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PEGylated liposomal doxorubicin (PLD) has effectively reduced the cardiac toxicity of free doxorubicin (DOX) due to its unique nanoscale properties. However, an unexpected accumulation of PLD in the skin has led to hand-foot syndrome (HFS), negatively impacting quality of life and psychological well-being. In this study, self-limiting HFS rat models were created to mimic human symptoms through varying dosing schedules and intensities of PLD. The effects of PLD formulation parameters on HFS were also investigated. The results demonstrated that replacing ammonium sulfate with citric buffer, increasing liposome size, or reducing DSPE-mPEG 2000 modification density alleviated HFS. Additionally, liposomes without DSPE-mPEG 2000 modification completely avoided HFS, suggesting that PEGylated phospholipid was the key formulation parameter contributing to PLD-induced HFS. Furthermore, the correlation between liposome pharmacokinetics and HFS indicated that PEGylation, rather than the extended circulation time of liposomes, may mediated PLD-related HFS. Better understanding of the formulation parameters that trigger HFS can guide reformulation strategies to mitigate or prevent this syndrome., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Palmar-plantar erythrodysesthesia (PPE), also known as hand and foot syndrome, is a condition characterized by inflammation-mediated damage to the skin on the palms and soles of the hands and feet. PPE limits the successful therapeutic applications of anticancer drugs. However, identifying this toxicity during preclinical studies is challenging due to the lack of accurate in vitro and in vivo animal-based models. Therefore, there is a need for reliable models that would allow the detection of this toxicity early during the drug development process. Herein, we describe the use of an in vitro skin explant assay to assess traditional DXR, Doxil reference listed drug (RLD) and two generic PEGylated liposomal DXR formulations for their abilities to cause inflammation and skin damage. We demonstrate that the results obtained with the in vitro skin explant assay model for traditional DXR and Doxil correlate with the clinical data., Competing Interests: Declaration of competing interest A.I., M.F., S.Sh., and A.D. are employees of Alcyomics Ltd., a contract research organization that owns the intellectual property and receives royalties from using the skin explant assay (trading as Skimune®.) All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR) are relatively common toxicities that interfere with the quality of life (QoL) of patients with cancer. Anti-inflammatory tripeptide cream (ATPC) is a complex formulation of anti-inflammatory tripeptides, the CD99-agonist Binterin and the Wnt-antagonist Winhibin. The present study aimed to assess the therapeutic effects of ATPC in HFS/HFSR associated with anticancer drugs., Materials and Methods: This was a single-center, randomized, double-blind, placebo-controlled trial. Patients who developed grade 1 HFS/HFSR after systemic anticancer treatments were enrolled, and randomly assigned to receive either ATPC or placebo cream (PC) and followed up at 3-week intervals for up to 9 weeks. Primary endpoint was the development of grade ≥ 2 HFS/HFSR., Results: Between April 2019 and July 2022, 60 patients (31 in the ATPC and 29 in the PC group) completed the study. The incidence of grade ≥ 2 HFS/HFSR was significantly lower in the ATPC than in the PC group (25.8% vs. 51.7%, p=0.039). The ATPC showed trends towards a better QoL score, assessed by a HFSR and QoL questionnaire at 9 weeks (26.0 vs. 29.9, p=0.574), and a lower frequency of discontinuation, interruption, or dose reduction of anticancer drugs (51.6% vs. 58.6%, p=0.586) than the PC group over 9 weeks, though without statistical significance., Conclusion: Our results showed that ATPC significantly decreased the development of grade ≥ 2 HFS/HFSR in patients already with HFS/HFSR. Therefore, ATPC may be an effective treatment for HFS/HFSR associated with anticancer drugs.

This study examines the effects of comprehensive nursing care on hand-foot syndrome (HFS) in breast cancer patients treated with capecitabine. A retrospective analysis was conducted on 71 patients, divided into a study group receiving comprehensive care and a control group receiving conventional care. Results showed that the study group experienced significant improvements in skin symptoms, self-efficacy, quality of life, and lower anxiety and depression levels compared to the control group. Additionally, patients who were compliant with medications were notably better in the study group. Comprehensive care effectively alleviates the symptoms of hand-foot syndrome in breast cancer patients treated with capecitabine and enhances patient well-being., Competing Interests: The Authors declared no conflict of interest, (African Journal of Reproductive Health © 2024.)

Introduction: Immune checkpoint inhibitors (ICIs) are linked with various cutaneous side effects ranging from mild to life-threatening. Herein, we present a unique case of palmar-plantar erythrodysesthesia (PPE) in a patient treated with atezolizumab., Case Report: A 72-year-old white man was diagnosed with Tumor, node, metastasis (TNM) stage IIIA lung adenocarcinoma in November 2022. He underwent right lower lobectomy and mediastinal lymphadenectomy followed by adjuvant cisplatin-pemetrexed. As of May 2023, he did not have any evidence of relapse. He then started switch maintenance therapy with atezolizumab. At 24 weeks, the patient developed erythematous palmar skin lesions, followed by blisters and peeling of both palms, which were associated with swelling and pain, consistent with grade 2 PPE., Management and Outcome: Causality assessment between nivolumab and PPE via adverse drug reaction probability scale revealed a score of 5. Atezolizumab was continued, and he started on a cream consisting of trolamine and 75% water to palms twice daily. A follow-up visit 6 weeks later showed significant improvement in symptoms and appearance of palmar lesions., Discussion: Cutaneous side effects are commonly seen with ICIs. PPE is a common dermatologic toxicity of certain tyrosine kinase inhibitors (TKIs). This effect has been previously reported with combination therapies consisting of an ICI plus a TKIs, but not with ICI monotherapy. Awareness of this potential side effect of ICIs would prevent unnecessary work-up, and lead to its prompt diagnosis and treatment., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: Lenvatinib mesylate (LEN) is an oral tyrosine kinase inhibitor used to treat various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events. This study was aimed at investigating the incidence of LEN-induced palmar-planter erythrodysesthesia syndrome (PPES) and its relationship with patient demographics by analyzing clinical laboratory data of LEN-treated patients with HCC., Methods: This was a single-centre, retrospective study of patients with HCC who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration., Results: Overall, 75 patients with HCC were enrolled. LEN-induced PPES was found in 48.0% (36/75 patients). In these patients, alkaline phosphatase (ALP), γ-Glutamyl transpeptidase (γ-GTP) and monocytes (MONO) were significantly high (ALP: p = 1.32 × 10 -3 , γ-GTP: p = 4.25 × 10 -3 and MONO: p = 0.013). The cut off values of ALP, γ-GTP and MONO for LEN-induced PPES were estimated at 573 U/L, 89 U/L, and 310 counts/μL, respectively. In the multivariate analysis, γ-GTP and MONO were independent risk factors for LEN-induced PPES., Conclusions: High γ-GTP and high MONO were risk factors for LEN-induced PPES., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: The aim of this study was to assess the clinical impact of hand-foot syndrome (HFS) during treatment with two multikinase inhibitors, sorafenib and lenvatinib, in a large group of patients with advanced thyroid cancer. Moreover, we looked for possible associations between HFS occurrence and clinical and pathological features., Methods: We retrospectively evaluated 239 patients with advanced thyroid cancer: 165 treated with lenvatinib and 74 with sorafenib. Statistical analyses were performed to verify which features could be correlated with HFS development., Results: HFS was observed in 35/74 (47.4%) and in 43/165 (26.7%) patients treated with sorafenib or lenvatinib, respectively. The median latency from the drug beginning and HFS appearance was 27 days for sorafenib and 2.9 months for lenvatinib. G3/G4 toxicity was observed in 16/35 (45.7%) patients treated with sorafenib and only in 3/43 (7%) treated with lenvatinib. Drug dose reduction due to HFS was required in 19/74 (25.7%) and 3/165 (1.8%) patients treated with sorafenib and lenvatinib, respectively. HFS occurrence was significantly associated with a longer duration of therapy in both groups., Conclusion: HFS was a frequent adverse event during both lenvatinib and sorafenib therapy, with a higher frequency and toxicity grade during sorafenib treatment. HFS was the most frequent reason for drug reduction or discontinuation in patient treated with sorafenib. Early diagnosis of HFS is important to allow early intervention, possibly in a multidisciplinary setting, and to avoid treatment discontinuation, which is highly relevant to obtain the maximum effectiveness of systemic therapy.

Purpose: Treatment with regorafenib, which inhibits vascular endothelial growth factor (VEGF) receptor, frequently results in hand-foot skin reaction (HFSR), requiring treatment discontinuation or dose reduction. In our prospective study of regorafenib on patients with metastatic colorectal cancer, 17% of patients developed grade 3 HFSR. Herein, we retrospectively examined genetic polymorphisms associated with regorafenib-induced severe HFSR., Methods: To identify associated polymorphisms, exploratory whole-exome sequencing focusing on factors related to VEGF-mediated signaling pathways was first performed in seven patients each, with grade 3 HFSR and without HFSR. The identified HFSR-associated polymorphisms were analyzed in all the 40 patients., Results: The genotype frequency of rs3025009 G/A or A/A in the gene encoding VEGF-A (VEGFA) in patients with ≥ grade 2 HFSR was significantly higher than in other patients (P = 0.0257, Pc = 0.0771 [Bonferroni correction]). The frequency of C-C motif of chemokine ligand 4-like 2 (CCL4L2) rs3744596 A/T or T/T in patients with grade 3 HFSR was significantly lower than in others (P = 0.00894, Pc = 0.0268). The combination of the risk genotypes VEGFA rs3025009 G/A or A/A and CCL4L2 rs3744596 A/A was significantly associated with a higher incidence of grade 3 (P = 0.000614, Pc = 0.00246) and a longer median progression-free survival (P = 0.0234) than others., Conclusions: These VEGF-related polymorphisms were found to be associated with HFSR and the survival benefits of regorafenib treatment., Trial Registration Number and Date: UMIN000013939, registered on May 12, 2014, when 6 months after the approval by the Institutional Review Board of Showa University., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hand-foot syndrome (HFS) is a frequently occurring and treatment-requiring adverse effect of docetaxel. We previously reported that systemic dexamethasone (DEX) prevents the other docetaxel-induced adverse inflammatory effects in a dose-dependent manner. This study aimed to evaluate the dose-dependent efficacy of systemic DEX in attenuating HFS in patients with breast cancer receiving docetaxel. Patients with breast cancer receiving docetaxel (75 mg/m 2 )-containing regimens (n = 111) were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2-4, and analyzed retrospectively. Development of all-grade HFS in all treatment cycles was significantly lower in the 8 mg group (50.0%) than in the 4 mg group (73.0%, P = 0.03), with primary endpoint accomplishment. Moreover, its development in the first cycle was also lower in the 8 mg group than in the 4 mg group. These results were confirmed in a propensity score-matched population. Logistic regression analysis suggested higher DEX dosage as an independent preventive factor (adjusted odds ratio 0.35; 95% confidence interval 0.14-0.86, P = 0.02 for all cycles; 0.26, 0.11-0.63, P = 0.003 for the first cycle). Our study suggests that systemic DEX prevents the occurrence of docetaxel-induced HFS in patients with breast cancer in a dose-dependent manner in a real-world setting., (© 2024. The Author(s).)

Introduction: Capecitabine has been widely prescribed to treat various cancers. The hand foot syndrome (HFS) is the most troublesome adverse effect. Urea cream has been pre-emptively co-prescribed, even though its efficacy is doubtful. Aloe vera gel with urea cream might potentiate each other. This trial was intended to prove the efficacy of this combination., Materials and Methods: The investigators conducted a randomized single-blinded phase II study. The participants were randomized 1:1 to receive the combination of aloe vera gel and 10% urea cream (n = 30), the experimental A+U arm and 10% urea cream alone (n = 31), the U arm. The sample size was calculated to have 90% power to show the significant 20% reduction in the incidence of HFS grade 2-3 of the combination therapy with alpha level = 0.05. Both the CTCAE criteria version 5 and the dermatology life quality index (DLQI) were assessed to determine the severity of HFS and quality of life, respectively., Results: Most of the participants had rectal cancer (A+U: 43.3%; U: 41.9%). In the A+U group, 86.7% had grade 0-1 HFS and 13.3% had grade 2-3 HFS. In the U group, 64.5% had grade 0-1 HFS and 35.5% had grade 2-3 HFS (Mann-Whitney U test, p = 0.045). Grade 2-3 HFS was significantly lower in the combination group., Conclusion: Combination of aloe vera gel and 10% urea cream ameliorated the severity of HFS in participants taking capecitabine; however, no significant difference in DLQI between the groups was demonstrated.

Purpose: Hand-foot skin reaction (HFSR), a side effect of tyrosine kinase inhibitor (TKI) treatment, makes it difficult to walk and perform daily activities because of pain in the limbs. HFSR occurs predominantly in the sites where external forces (pressure and shear stress) are applied. This study aimed to determine whether pressure or shear stress induces the occurrence of HFSR., Methods: This cohort study was conducted in patients who received TKI treatment for hepatocellular carcinoma. The external forces applied to the sole of the patients' foot while walking was measured, and its association with the occurrence of HFSR was examined. The degree of HFSR was assessed by the patient's response during the examination and by photographs of their feet. The patients' feet were divided into low (grade <2) or high (grade ≥2) HFSR foot group, and the differences in external forces between the groups were analyzed using t-test and Cox hazard analysis., Results: Analysis of the feet of 55 study participants (n = 110) showed no significant difference between the groups on t-test (p ≥ 0.05), however, Cox hazard analysis showed an increased risk of HFSR with higher peak shear stress values at the fifth metatarsal head (hazard ratio = 1.01, p = 0.047; 95% confidence interval = 1.00-1.02)., Conclusion: Shear stress is possibly related to HFSR occurrence. Nurses should assess whether patients' shoes fit their feet before initiating TKI treatment. They should instruct patients to wear shoes that are fit of both diameter and width for their feet., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yukie Tahara reports financial support was provided by Yamaji Fumiko Nursing Research Fund. Sadahisa Ogasawara reports a relationship with Bayer Corporation that includes: funding grants and speaking and lecture fees. Sadahisa Ogasawara reports a relationship with Eisai Inc that includes: funding grants and speaking and lecture fees. Sadahisa Ogasawara reports a relationship with Eli Lilly that includes: consulting or advisory, funding grants, and speaking and lecture fees. Sadahisa Ogasawara reports a relationship with Chugai Pharmaceutical Co Ltd that includes: consulting or advisory and speaking and lecture fees. Sadahisa Ogasawara reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory, funding grants, and speaking and lecture fees. Sadahisa Ogasawara reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Sadahisa Ogasawara reports a relationship with AbbVie Inc that includes: speaking and lecture fees. Sadahisa Ogasawara reports a relationship with Gilead Sciences that includes: funding grants and speaking and lecture fees. Sadahisa Ogasawara reports a relationship with Merck & Co Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Naoya Kato reports a relationship with Bayer Corporation that includes: funding grants and speaking and lecture fees. Naoya Kato reports a relationship with Eisai Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Naoya Kato reports a relationship with Sumitomo Dainippon Pharma Oncology, Inc. that includes: speaking and lecture fees. Naoya Kato reports a relationship with Merck & Co Inc that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Hand foot skin reaction (HFSR) is a common dose-limiting adverse effect of multi kinase inhibitors (MKI) whose mechanism is not fully understood, and the prophylaxis is inadequate., Objective: In this pilot study, a double-blind, randomized placebo-controlled trial was conducted to evaluate the effect of topical urea in secondary prevention of sunitinib-induced HFSR in renal cell cancer patients., Methods: Out of 55 screened patients, 14 were randomized to receive topical urea or placebo for four weeks. The association of HFSR with drug levels of sunitinib and its metabolite (n-desethyl sunitinib), genetic polymorphism of VEGFR2 gene, quality of life (QOL) and biochemical markers was also assessed., Results: The results showed that urea-based cream was not superior to placebo (P = .075). There was no change in the QOL in both the groups. Single nucleotide polymorphism was checked for two nucleotides rs1870377 and rs2305948 located in VEGFR2 gene on chromosome 4. SNP (variant T > A) at rs1870377 was associated with appearance of new HFSR as compared to the wild type, although the association was not statistically significant (OR 0.714). There was no statistically significant difference between mean plasma levels of sunitinib and N-desethyl sunitinib in urea arm as compared to placebo arm as compared to placebo. The best fit population pharmacokinetic model for sunitinib was one compartment model with first order absorption and linear elimination. The median (IQR) of population parameters calculated from the population pharmacokinetics model for Ka, V and Cl was 0.22 (0.21-0.24) h-1, 4.4 (4.09-4.47) L, 0.049 (0.042-0.12) L/hr, respectively., Conclusion: The study suggested that the urea-based cream was not superior to placebo in decreasing the appearance of new HFSR in renal cancer patients receiving 4:2 regimen of sunitinib., Competing Interests: Disclosure The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Hand-foot syndrome (HFS) and nail changes are frequent adverse events of anticancer therapies., Objectives: To provide a review of current evidence in HFS and nail disorders associated with medical tumor treatment., Materials and Methods: Basis is the current German S3 guideline "Supportive therapy in oncologic patients" and literature on this topic published since the guideline was finalized., Results: Two variants of HFS are distinguished: a chemotherapy-associated and a kinase-inhibitor-associated variant. In the first form, painful erythema, blisters and ulceration can occur, also in other areas with a high number of sweat glands such as axillary and inguinal regions. Thus, the secretion of toxic substances through sweat glands is a proposed pathogenetic mechanism. For the second form, which results in callus-like painful thickening of the horny layer on areas of mechanic pressure, a vascular mechanism is proposed. For prophylaxis of HFS, avoidance of mechanical stress, regular cleaning of predisposed areas, and also urea- and diclofenac-containing ointments are recommended; in case of infusions (taxanes, doxorubicine), cooling of hands and feet during infusion is recommended. In case of manifest HFS, dose reduction or prolongation of intervals of the associated treatment are recommended. Nail changes often develop under therapy with chemotherapeutic agents but also under treatment with agents such as checkpoint inhibitors or under targeted therapy. Different components of the nail unit may be involved such as the nail matrix, nail bed, nail plate, hyponychium, lunula and proximal and lateral nail folds., Conclusion: This work gives insight into the pathophysiology of HFS and nail disorders that develop under systemic oncologic treatments and gives recommendations for prophylaxis and treatment., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Hand-foot syndrome (HFS) is a common side effect of fluoropyrimidine anticancer drugs and often becomes a dose-limiting manifestation of toxicity once it occurs. The precise mechanism of HFS remains unclear, and effective measures to prevent or relieve it are currently limited. To investigate the pathogenesis of HFS and effective measures for treating or preventing it, establishment of animal models is crucial. Here, we gave male SD rats 170 mg/kg of tegafur (prodrug of 5-FU) daily for 35 days and evaluated their clinical and histopathological characteristics and pain-related behavioral tests. TUNEL-positive apoptotic cells and 5-FU concentrations in the plantar skin were also evaluated to investigate the mode of toxicity. Tegafur treatment induced hypersensitivity to mechanical pressure on the plantar surface beginning in Week 3, with decreased locomotor activity. Focal desquamation of the plantar skin was observed almost concomitantly and gradually worsened to palmar and plantar skin thickening with severe desquamation, cracks, or both. Histopathological lesions in the plantar skin at treatment end included desquamation and thickening, with epidermal cell swelling and spongiosis and focal inflammation in the dermis. The time-course of development and the characteristics of the tegafur-induced skin lesions were highly similar to those in human fluoropyrimidine-induced HFS, indicating that a HFS rat model was successfully established. Localized high concentrations of 5-FU in the palmar and plantar skin, with increased apoptosis, are likely involved in the mode of toxicity. Our model should clarify the pathogenesis of HFS, providing new insights into the best supportive care and prevention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

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.

Introduction: Hand-foot syndrome (HFS) significantly impacts quality of life in cancer patients undergoing capecitabine treatment. This study assessed capecitabine-associated HFS prevalence, its impacts on chemotherapy treatment, and identified risk factors in multiracial Malaysian patients., Methods: We included adult cancer patients receiving capecitabine at Sarawak General Hospital for at least two cycles from April 1, 2021 to June 30, 2022. HFS rates, time to HFS, and proportions of HFS-related treatment modifications were determined. Characteristics between patients with and without HFS were compared and multivariable logistic regression was used to identify risk factors for all-grade HFS and grade ≥2., Results: Among 369 patients, 185 (50.1%) developed HFS, with 14.6% experiencing grade ≥2 and 21.6% (40/185) underwent treatment modifications. Risk factors for all-grade HFS include older age (OR 1.03 95%CI 1.01, 1.06), prior chemotherapy (OR 2.09 95%CI 1.22, 3.58), higher capecitabine dose (OR 2.96 95%CI 1.62, 5.38), prolonged treatment (OR 1.36 95%CI 1.21, 1.51), folic acid intake (OR 3.27 95%CI 1.45, 7.35) and lower neutrophil count (OR 0.77 95%CI 0.66, 0.89). For HFS grade ≥2, older age (OR 1.04 95%CI 1.01, 1.08), female sex (OR 2.10 95%CI 1.05, 4.18), Chinese race (OR 2.10 95%CI 1.06, 4.18), and higher capecitabine dose (OR 2.62 95%CI 1.28, 5.35) are significant risk factors. Use of calcium channel blockers were associated with reduced risks of all-grade HFS (OR 0.27, 95%CI 0.12, 0.60) and grade ≥2 (OR 0.21 95%CI 0.06, 0.78)., Conclusion: This study provides real-world data on capecitabine-induced HFS in Malaysian patients and identifies risk factors that may offer insights into its understanding and management., (© 2024. The Author(s).)

Endometrial cancer (EC) is the most common gynaecological cancer. The combination of lenvatinib and pembrolizumab has exhibited efficacy as the second line treatment for advanced EC, with a significant benefit in terms of progression free survival (PFS) and overall survival, but the adverse events (AE) profile is complex. AEs associated with the treatment may represent a limitation to this combination. Here, we report the case of a 38-year-old female patient diagnosed with stage IV EC elsewhere, whose disease progressed after the first line of treatment and was referred to a specialised cacncer centre in Muscat, Oman, in 2021. We treated her with the combination of lenvatinib and pembrolizumab. During the course of the treatment, she developed hand-foot syndrome grade III and hypothyroidism grade II. The AEs were managed with supportive medications, dose interruptions, dose reductions and multidisciplinary care, which allowed the continuation of the treatment. The patient achieved a good partial response and an ongoing PFS of more than 12 months., (© Copyright 2024, Sultan Qaboos University Medical Journal, All Rights Reserved.)

Background: Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer., Methods: Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25., Results: Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks., Conclusions: The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted., Clinicaltrials.gov Identifier: NCT02393755., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Hand-foot syndrome, also known as palmar-plantar erythrodysesthesia (PPE), is a complication caused by chemotherapy. Clinically, it manifests as erythema and oedema on the palms of the hands and feet, dry and scaly skin, accompanied by a sensation of tightness and pain. Extreme cases have blisters and ulcerations that may require hospitalisation and/or pause in cancer treatment. It can also be accompanied by paraesthesia. Considering the characteristics, photobiomodulation (PBM) may reduce the PPE effects. The objective of this protocol will be to evaluate the efficacy of PBM in reducing PPE induced by capecitabine and 5-fluorouracil chemotherapy., Methods and Analysis: This will be a randomised controlled, double-blind, double-centre clinical trial (Centro Asistencial del Sindicato Médico del Uruguay and Instituto Nacional del Cáncer from Uruguay). The sample population (40 individuals) will be divided into two groups: group 1 will receive moisturising cream plus PBM treatment and group 2 moisturising cream plus PBM sham treatment, at the ratio of 1:1. PBM will be performed at 630 nm two times per week in palmoplantar areas of the hands and feet (4 J/cm 2 ), for 4 weeks. The PPE degree and the data referring to the chemotherapy treatment plan will be measured, prior to the start of treatment in the middle and at the end of it. Quality of life questionnaires will be applied at the beginning of the trial and at the end of treatment. The data will be analysed based on the intention-to-treat analysis and α<0.05 will be considered statistically significant., Ethics and Dissemination: The protocol was approved by the Research Ethics Committee of Universidad Católica del Uruguay (220316b), of Centro Asistencial del Sindicato Médico del Uruguay (221989) and of Instituto Nacional del Cáncer (2023-04). The recruitment has already started (March 2023)., Protocol Version: V.2, 27 October 2023., Trial Registration Number: ClinicalTrials.gov Registry (NCT05337423)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Mercaptopurine (6MP) and methotrexate (MTX) are commonly used for maintenance chemotherapy for acute lymphoblastic leukemia (ALL). These medications have been associated with various side effects such as myelosuppression, colitis, and thyroiditis in addition to numerous cutaneous adverse events. Cutaneous side-effects most reported include mucositis, alopecia, xerosis, and pruritus. We report an interesting case of hand-foot syndrome to 6MP in a child on maintenance therapy for B-cell ALL from an alteration in medication metabolism., Case: We report a 10-year-old male on maintenance chemotherapy for pre-Bcell ALL who presented to the hospital with worsening oral lesions and erythematous, fissured plaques on the palms and soles. Maintenance therapy consisted of IV vincristine and 5-day pulse of steroids every 12 weeks, daily 6MP, and weekly MTX, which were increased to  ≥ 150% of standard dosing due to persistent absolute neutrophil counts  > 1500. Metabolites obtained on admission demonstrated elevated 6MMP metabolites at 35,761 (normal < 5700). TPMT and NUDT15 enzyme activity were normal and no alterations in genotyping were discovered., Outcome: Patient's oral chemotherapy, including both 6MP and MTX, were stopped and allopurinol 100 mg daily was initiated, which lead to overall improvement., Discussion: Clinical findings of acute mucositis and worsening of hand-foot syndrome, in the setting of inadequate myelosuppression in a child on maintenance therapy for ALL should raise concerns to consider altered metabolism pathway leading to toxic metabolite buildup. Allopurinol can play in improving cutaneous manifestation and chemotherapeutic dosing in patients with altered metabolism., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Anthracycline anti-cancer drugs have been widely used in the treatment of several cancers; however, their use is limited by adverse effects (AEs). Alopecia is a common AE that is minimally invasive, but adversely affects mental health and reduces quality of life (QoL). Hand-foot syndrome (HFS) is a dose-limiting AE of DOXIL, a liposomal formulation of doxorubicin (DOX). Although it is not a life-threatening condition, HFS affects function and reduces QoL. TXB-001 is a new candidate polymer-conjugated anthracycline anti-cancer drug, and modified and optimized polymerized pirarubicin (THP), known as P-THP, is expected to have low toxicity and high efficacy. The anti-cancer effects of TXB-001 were examined using the 4T1 mouse model. An alopecia mouse model and HFS rat model were used to evaluate the alopecia- and HFS-inducing effects of TXB-001 and compare their severity with existing anthracycline anti-cancer drugs. A pharmacokinetic analysis of plasma as well as chest, palmar, and plantar skin samples after the single intravenous administration of DOXIL and TXB-001 to rats was also performed. The results obtained revealed that TXB-001 exerted similar anti-cancer effects to those of DOXIL in mice, weaker alopecia-inducing effects than DOX, DOXIL, and THP in mice, and no or markedly weaker HFS-like changes than DOXIL, which induced significant histopathological changes. The results of the pharmacokinetic analysis showed the accumulation of DOXIL, but not TXB-001, in skin, particularly palmar and plantar skin samples, and these differences were considered to contribute to their HFS-inducing effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Patients with residual nasopharyngeal carcinoma after receiving definitive treatment have poor prognoses. Although immune checkpoint therapies have achieved breakthroughs for treating recurrent and metastatic nasopharyngeal carcinoma, none of these strategies have been assessed for treating residual nasopharyngeal carcinoma. In this single-arm, phase 2 trial, we aimed to evaluate the antitumor efficacy and safety of toripalimab (anti-PD1 antibody) plus capecitabine in patients with residual nasopharyngeal carcinoma after definitive treatment (ChiCTR1900023710). Primary endpoint of this trial was the objective response rate assessed according to RECIST (version 1.1). Secondary endpoints included complete response rate, disease control rate, duration of response, progression-free survival, safety profile, and treatment compliance. Between June 1, 2020, and May 31, 2021, 23 patients were recruited and received six cycles of toripalimab plus capecitabine every 3 weeks. In efficacy analyses, 13 patients (56.5%) had complete response, and 9 patients (39.1%) had partial response, with an objective response rate of 95.7% (95% CI 78.1-99.9). The trial met its prespecified primary endpoint. In safety analyses, 21 of (91.3%) 23 patients had treatment-related adverse events. The most frequently reported adverse event was hand-foot syndrome (11 patients [47.8%]). The most common grade 3 adverse event was hand-foot syndrome (two patients [8.7%]). No grades 4-5 treatment-related adverse events were recorded. This phase 2 trial shows that combining toripalimab with capecitabine has promising antitumour activity and a manageable safety profile for patients with residual nasopharyngeal carcinoma., (© 2024. The Author(s).)

Hand-foot skin reaction (HFSR) is a specific but uncommon cutaneous side effect mainly following chemotherapeutic drugs such as multitargeted kinase inhibitors. HFSR is reversible and non-life-threatening. HFSR, also known as palmoplantar erythrodysesthesia, presents with various degrees of erythema, edema, hyperkeratosis, blister, and sometimes with a fine white scale. Dolutegravir, a first next-generation integrase inhibitor, is used with other antiretroviral therapy (ART) to treat mainly HIV infections. HFSR is diagnosed depending on the suggestive association of drug intake and characteristic palmoplantar eruption. ART can cause several cutaneous adverse drug reactions though no case report of dolutegravir-induced HFSR has been reported till date in literature. Here, we present a case of HFSR in a seropositive male on ART., (Copyright © 2024 Copyright: © 2024 Indian Journal of Pharmacology.)

Purpose: To analyze the safety and efficacy of orally administered metronomic capecitabine plus pyrotinib in HER2 positive metastatic breast cancer (MBC) patients, we conducted a prospective phase II study with a single-arm design., Methods: HER2 positive patients received oral metronomic capecitabine 500 mg three times a day and pyrotinib 400 mg per day. The primary endpoint was progression-free survival (PFS). Other endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR) and safety., Results: The study included 50 patients with MBC that was HER2-positive, while 1 patient was excluded due to nonstandard medication. The median PFS and OS was 11.9 months (95%CI 8.8-14.6) and 29.3 months (95%CI 24.4-34.8) respectively. ORR was 34.7%, and CBR was 81.6% with 2 CR (4.1%), 15 PR (30.6%) and 23 SD (46.9%). The mPFS in first- or second-line treatment was 12.2 months. The most frequent treatment-related adverse events included hand-foot syndrome, diarrhea, vomiting and nausea. Grade 3 adverse events occurred in 15(30.6%) patients, including hand-foot syndrome (12.2%), diarrhea (12.2%), vomiting (4.1%), and nausea (2.0%). 1 grade 4 adverse event of diarrhea (2.0%) was observed., Conclusion: The combination of metronomic capecitabine and pyrotinib is a promising regimen with competitive efficacy and improved tolerability in HER2 positive metastatic breast cancer patients., Competing Interests: Declaration of Competing interest The authors declare that there are no conflict of interests, we do not have any possible conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

Hand-foot syndrome (HFS) can be categorized as a frequent dose-limiting side effect following administration of chemotherapeutic agents, which needs an effective medication to avoid dose reduction or discontinuation. Oral celecoxib has been proved to be the best pharmacological intervention to ameliorate the skin lesions. However, due to reported gastrointestinal and cardiovascular toxicity following its long-term administration, celecoxib topical application would be a safe alternative for skin disorders. In this work, first, we formulated and optimized a topical hydrogel of celecoxib (1%) and then we investigated its efficacy in the management of chemotherapy-induced HFS in cancer patients. Optimized hydrogel showed acceptable results for drug content, pH, rheology, and stability. Analyzing in vitro drug release study by various mathematical models, the optimized hydrogel showed a zero-order release pattern with 93.27 ± 1.56% cumulative celecoxib release within 8 h. Ex vivo permeation studies across Wistar rat skin indicated suitable skin retention of celecoxib for topical delivery. Twenty-nine patients suffering from HFS were randomized to receive celecoxib and the placebo hydrogels 2 times a day for 3 weeks. At the baseline and at the end of the trial, HFS grades were determined. No serious adverse events occurred in patients who completely followed the instructions. No statistically significant differences between two arms were observed at the baseline (p value = 0.38). By contrast, Wilcoxon signed-rank test showed significant differences when secondary grades (p value = 0.05) and grade differences (p values < 0.001) were analyzed. Overall, the study proved that celecoxib hydrogel could be a promising intervention to manage HFS side effect., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hand-foot syndrome (HFS), also known as palmoplantar erythrodysesthesia or acral erythema, is a known adverse effect of chemotherapeutic agents that most commonly presents as palmoplantar dysesthesia and erythematous plaques localized to the palms and soles. Paclitaxel is an uncommon cause of HFS and is notable for its unique presentation on the dorsal hands and feet. We present an unusual case of paclitaxel-induced HFS localized to the dorsal hands of a 66-year-old man with metastatic angiosarcoma. Early identification and management of HFS is critical to allow for continuation of chemotherapy while improving patient quality of life.

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/m 2 and 40 mg/m 2 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., (© 2023. The Author(s).)

Background: Fluoropyrimidines (FPs) are an essential part of the majority of systemic regimens in the treatment of metastatic colorectal cancer (CRC). The use of the oral FP S-1 has been approved by the European Medicines Agency as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, for the treatment of patients with metastatic CRC in whom it is not possible to continue treatment with another FP due to hand-foot syndrome (HFS) or cardiovascular toxicity (CVT). Subsequently, this indication has been included in the 2022 ESMO guidelines for metastatic CRC. Recommendations for use in daily practice are not available., Patients and Methods: Based on peer-reviewed published data on the use of S-1 in Western patients with metastatic CRC who switched from infusional 5-fluorouracil (5-FU) or capecitabine to S-1 for reasons of HFS or CVT, recommendations for its use were formulated by an international group of medical oncologists with expertise in the treatment of metastatic CRC and a cardio-oncologist., Results: In patients who experience pain and/or functional impairment due to HFS during treatment with capecitabine or infusional 5-FU, a switch to S-1 is recommended without prior dose reduction of capecitabine/5-FU. S-1 should preferably be initiated at full dose when HFS has decreased to grade ≤1. In patients with cardiac complaints, in whom an association with capecitabine or infusional 5-FU treatment cannot be excluded, capecitabine/5-FU should be discontinued and a switch to S-1 is recommended., Conclusions: These recommendations should guide clinicians in daily practice in the treatment of patients with metastatic CRC with FP-containing regimens., Competing Interests: Disclosure CJAP reports an advisory role for Nordic Pharma. VH reports honoraria from Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS, MSD, Novartis, Boehringer Ingelheim, Celgene, SIRTEX, Terumo, OncoSil, Nordic Pharma, Seagen; and research funding from Merck, Amgen, Roche, Sanofi, Boehringer-Ingelheim, SIRTEX, and Servier. TM reports an advisory role for Nordic Pharma, Perspectum, and AstraZeneca. CC reports honoraria from Amgen, Bayer, Servier, Merck-Serono, MSD, Organon, Pierre-Fabre, Roche, and Nordic Pharma; research grants from Merck-Serono, Bayer, and Servier. EVC reports participation in advisory boards for AbbVie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, and Zymeworks; and research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier paid to his institution. RM reports advisory board fees from Astellas Pharma, Bayer, Bristol Myers Squibb, Clovis Oncology, F. Hoffmann–La Roche, Ipsen Biopharm, Janssen Biotech, Merck, and Pfizer; and clinical trial fees from Regeneron Pharmaceuticals. GB reports advisory role for Amgen, Astellas, Bayer, Janssen, Lilly, MSD, Merck, Nordic Pharma, Novartis, Pfizer, Roche, and Ipsen; and lecture fees from Amgen, Bayer, GSK, Merck, Nordic Pharma, Novartis, and Roche. TA reports honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pierre Fabre, Roche/Vantana, Sanofi, and Servier; consulting or advisory roles for Amgen, Astellas Pharma, Bristol-Myers Squibb, GamaMabs Pharma, Gritstone Oncology, Merck Sharp & Dohme, Nordic Pharma, Pierre Fabre, Seagen, and Servier; and Transgène speaker’s bureaus for Bristol-Myers Squibb, Merck Sharp & Dohme, Seagen, and Servier; travel and accommodation expenses from Merck Sharp & Dohme, and Bristol-Myers Squibb; and nonremunerated activities for the ARCAD Foundation and GERCOR Group. PO reports honoraria from/advisory role for Amgen, Astra Zeneca/Daiichi Sankyo, Bristol-Myers Squibb, Eisai/Ewopharma, Fresenius, Incyte, Janssen, Merck, Merck, Sharp & Dome, Nordic Drugs/Pharma, Nutricia, Pierre Fabre, Roche, Sanofi, and Servier; research support to institution from Amgen, Eli Lilly, Merck, Roche, Sanofi, and Servier; and nonremunerated activities with Colores, Duodecim, ESMO faculty, ESMO scientific committee, ESMO guidelines committee, ASCO/ESMO global curriculum, and the ESMO Lines of therapy project. PP reports advisory role for Servier, Nordic Pharma, and MSD; and research funding for institution from Servier, Nordic Drugs, Shire, Merck, Egetis, Isofol, Lilly, Roche, Merck-Serono, Amgen, and Celgene. AJT has declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: This retrospective study was conducted to identify risk factors for developing hand-foot syndrome (HFS) and to determine new strategies for improving quality of life (QoL) in patients undergoing chemotherapy., Methods: Between April 2014 and August 2018, we enrolled 165 cancer patients at our outpatient chemotherapy center who were undergoing capecitabine chemotherapy. Variables related to the development of HFS were extracted from the clinical records of patients for use in regression analysis. HFS severity was assessed at the time of completing capecitabine chemotherapy. The degree of HFS was classified in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Multivariate ordered logistic regression analysis was performed to identify risk factors for the development of HFS., Results: Risk factors for the development of HFS included concomitant use of a renin-angiotensin system (RAS) inhibitor (odds ratio [OR] = 2.85, 95% confidence interval [CI] = 1.20-6.79; p = 0.018), body surface area (BSA) (high) (OR = 12.7, 95% CI = 2.29-70.94; p = 0.004), and albumin (low) (OR = 0.44, 95% CI = 0.20-0.96; p = 0.040)., Discussion/conclusion: Concomitant use of RAS inhibitor, high BSA, and low albumin were identified as risk factors for the development of HFS. The identification of potential risk factors of HFS may assist in the development of strategies that can be used to improve QoL in patients receiving chemotherapy regimens that include capecitabine., (© 2023 S. Karger AG, Basel.)

Background: Hand-foot syndrome (HFS) is a serious dose-limiting cutaneous toxicity of capecitabine-containing chemotherapy, leading to a deteriorated quality of life and negative impacts on chemotherapy treatment. The symptoms of HFS have been widely reported, but the precise molecular and cellular mechanisms remain unknown. The metabolic enzyme of capecitabine, thymidine phosphorylase (TP) may be related to HFS. Here, we investigated whether TP contributes to the HFS and the molecular basis of cellular toxicity of capecitabine., Methods: TP-/- mice were generated to assess the relevance of TP and HFS. Cellular toxicity and signalling mechanisms were assessed by in vitro and in vivo experiments., Results: TP-/- significantly reduced capecitabine-induced HFS, indicating that the activity of TP plays a critical role in the development of HFS. Further investigations into the cellular mechanisms revealed that the cytotoxicity of the active metabolite of capecitabine, 5-DFUR, was attributed to the cleavage of GSDME-mediated pyroptosis. Finally, we demonstrated that capecitabine-induced HFS could be reversed by local application of the TP inhibitor tipiracil., Conclusion: Our findings reveal that the presence of elevated TP expression in the palm and sole aggravates local cell cytotoxicity, further explaining the molecular basis underlying 5-DFUR-induced cellular toxicity and providing a promising approach to the therapeutic management of HFS., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: This study aimed to evaluate the frequency of nail disorders and the presence of fungi on the nails of the hands and feet of patients with hand-foot syndrome secondary to treatment with paclitaxel., Methods: Prospective study, carried out from October 2018 to December 2019, which included 81 patients undergoing treatment for breast cancer using paclitaxel and had signs and or symptoms of hand-foot syndrome with or without nail disorders. The data were collected through interviews guided by a structured questionnaire, information from medical records and reports of mycological exams., Results: The average age of women was 54.7 ± 7.4 years. Nail disorders occurred in 69 patients (85.2%), and of these, 43 (62.3%) were positive for fungi. The fungi were yeasts ( n  = 38; 69%), dermatophytes ( n  = 15; 27.2%) and non-dermatophyte filamentous fungi ( n  = 8; 14.5%)., Conclusions: Nail disorders were the most frequent manifestations in patients with hand-foot syndrome treated with paclitaxel and occurred in 85.2% of them. It was evidenced that fungi are present on the nails of these patients and can occur in up to 65.28%. The most prevalent fungi were Candida and Trichophyton . The nail lesion was associated with the type of treatment protocol used by the patient. The results of the study point to the need to select safe management alternatives for patients, so they can prevent nail lesions and prevent the proliferation of fungi, consequently reducing negative life impact during treatment.

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2022 Wiley Periodicals LLC.)

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., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The oral fluoropyrimidine S-1 has shown comparable efficacy to capecitabine in Asian and some Western studies on metastatic colorectal cancer. S-1 is associated with a lower incidence of hand-foot syndrome (HFS) and cardiac toxicity. We assessed the long-term tolerability of S-1 in patients who discontinued capecitabine for reasons of HFS or cardiac toxicity., Patients and Methods: Patients with metastatic colorectal cancer who switched from capecitabine to S-1, given as monotherapy or in combination with other agents, were identified in a Dutch prospective cohort study (2016-2021). The incidence and severity of HFS, cardiotoxicity and other toxicities were assessed., Results: Forty-seven patients were identified. The median duration of capecitabine treatment was 81 days (range 4-454). In 19 patients (40%) a dose reduction was applied prior to switch to S-1. Reasons for discontinuation of capecitabine were HFS in 36 (77%) patients, coronary artery vasospasms in 10 (21%) patients, and gastrointestinal toxicities in 1 patient (2%). The median number of S-1 cycles was 6 (range 1-36). The median time between last dose of capecitabine and first dose of S-1 was 11 days (range 1-49). After switch to S-1, all patients with prior HFS developed a lower grade or complete resolution of symptoms, and in all other patients symptoms did not recur. Other S-1-related adverse events were limited to grade 1-2. Six patients (13%) discontinued S-1 due to either known fluoropyrimidine-related or bevacizumab-related toxicities. Switch to S-1 did not appear to compromise treatment efficacy., Conclusion: S-1 is a valid alternative to capecitabine in case HFS or cardiotoxicity occurs., (Copyright © 2022. Published by Elsevier Inc.)

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., (© 2022. The Author(s).)

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., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Hand-foot syndrome (HFS) is a common adverse event in patients receiving capecitabine therapy for breast cancer, and the symptoms of HFS significantly impair patient quality of life. However, currently there are no effective drugs or measures to prevent and alleviate the occurrence of HFS., Aim: To assess the effectiveness of a novel soaking solution, a mixture solution of dexamethasone, gentamicin and vitamin B12, in patients with grade 2-3 HFS after capecitabine treatment for breast cancer., Materials and Methods: Patients with grade 2-3 HFS according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) were enrolled in this randomized, single-center, self-controlled trial. Each patient's right and left hands or feet were individually randomized to soak in either a novel soaking solution (treated hands or feet) or a placebo liquid (control hands or feet) for three times a day, each time for 15 minutes and for four weeks. Effectiveness was evaluated according to CTCAE grades, defined as a reduction of 1 or more CTCAE grades., Results: A total of 60 patients were enrolled. The HFS CTCAE grade of the treated hands and feet at 4 weeks of HFS treatment was significantly decreased compared to that of the control hands and feet (P = .005). Significant differences were also observed between the treatment conditions in terms of the HFS effectiveness rate: treated group 80% and placebo group 51.7% (P = .001). No adverse or unexpected events were observed during the whole trial., Conclusion: Soaking affected hands or feet in a novel soaking solution safely and effectively reduced the severity of HFS following treatment with capecitabine for breast cancer., (Copyright © 2022. Published by Elsevier Inc.)

Hand-foot syndrome (HFS) is a common adverse effect of anticancer therapy. It is known to cause dermatological symptoms including acral erythema and dysesthesia of the palms and soles of the feet, swelling, pain, itching, and scaling. Some drugs, like capecitabine, are known to trigger this condition. However, pigmentation of the oral mucosa is a rare adverse effect. This study aims to report a case of oral mucosa hyperpigmentation caused by capecitabine therapy before the clinical diagnosis of HFS. A 58-year-old female, diagnosed with invasive breast duct carcinoma, had the central nervous system, liver, skin, and lung metastasis, using capecitabine every day for 14 cycles. Oral examination revealed multifocal black macules on the hard palate, bilateral buccal mucosa, gingival mucosa, and dorsum of the tongue. The clinical hypothesis was oral mucosa hyperpigmentation by capecitabine use and only periodic follow-up was necessary. Hyperpigmentation of oral mucosa by capecitabine is a rare consequence of neoplastic therapy and your association with HFS is unclear, and poorly reported. The report of these events is important to alert oncology health teams about the individual tolerance to capecitabine therapy.

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., (© 2022. Springer Nature Switzerland AG.)

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., (© 2022. The Author(s).)

Early detection and management of adverse drug reactions (ADRs) is crucial for improving patients' quality of life. Hand-foot syndrome (HFS) is one of the most problematic ADRs for cancer patients. Recently, an increasing number of patients post their daily experiences to internet community, for example in blogs, where potential ADR signals not captured through routine clinic visits can be described. Therefore, this study aimed to identify patients with potential ADRs, focusing on HFS, from internet blogs by using natural language processing (NLP) deep-learning methods. From 10,646 blog posts, written in Japanese by cancer patients, 149 HFS-positive sentences were extracted after pre-processing, annotation and scrutiny by a certified oncology pharmacist. The HFS-positive sentences described not only HFS typical expressions like "pain" or "spoon nail", but also patient-derived unique expressions like onomatopoeic ones. The dataset was divided at a 4 to 1 ratio and used to train and evaluate three NLP deep-learning models: long short-term memory (LSTM), bidirectional LSTM and bidirectional encoder representations from transformers (BERT). The BERT model gave the best performance with precision 0.63, recall 0.82 and f1 score 0.71 in the HFS user identification task. Our results demonstrate that this NLP deep-learning model can successfully identify patients with potential HFS from blog posts, where patients' real wordings on symptoms or impacts on their daily lives are described. Thus, it should be feasible to utilize patient-generated text data to improve ADR management for individual patients., Competing Interests: HY is the CEO of Mediaid Corporation, which operates LifePalette. The other author(s) declare no competing interests.

Background/aim: Hand-foot syndrome (HFS) is the most common adverse event associated with capecitabine, and its pathogenesis is known to be associated with inflammation. Proton pump inhibitors (PPIs) reportedly exert anti-inflammatory effects; however, the impact of PPIs on capecitabine-induced HFS needs to be clarified in the clinical setting. In the present study, we retrospectively investigated the efficacy and safety of PPIs in patients with breast cancer receiving capecitabine., Patients and Methods: We analyzed the effects of PPIs on the development of severe HFS (grade ≥2), progression-free survival (PFS), and overall survival (OS) in 195 patients who received capecitabine chemotherapy for breast cancer., Results: In total, 50 patients (26%) were treated with PPIs, while 145 patients (74%) did not receive PPIs. The incidence of severe HFS was significantly lower in patients who received PPIs (18%) than in patients who did not receive PPIs (43%, p=0.001), and the discontinuation rate of capecitabine therapy due to HFS was also lower in patients receiving PPIs than in those who did not receive PPIs (p=0.003). Multivariate analysis revealed that concomitant PPIs use was an independent factor that significantly contributed to the prevention of severe HFS (odds ratio (OR)=0.265, p=0.003). Meanwhile, no significant difference in median PFS and OS values was observed between patients treated with and without PPIs., Conclusion: Concomitant use of PPIs could ameliorate capecitabine-induced HFS in patients with breast cancer., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Chemotherapy drugs can be responsible of several side effects such as hand-foot syndrome (HFS). This syndrome is also called "palmar-plantar erythrodysesthesia" and "acral erythema." Without proper management, it can deteriorate the quality of life of a patient, leading to temporary or definitive stop of chemotherapy., Aim of This Study: To identify the epidemiological and clinical characteristics of patients, the risk factors for occurrence and worsening of this syndrome, and the drugs most likely to be responsible of HFS., Methods: Our study was retrospective, including 42 patients with HFS secondary to a chemotherapy drug. These cases were notified to the National Center of Pharmacovigilance over 7 years. The severity of HFS has been classified according to the NCI-CTCAE v4.0 classification., Results: Our population was composed of 40 women and 2 men. The mean age was 51 years. Docetaxel was the main drug associated with this adverse effect. Hands were involved in all cases and were sometimes associated with other skin surfaces apart from feet. Erythema of the hands and/or feet was present in all patients; it was associated with edema in more than half of the cases. The distribution of different grades according to the NCI-CTCAE classification among the patients was almost equal: 28% Grade 1, 36% Grade 2, and 36% Grade 3. HFS occurred mainly after the first course of chemotherapy with a mean period of 3-4 days. The regression of HFS occurred more rapidly for Grade 1 and Grade 2 compared with Grade 3, especially when assisted by symptomatic treatment. The recurrence rate of HFS for those patients with decreased doses, spacing of cures, and/or symptomatic and prophylaxis treatment was 25%., Conclusion: An early detection of HFS, associated with preventive measures, enables patients to continue the chemotherapy., Competing Interests: None