment. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary end point was the incidence of grade 2 or 3 HFS (Common Terminology Criteria for Adverse Events version 5), which was compared between the two groups using simple logistic regression. RESULTS: In total, 264 patients were randomly assigned to receive topical diclofenac gel (n = 131) or placebo (n = 133). Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003). Grade 1-3 HFS was lower in the diclofenac group than in the placebo group (6.1% v 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4). CONCLUSION: Topical diclofenac prevented HFS in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated HFS.

Efficacy of regional cooling + oral dexamethasone for primary prevention of hand-foot syndrome associated with pegylated liposomal doxorubicin.

PURPOSE: Pegylated liposomal doxorubicin (PLD)-induced hand-foot syndrome (HFS) frequently lowers the quality of life of ovarian cancer patients. Wrist and ankle cooling, having a limited preventive effect, has been the commonest supportive HFS care. In this study, we retrospectively assessed the primary preventive effect of a combination of regional cooling and oral dexamethasone therapy (cooling + oral Dex) on HFS. METHODS: This study is a single-arm retrospective, observational study. Recurrent ovarian cancer patients were administered PLD ± bevacizumab. We retrospectively examined the efficacy of hands and feet cooling (from the start of PLD to the end) + oral Dex (day 1-5: 8 mg/day, day 6, 7: 4 mg/day) for primary HFS prevention. RESULTS: This study included 74 patients. The initial dose of PLD was 50 mg/m2 and 40 mg/m2 for 32 (43.2%) and 42 (56.8%) patients, respectively. HFS of Grade ≥ 2 and Grade ≥ 3 developed in five (6.8%) and one (1.4%) patient(s), respectively. The incidence of ≥ Grade 2 and ≥ Grade 3 HFS was much lower than those reported in previous studies. Dose reduction was required in 13 patients (17.6%) mainly because of neutropenia or mucositis; there was no HFS-induced dose reduction. Meanwhile, PLD therapy was discontinued mainly because of interstitial pneumonia (4 patients) and HFS (one patient). CONCLUSIONS: We demonstrated the efficacy of regional cooling and oral Dex for primary prevention of PLD-induced HFS. Although future prospective studies are needed to confirm its efficacy, this combination therapy can be considered for primary prevention of HFS in ovarian cancer patients on PLD.

Thymidine phosphorylase as a molecular target for quercetin-incorporated collagen matrix in the prevention of hand-foot syndrome induced by capecitabine in rats.

Hand-foot syndrome (HFS) is a common adverse effect of capecitabine affecting the quality of life of cancer patients. To enhance the tolerability of capecitabine, this work evaluated the incorporation of quercetin into topical collagen matrix formula to target thymidine phosphorylase enzyme, oxidative stress, and apoptosis underlying HFS. Forty Sprague Dawley rats were allocated to four equal groups. The control group received distilled water orally. HFS was induced by oral capecitabine (200 mg/kg/day) for 21 days. The untreated HFS group received no treatment. In the treated groups, topical collagen and quercetin-incorporated collagen matrix formula were administered concomitantly with the HFS induction protocol. Treatment with quercetin-incorporated collagen matrix showed a significant decrease in thymidine phosphorylase level compared with the untreated and collagen-treated groups. Treatment with quercetin-incorporated collagen matrix showed a significant decrease in malondialdehyde and caspase-3 levels, and a significant increase in the total antioxidant capacity of the skin and B cell lymphoma/leukemia 2 levels compared with the untreated group. Additionally, a significant improvement in the gross picture and histopathological score of HFS was observed. In conclusion, the quercetin-incorporated collagen matrix is a promising formula for the prevention of HFS, due to the targeted effect on thymidine phosphorylase and subsequent antioxidant and antiapoptotic effects.

Effect of Extra-Virgin Olive Oil on Hand Foot Syndrome and hs-CRP in Patients Receiving Capecitabine: A Randomized Trial.

BACKGROUND: Hand Foot Syndrome (HFS) is a frequent adverse effect observed in patients undergoing capecitabine chemotherapy, often leading to treatment disruptions and dose adjustments. Elevated C-Reactive Protein (hs-CRP) levels have been associated with the development of HFS. This study aimed to assess the potential of unrefined Extra Virgin Olive Oil (EVOO) supplementation in mitigating HFS and hs-CRP elevation among individuals receiving capecitabine chemotherapy. METHODS: Between November 2022 and May 2023, forty-five eligible participants were enrolled in this randomized trial. Patients with advanced colorectal or breast cancer were randomly allocated into three groups: an intervention group receiving unrefined EVOO supplementation (30 mL per day) alongside capecitabine, a placebo group receiving refined extra light olive oil (ELOO) supplementation (30 mL per day) alongside capecitabine, and a control group receiving capecitabine alone. The masking of both placebo and intervention groups was ensured through identical packaging and instructions, maintaining participant and physician blindness to the assigned treatments. Randomization, achieved via computer-generated sequences, ensured even distribution among the three groups. RESULTS: HFS incidences were notably lower in the EVOO group (13.3%) compared to the placebo (66.7%) and control (80%) groups. Instances of Grade 2 or more severe HFS were observed in 20% of placebo and 40% of control group patients. No cases of severe HFS were reported in the EVOO group. Moreover, EVOO supplementation led to a significant reduction in hs-CRP levels when contrasted with the placebo and control groups. These findings suggest that EVOO may serve as a preventive measure against HFS and exhibit anti-inflammatory effects in patients undergoing capecitabine chemotherapy. CONCLUSION: This study demonstrates the potential benefits of incorporating unrefined EVOO into the regimen of patients undergoing capecitabine chemotherapy. EVOO supplementation was associated with lower incidences of HFS and a reduction in hs-CRP levels, indicating its possible role in preventing HFS development and mitigating inflammation.

Pyridoxine Is Effective for Preventing Hand-Foot Syndrome Induced by Pegylated Liposomal Doxorubicin for Multiple Myeloma: The Results of a Randomized Study.

PURPOSE: Pegylated liposomal doxorubicin (PLD) is highly effective for treating multiple myeloma (MM). Hand-foot syndrome (HFS) is a dose-limiting adverse event of PLD that may reduce a patient's quality of life or prevent certain patients from receiving PLD. Several researchers have discovered that pyridoxine, an activated form of vitamin B6, may prevent PLD-associated HFS. We designed a prospective randomized trial to examine whether prophylactic pyridoxine might prevent the incidence or delay the occurrence of PLD-induced HFS in patients with MM. METHODS: Patients who met the trial's eligibility requirements were randomized and then administered either pyridoxine 100 mg twice daily or no pyridoxine, in both cases accompanied by their PLD-containing chemotherapeutic agent. Follow-up of patients was performed until the completion of induction therapy, the development of HFS or disease progression. RESULTS: Between January 1, 2017, and January 1, 2019, 105 patients were randomly assigned to the pyridoxine group (n = 52) or the no pyridoxine group (n = 53). In the pyridoxine and no pyridoxine groups, HFS developed after a median of 4 (range, 1-8 cycles) and 3 (range, 1-7 cycles) chemotherapeutic cycles, respectively. There were no grade 3 incidents recorded. Overall, 13.3% of patients experienced HFS. A 11 of 53 (20.8%) patients in the no pyridoxine group experienced HFS, compared to 3 of 52 (5.8%) patients in the pyridoxine group (P = .042); there was no difference in HFS grades (P = .725). CONCLUSIONS: The findings of benefit from prophylactic pyridoxine in this open-label trial have suggested its promise as a treatment for reducing HFS in MM patients. Further research with a placebo-controlled design is recommended. CLINICAL TRIAL REGISTRATION: ChiCTR2100050294.

Pharmacological prevention strategy for capecitabine-induced hand-foot syndrome: A network meta-analysis of randomized control trials.

Capecitabine-induced hand-foot syndrome (HFS) is common in clinical practice. There are many regimens used to prevent HFS. However, the most effective preventive regimen has not yet been identified. Thus, we conducted a network meta-analysis to investigate the best preventive regimen for HFS. The PRISMA-NMA guidelines were used in this study. The PubMed, Cochrane, and Embase databases were searched. The main endpoint was set as HFS of National Cancer Institute grade 2 or more. We included only randomized control trials. The P-score was used to rank the regimens. Among all the regimens, topical silymarin had the best preventive ability compared with the placebo (OR: 0.08; 95% CI: 0.01-0.71). The other identified effective regimen included pyridoxine (400 mg) and celecoxib; compared with the placebo, the odds ratio was 0.27 (95% CI: 0.08-0.91) and 0.41 (95% CI: 0.18-0.95), respectively. Topical silymarin is the most useful regimen for preventing capecitabine-induced HFS.

Study protocol of a single-arm phase 2 study evaluating the preventive effect of topical hydrocortisone for capecitabine-induced hand-foot syndrome in colorectal cancer patients receiving adjuvant chemotherapy with capecitabine plus oxaliplatin (T-CRACC study).

BACKGROUNDS: Clinical evidence of the preventive effectiveness of medium-class topical corticosteroids for capecitabine-induced hand foot syndrome (HFS) is limited. Although the pathogenesis and mechanism of HFS are unclear, inflammatory reactions are thought to be involved in HFS development. This study aimed to evaluate the preventive effect of medium-class topical corticosteroids (hydrocortisone butyrate 0.1% topical therapy) for capecitabine-induced HFS in patients with colorectal cancer receiving adjuvant chemotherapy with capecitabine plus oxaliplatin. METHODS: This is a single-center, single-arm, phase 2 study. Patients with colorectal cancer scheduled to receive adjuvant chemotherapy with capecitabine plus oxaliplatin are enrolled, and topical hydrocortisone butyrate 0.1% is applied prophylactically in addition to standard moisturizing therapy. The primary endpoint is the incidence of grade ≥ 2 HFS within three months. The secondary endpoints are the time to onset of HFS, rates of dose reduction, schedule delay, discontinuation caused by capecitabine-induced HFS, and other adverse events. All adverse events are evaluated by clinical pharmacists and attending physicians. DISCUSSION: This study is expected to contribute to the establishment of new supportive care for preventing HFS, not only for colorectal cancer patients receiving adjuvant chemotherapy, but also for various cancer patients receiving capecitabine-based chemotherapy. TRIAL REGISTRATION: This trial was registered in the Japan Registry of Clinical Trials (jRCT) as jRCTs031220002. Registered 5 April 2022, https://jrct.niph.go.jp/search Protocol version V.1.0, 16 February 2022.

Prophylactic strategies for hand-foot syndrome/skin reaction associated with systemic cancer treatment: a meta-analysis of randomized controlled trials.

PURPOSE: Hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR) are common toxicities of several systemic cancer treatments. Multikinase inhibitor-induced HFSR is distinguished from chemotherapy-induced HFS in terms of pathogenesis, symptomatology, and treatment. Multiple trials have investigated the efficacy of preventive strategies such as COX-inhibitors, pyridoxine, and urea cream; however, no consensus has been made. This meta-analysis evaluated data from high-quality trials to provide strong evidence in forming recommendations to prevent systemic cancer therapy-induced HFS/HFSR. METHODS: A systematic search of PubMed, Embase, Cochrane, clinical trials databases, and hand searching were utilized to identify randomized trials (RCTs) investigating prophylactic strategies for HFS/HFSR in cancer patients receiving systemic treatment. Trials published until August 2021 were included. Using the random effects model, pooled odds ratios were calculated for rates of all-grade and severe HFS/HFSR. Subgroup analysis based on type of cancer treatment given was done. RESULTS: Sixteen RCTs were included (N=2814). For all-grade HFS/HFSR, celecoxib (OR 0.52, 95% CI 0.32-0.85, p=0.009) and urea cream (OR 0.48, 95% CI 0.39-0.60, p<0.00001) both showed statistically significant risk reduction. Celecoxib was effective in preventing HFS in patients who received capecitabine (50.5% vs 65%, p=0.05), while urea cream was effective in both capecitabine HFS (22.3% vs 39.5%, p=0.02) and sorafenib-induced HFSR (54.9% vs 71.4%, p<0.00001). Pyridoxine at higher doses showed a trend towards benefit in preventing all grade HFS (69.6% vs 74.1%, p=0.23). CONCLUSIONS: Urea cream and celecoxib are both effective in preventing HFS/HFSR in patients receiving systemic cancer treatment. Particularly, celecoxib is more effective in preventing all-grade capecitabine-induced HFS, while urea cream shows more benefit in preventing moderate to severe sorafenib-induced HFSR. Studies investigating optimal dosing for celecoxib and urea cream are recommended. There is inadequate evidence to make recommendations regarding pyridoxine.

Randomized double-blind, placebo-controlled study of topical diclofenac in the prevention of hand-foot syndrome in patients receiving capecitabine (the D-TORCH study).

INTRODUCTION: Hand-foot syndrome (HFS) is a common cutaneous side effect of capecitabine therapy. Apart from oral cyclooxygenase-2 (COX-2) inhibitor (celecoxib), there are no proven strategies for the prevention of HFS. However, celecoxib is associated with significant cardiotoxicity. To date, no study has evaluated the role of topical COX inhibitor, diclofenac. In this study, we aim to compare topical 1% diclofenac gel with placebo in the prevention of capecitabine-induced HFS. METHODS: This is a randomized, placebo-controlled, double-blind, parallel-group superiority trial: the Diclofenac Topical in Reducing Capecitabine induced HFS (D-TORCH) study. A total of 264 patients with breast and gastrointestinal malignancies will be randomly allocated (stratified by sex and type of therapy [monotherapy or combination regimen with capecitabine]) to receive either 1% topical diclofenac or placebo that will be applied over the palmar and dorsal surface of the hands twice daily whilst taking capecitabine for 12 weeks. The patients will be followed up until the end of four cycles. The primary objective of this study is to compare the effect of topical diclofenac with placebo in preventing HFS (incidence of NCI CTCAEv5.0 grade 2 or higher HFS). The secondary objective is to compare the effect of topical diclofenac with placebo on preventing all grades of HFS (incidence of NCI CTCv5.0 all grade HFS), time to develop HFS (from the start of capecitabine), patient-reported outcomes (PROs) (HF-HRQoL questionnaire), adherence with the application (self-reported), capecitabine dose changes (number of patients with dose modifications due to HFS) and safety profile (NCICTCv5.0 all grade HFS) DISCUSSION: The D-TORCH study aims to determine if 1% topical diclofenac reduces the incidence of grade 2 or higher HFS in patients receiving capecitabine. To date, there have been a lot of trials for hand-foot syndrome prevention using agents like pyridoxine, vitamin E, carvedilol, and various polyherbal formulations, but none has been found successful. If the trial meets the primary end point, 1% topical diclofenac will be the new standard of care for HFS prevention. TRIAL REGISTRATION: Clinical Trials Registry of India  CTRI/2021/01/030592 . Prospectively registered on January 19, 2021.

Topical henna and curcumin (Alpha®) ointment efficacy for prevention of capecitabine induced hand-foot syndrome: A randomized, triple-blinded, placebo-controlled clinical.

PURPOSE: In this clinical trial, we evaluated Alpha® ointment efficacy in prevention of capecitabine induced hand-foot syndrome (HFS) in patients with gastrointestinal or breast cancers, for the first time. METHODS: During this pilot, randomized, triple-blinded, placebo-controlled clinical trial, the effect of Alpha® ointment (Lawsonia inermis 3 g and Curcuma longa 0.15 g/ 30 g) was assessed. It was applied on the palms and the soles, two times daily starting at the first day of chemotherapy for 4 consecutive courses. The severity of HFS was assessed at the end of the chemotherapy courses based on World Health Organization (WHO) scale and scored between 0-4. RESULTS: Ninety eligible patients were included randomly in the treatment or placebo group. Median WHO HFS grade was not significantly different between the two groups, during the follow-up period (P > 0.05). In the weekly assessment, the scores increased meaningfully in both the placebo and treatment groups, but there was a delay in HFS occurrence and deterioration in Alpha ointment group based on post hoc analysis. CONCLUSION: Administration of Alpha® ointment containing henna and curcumin could not significantly prevent capecitabine induced HFS during 4 courses of treatment, but can somewhat delay its occurrence in patients with gastrointestinal or breast cancer.

Effect of Urea Cream on Hand-Foot Syndrome in Patients Receiving Chemotherapy: A Meta-analysis.

BACKGROUND: Hand-foot syndrome (HFS) is a specific adverse effect of certain chemotherapy that may lead to dosage reduction or chemotherapy discontinuation in patients with cancer. Topical urea cream may reduce symptom severity in patients with HFS. However, these studies have not provided consonant results. OBJECTIVE: To determine the effectiveness of urea cream, we conducted a meta-analysis of clinical trials to evaluate the prevention and treatment of HFS. METHODS: PubMed, EMBASE, and Cochrane Library databases were searched for studies published before September 2020. The study registered at PROSPERO (CRD 42020203164). Incidence of HFS reported in studies at any grade and at second grade or greater was assessed within 3 to 12 weeks. Secondary outcomes were time to HFS, incidence of skin-related adverse events, chemotherapy dose reduction, and quality of life. RESULTS: Seven trials involving 1387 patients were reviewed. In the prophylactic subgroup, patients with urea cream intervention showed a significantly lower incidence of HFS at second grade or greater (risk ratio, 0.72; 95% confidence interval, 0.58-0.90) and a nonsignificant lower incidence of any-grade HFS (risk ratio, 0.79; 95% confidence interval, 0.58-1.08) than those not receiving urea cream intervention. CONCLUSIONS: Urea cream has advantages to reduce the incidence of severe HFS. IMPLICATIONS FOR PRACTICE: Urea cream is a safe and viable topical prevention strategy that can reduce the incidence of high-grade HFS in patients undergoing chemotherapy. We recommend a routine treatment option before chemotherapy for the patients.

Validation of the prophylactic efficacy of urea-based creams on sorafenib-induced hand-foot skin reaction in patients with advanced hepatocellular carcinoma: A randomised experiment study.

BACKGROUND: Hand-foot skin reaction may influence the effectiveness of patients' treatment, patient quality of life, and the economics of health care. An effective prophylactic dermatological cream for preventing sorafenib-induced hand-foot skin reaction (HFSR) is yet to be identified. AIM: The aim of this study is validated the prophylactic efficacy of urea-based creams on sorafenib-induced hand-foot skin reaction in patients with advanced hepatocellular carcinoma. METHODS: This was a randomised double-blind experimental study. A total of 129 patients with advanced HCC were randomly assigned to three groups. The comparison group received best supportive care (BSC), group A received BSC plus a moisturising cream, and group B received BSC plus a 10% urea-based cream. Incidence of HFSR and cutaneous wetness were assessed 3 days before starting sorafenib and each week after starting sorafenib for 8 weeks. RESULTS: No significant difference was observed in the incidence density of sorafenib-induced HFSK (comparison group/A group, p > .05; comparison group/B group, p > .05). Group B reported significantly better cutaneous wetness of hands in the seventh week after starting sorafenib (p < .05) and of feet during the first 6 weeks (p < .05-.001). CONCLUSION: This study found a nut size amount of a 10% urea-based cream applied twice a day can maintain patients' cutaneous wetness in the first 6 weeks after starting sorafenib than moisturising-alone cream. But it cannot reduce the occurrence of HFSR. Thus, the result supports nut-size dose of the 10% urea-based cream three times a day may be an appropriate dose to prevent HFSR. Clinical Trail Registration Number: NCT04568330.

Preemptive Versus Reactive Topical Clobetasol for Regorafenib-Induced Hand-Foot Reactions: A Preplanned Analysis of the ReDOS Trial.

BACKGROUND: Hand-foot skin reaction (HFSR) is the most common regorafenib-induced adverse event and is in need of effective prevention and palliation. MATERIALS AND METHODS: The 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. RESULTS: Sixty-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. CONCLUSION: Preemptive clobetasol might lessen regorafenib-induced hand-foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort. IMPLICATIONS FOR PRACTICE: Regorafenib 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.

Pyridoxine for prevention of hand-foot syndrome caused by chemotherapy agents: a meta-analysis.

BACKGROUND: Hand-foot syndrome (HFS) is a common systemic skin toxicity syndrome caused by chemotherapy agents. However, there is no uniform clinical treatment for HFS. It is reported that pyridoxine (vitamin B6) can be used to prevent HFS, but the evidence is insufficient. AIM: To determine whether pyridoxine can be used to prevent HFS caused by chemotherapy agents. METHODS: Literature database searches were performed on PubMed, Web of Science, Embase, Cochrane Library and China National Knowledge Infrastructure. The efficacy of pyridoxine was evaluated by the incidence of HFS (any grade) or severe HFS (grade ≥ 2). RESULTS: Fourteen studies involving 1570 patients were included in this meta-analysis. There were no significant differences between the pyridoxine and control groups in the prevention of HFS (OR = 0.84, 95% CI 0.67-1.05, P = 0.09) or in the incidence of grade ≥ 2 HFS (OR = 0.87, 95% CI 0.70-1.09, P = 0.39, respectively). The subgroup analysis of pyridoxine dose also showed no significant difference between the two groups in preventing HFS grade ≥ 2 (OR = 0.79, 95% CI 0.62-0.99, P = 0.30). CONCLUSIONS: We did not find adequate evidence to support the idea that the use of pyridoxine can prevent HFS and reduce the incidence of HFS grade ≥ 2. However, the preventive use of pyridoxine might have a tendency to reduce the incidence of HFS.

[Effect of ozone oil for prevention and treatment of sorafenib-induced hand-foot skin reactions: a randomized controlled trial].

OBJECTIVE: To compare the effects of medical ozone oil and urea ointment for prevention and treatment of hand-foot skin reaction (HFSR) caused by sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: A total of 99 patients diagnosed with advanced HCC according to National Comprehensive Cancer Network (NCCN) who were scheduled to receive sorafenib treatment for the first time were enrolled in this study between April, 2018 and January, 2020. The patients were randomized into medical ozone oil group (n=49) and urea ointment group (control group, n=49) for treatment with local application of 1 mL medical ozone oil (experimental group) and 10% urea ointment (2 g) on the palm and plantar skin (including the fingers and joints) for 12 weeks (3 times per day) starting at the beginning of sorafenib treatment, respectively. The patients were observed for occurrence of HFSR every 2 weeks for 14 weeks. RESULTS: Eight patients were excluded for poor compliance or protocol violations, leaving a total of 91 patients for analysis, including 44 in medical ozone oil group and 47 in urea ointment group. Sixteen (36.4%) of patients in ozone oil group developed HFSR, a rate significantly lower than that in urea ointment group (57.4%; P < 0.05). The incidence of grade 2/3 HFSR was also lower in ozone oil group than in urea ointment group (15.9% [7/44] vs 27.7 [13/47]). CONCLUSIONS: Medical ozone oil can significantly reduce the incidence and severity of HFSR to improve the quality of life of HCC patients receiving sorafenib treatment.

Effect of a Structured Teaching Module Including Intensive Prophylactic Measures on Reducing the Incidence of Capecitabine-Induced Hand-Foot Syndrome: Results of a Prospective Randomized Phase III Study.

LESSONS LEARNED: A structured teaching module including intensive prophylactic measures to alleviate hand-foot syndrome (HFS) during capecitabine therapy is feasible but ineffective at protecting patients from HFS. Pharmacologic therapeutic interventions should be investigated for the management of this complication. BACKGROUND: Capecitabine-induced hand-foot syndrome (HFS) has a detrimental effect on quality of life. The effect of a structured teaching module including intensive prophylactic measures was evaluated. METHODS: This non-crossover phase III double-blinded clinical trial randomized patients in a 1:1 ratio to either a control group or to a group administered a structured teaching model including intensive prophylactic measures on HFS administered by a trained oncology nurse at regular intervals (case) versus standard information on HFS care administered by treating clinician (control). The primary endpoint was comparison of fraction of patients in both arms developing at least grade 2 HFS. RESULTS: Between June 15, 2016, and April 4, 2018, 280 patients (140 to case and 140 to control) were enrolled. The median number of capecitabine chemotherapy cycles was eight; 269 patients (96%) were evaluable for HFS, of whom 89 patients (33.08%) developed at least grade 2 HFS (grade 2 HFS, 73 patients [26.1%]; grade 3 HFS, 16 patients (5.7%}). There was no difference in at least grade 2 HFS between evaluable case and control arms of the study (control group, 45/135 [33.3%]; case, 44/134 [32.8%]; p = .93). CONCLUSION: The use of a structured teaching module including intensive prophylactic measures was feasible, but this did not reduce the incidence and severity of capecitabine-induced HFS.

The effect of TJ-28 (Eppikajutsuto) on the prevention of hand-foot syndrome using Capecitabine for colorectal cancer: The Yokohama Clinical Oncology Group Study (YCOG1102).

BACKGROUND: Eppikajututo (TJ-28, a Kampo medicine) is effective against rheumatoid arthritis and eczema. We conducted a randomized comparative trial to assess the efficacy of TJ-28 for preventing hand-foot syndrome (HFS) as a complication of adjuvant chemotherapy using capecitabine. METHODS: The present study was a multi-institutional randomized-controlled trial (UMIN000005899). Colorectal cancer patients scheduled to receive capecitabine chemotherapy as adjuvant therapy were randomly assigned to receive TJ-28 (7500 mg/day) or oral pyridoxine (60 mg/day). Patients were monitored for the development of grade ≥ 2 HFS according to the National Cancer Institute Common Toxicity Criteria until chemotherapy completion. RESULTS: Twenty-two patients were enrolled in this study. The relative dose intensity of capecitabine was 76.2% in the TJ-28 group and 68.2% in the pyridoxine group. Grade ≥ 2 HFS developed in 6 (50.0%) of 12 TJ-28 patients and in 4 (40.0%) of 10 pyridoxine patients. Chemotherapy treatment failure was observed in seven patients, mainly due to HFS, liver dysfunction, diarrhea, and neutropenia. Chemotherapy treatment failure due to HFS occurred in none of the TJ-28 group and 2 patients (20.0%) in the pyridoxine group (p = 0.114). CONCLUSION: Capecitabine-associated HFS was not markedly prevented by TJ-28 compared with pyridoxine. However, TJ-28 might support the continuation of chemotherapy with capecitabine. Further studies are warranted to clarify the benefits of TJ-28.

Risk of hand-foot skin reaction associated with vascular endothelial growth factor-tyrosine kinase inhibitors: A meta-analysis of 57 randomized controlled trials involving 24,956 patients.

BACKGROUND: Multiple randomized controlled trials have assessed hand-foot skin reaction (HFSR) caused by vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). OBJECTIVE: We performed a meta-analysis to determine the incidence and the relative risk (RR) of HFSR associated with these agents. METHODS: Databases were searched for relevant studies. Statistical analyses were conducted to calculate the summary incidences, RR, and 95% confidence intervals (CIs) by using random-effects or fixed-effects models according to the heterogeneity of the included studies. RESULTS: A total of 24,956 patients from 57 studies were included. The overall incidence of all-grade and high-grade HFSR associated with VEGFR-TKIs was 35.0% (95% CI, 28.6%-41.6%) and 9.7% (95% CI, 7.3%-12.3%), respectively. The use of VEGFR-TKIs significantly increased the risk of developing all-grade (RR, 5.09; 95% CI, 3.52-7.35; P < .001) and high-grade (RR, 9.42; 95% CI, 5.59-15.90; P < .001) HFSR. Subgroup analyses revealed that the risk of HFSR was significantly increased according to tumor type, VEGFR-TKI, trial phase, treatment regimen, and control therapy. No evidence of publication bias was observed. LIMITATION: High heterogeneity in most studies. CONCLUSION: High risk of HFSR is prone to develop in cancer patients receiving VEGFR-TKIs.

A systematic review and Meta-analysis on the association between Hand-Foot Syndrome (HFS) and Cancer Chemotherapy Efficacy.

Hand-foot syndrome (HFS) is a common skin toxicity of traditional chemotherapies. Some studies showed that HFS has an association with progression-free survival (PFS) and the overall survival (OS). So far, there is not available any systematic literature reviews or meta-analysis aimed to assess the associations between HFS, PFS and OS. For this reason, this study aims to quantitatively summarize, critically review, and interpret the recent literature related to the associations between HFS and efficacy of chemotherapy in terms of PFS and OS. Queries shaped by PICOM framework, a systematic search of three electronic databases (PubMed, Scopus, and Science Direct) was carried out for the period between January 2010 and December 2017. Quantitative data pooling was based on the calculation of Hazard Ratio (HR) with 95% Confidence Interval (95% CI) for the OS and PFS associated to the presence of HFS, through the data of original publications. Five papers were included in this systematic review for the quantitative data pooling. Patients with HFS showed improved PFS (HR = 0.532 [0.431-0.656]; p = 0.000) and improved OS (HR = 0.522 [0.427-0.638]; p = 0.000). HFS causes a reduction of compliance with oncology treatments. Healthcare providers should use this result as a trigger to foster patients' coping and the one of their family caregivers, enhancing their adherence to cancer treatments.

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.

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.