Identification of hand-foot syndrome from cancer patients' blog posts: BERT-based deep-learning approach to detect potential adverse drug reaction symptoms.

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.

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.

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.

Liposomal doxorubicin-related palmar-plantar erythrodysesthesia (hand-foot syndrome): a case report.

Hand-foot syndrome (HFS) is a skin toxicity that occurs in areas of compressed skin. HFS manifests mainly in insensitive palms and the soles of the feet or in erythematous areas on the extremities caused by chemotherapy, which may be related to the dosage. This paper reports a case of HFS caused by liposomal doxorubicin. A 64-year-old Asian woman presented with severe erythema, ulceration, pruritus, and edema-related pain in her back, hands, and feet after receiving four cycles of liposomal doxorubicin. Clinicians and a pharmacist analyzed and evaluated the patient's adverse reactions. After symptomatic treatment and patient education, her HFS symptoms were significantly relieved. The purpose of this study was to raise clinical awareness regarding adverse events following liposomal doxorubicin injection, and to provide new ideas for the clinical treatment of these adverse events.

Palmar-plantar erythrodysesthesia associated with high-dose methotrexate: Case report.

BACKGROUND: Palmar-plantar erythrodysesthesia (PPE) is a common adverse event seen with many chemotherapeutic agents as well as targeted therapies which is very debilitating for the patient. To the best of our knowledge there are only a few cases of PPE reported with methotrexate infusion to date. CASE AND CONCLUSION: We report a case of Burkitt Lymphoma, who developed severe PPE with methotrexate infusion and responded very well with conservative management and dose reduction in subsequent cycles.

MOMENTUM: A Phase I Trial Investigating 2 Schedules of Capecitabine With Aflibercept in Patients With Gastrointestinal and Breast Cancer.

BACKGROUND: Although data from preclinical and clinical studies provide a strong rationale for combining capecitabine with anti-angiogenic agents, clinical development of this fluoropyrimidine in combination with aflibercept has lagged behind other treatments. We conducted a nonrandomized, noncomparative, 2-arm, phase I trial to address this unmet need. PATIENTS AND METHODS: Patients with chemorefractory gastrointestinal and breast cancer were sequentially recruited into a continuous (Arm A, starting dose 1100 mg/m2/day) or intermittent (Arm B, 2 weeks on/1 week off, starting dose 1700 mg/m2/day) capecitabine dosing arm. Aflibercept was administered at a flat dose of 6 mg/kg every 3 weeks in both arms. A classical 3 + 3, dose-escalation design was used. The primary objective was to establish the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended dose for phase II trials. RESULTS: Thirty-eight eligible patients were recruited of whom 33 were assessable for DLTs (15 in arm A and 18 in arm B). Fourteen had colorectal cancer, 8 gastric cancer, and 11 breast cancer. DLTs included grade 2 hand-foot syndrome, grade 2 anorexia considered unacceptable by the patient, and grade 3 hypertension. The recommended dose for phase II trials for capecitabine was established at 1300 mg/m2/day in Arm A and 2500 mg/m2/day in Arm B with treatment-related grade ≥ 3 adverse events occurring in 47% and 50% of patients, respectively. Among 26 assessable patients, the objective response rate was 15.4% in Arm A and 7.7% in Arm B. CONCLUSION: Combining capecitabine with aflibercept is feasible and associated with a manageable safety profile and some anti-tumor activity in patients with chemorefractory gastrointestinal and breast cancer.

Apatinib-induced Grade 3 hand-foot syndrome in advanced lung adenocarcinoma successful treated with thalidomide: A case report.

Hand-foot syndrome (HFS) is a specific cutaneous toxicity caused by a variety of antitumor drugs. The most common drugs include capecitabine, pegylated liposomal doxorubicin and fluorouracil (PLD), tyrosine kinase inhibitor. It is a dose-limiting cutaneous toxicity of these drugs. We reported an advanced lung adenocarcinoma female patient, who developed a Grade 3 HFS after a third-line treatment with apatinib of 250 mg for 10 days, the patient developed intolerable pain with pruritus. Large erythema on the skin of the hand, with local ulceratio, exudation, and desquamation of cutaneous lesions. After treatment with 100 mg of thalidomide every night for 1 week, the patient's HFS was significantly relieved, and the duration of the remission was about 2 months, which not only significantly improved the patient's quality of life, but also maintained the antitumor strength.

Adherence to a topical moisturizing preparation for regorafenib-related hand-foot skin reaction.

OBJECTIVE: Application of topical moisturizing preparations is important for the prevention and palliation of hand-foot skin reaction induced by multi-kinase inhibitor. Application adherence of topical moisturizing preparations in clinical practice has rarely been reported. This study investigated the factors affecting adherence to the application of topical moisturizing preparations in patients administered regorafenib. METHODS: The subjects were patients administered regorafenib (n = 118). Consumption of a urea-based moisturizing ointment, hand-foot skin reaction grade (CTC-AE ver 3.0), treatment duration, and dose of regorafenib, factors that might affect the onset of symptoms and adherence, including age, sex, presence of a key person, working status, performance status, past use of capecitabine or epidermal growth factor receptor antibodies, and relative dose intensity were retrospectively investigated. The adherence to the topical moisturizing ointment (<21 g per week) was judged as poor. The data were analyzed by logistic regression analysis. RESULTS: Working status was associated with poor adherence, showing a positive correlation (odds ratio; 3.024, p = 0.023). In contrast, symptom grade of hand-foot skin reaction and regorafenib relative dose intensity showed negative correlation with poor adherence (odds ratio; 0.971, p = 0.012, and 0.485, p < 0.001, respectively). CONCLUSIONS: The results suggest that adherence decreases in patients with working. The relative dose intensity of regorafenib decreased when adherence to topical moisturizing ointments decreased. Severe hand-foot skin reaction could be associated with adherence. Patients consciously might not apply the ointment when hand-foot skin reaction did not become severe. It will be problematic for medical personnel to motivate patients for improving adherence to the use of moisturizing ointments.

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.

Sorafenib-associated hand-foot skin reaction: practical advice on diagnosis, mechanism, prevention, and management.

Introduction: Sorafenib is a multitargeted tyrosine kinase inhibitor, which has been mainly used in the treatment of advanced hepatocellular carcinoma and renal cancer. However, hand-foot skin reaction (HFSR), as one of the most common adverse reactions, have hindered its long-term clinical application. At present, the mechanism of its occurrence has not been clearly studied and it leads to the lack of effective means of intervention. This article reviews known mechanism and management methods of HFSR caused by sorafenib.Areas covered: The author reviews HFSR caused by the treatment of sorafenib including the mechanism and management. English language reports located through PubMed are reviewed.Expert opinion: There are some conjectures about the mechanism of HFSR. However, the mechanism of HFSR induced by sorafenib is still unclear at present. In the absence of understanding the mechanism of HFSR, the most common method for clinical treatment of sorafenib-induced HFSR is dose down-regulation or discontinuation of treatment, which affects efficacy and even survival. Future research should focus on the mechanism of HFSR to find out new ways for prevention. Precautionary measures before the occurrence of HFSR can also be studied in the future.

Aplicación de hipotermia en extremidades en la prevención de la eritrodisestesia palmo-plantar secundaria a administración de doxorrubicina liposomal pegilada / Applying hypothermia in extremities for the prevention of palmoplantar erythrodysesthesia secondary to the administration of pegylated liposomal doxor

La eritrodisestesia palmo-plantar o síndrome mano-pie es un efecto secundario de algunos tipos de quimioterapia. Se trata de una toxicidad cutánea que no pone en peligro la vida del paciente, pero sí que es dosis limitante y altera la calidad de vida. Se manifiesta en forma de eritema doloroso, a menudo precedido de parestesias en palmas de las manos y plantas de los pies, generando enrojecimiento, hinchazón y dolor, e incluso presencia de flictenas. Para su prevención y control existen medidas farmacológicas, pero también se utiliza la aplicación de crioterapia. Los cuidados de Enfermería son de gran importancia en el manejo de los síntomas, durante el tratamiento y el alivio de los efectos secundarios. El objetivo de este artículo es dar a conocer la eritrodisestesia palmo-plantar, así como aportar la experiencia clínica relacionada con la utilización de crioterapia preventiva mediante un caso clínico

Palmoplantar erythrodysesthesia or hand-foot syndrome is a side effect of some types of chemotherapy. This is skin toxicity not life-threatening for patients, but dose-limiting and with impact on Quality of Life. It appears as a painful erythema, often preceded by paresthesia in hand palms and feet soles, generating reddening, swelling and pain, and even the presence of phlyctenae. There are pharmacological measures for its prevention and control, but the application of cryotherapy can also be used. Nursing care is very important for symptom management, during treatment and relief of side effects. The objective of this article is to create awareness about palmoplantar erythrodysesthesia, as well as to offer the clinical experience associated with the use of preventive cryotherapy through a case report

Hand-Foot Syndrome and Progression-Free Survival in Patients Treated with Sunitinib for Metastatic Clear Cell Renal Cell Carcinoma.

Patients with metastatic clear cell renal cell carcinoma (mRCC) typically receive systemic treatment with tyrosine kinase inhibitors (TKI). Side effects include the hand-foot syndrome (HFS), tiredness, nausea, decreased appetite, diarrhea, myelosuppression, and hypertension. This study seeks to define the relationship between the incidence of HFS after the first cycle of treatment with sunitinib as the first-line treatment for mRCC (50 mg/day, 6-week schedule: 4 weeks on and 2 weeks off) and progression-free survival. We found that patients, treated with sunitinib for mRCC, who did not experience HFS had the median progression-free survival of 9.8 months. HFS symptoms appeared in 20% of patients after the first treatment cycle. The appearance of HFS was a predictor of a longer progression-free survival. In fact, progression-free survival was elongated in the HFS group over and beyond the observation period of 60 months, which rendered the median progression-free survival calculation impossible. These findings reaffirm the importance of monitoring skin toxicity during treatment with TKI. We conclude that the appearance of adverse skin symptoms presages better outcomes in patients treated with sunitinib for mRCC.

Association of Hand-Foot Skin Reaction with Regorafenib Efficacy in the Treatment of Metastatic Colorectal Cancer.

PURPOSE: Hand-foot skin reaction (HFSR) can deteriorate quality of life in patients receiving regorafenib. Cutaneous toxicity is a main adverse effect of multikinase inhibitors and has also been associated with clinical outcome. This study assessed the association between the antitumor efficacy of regorafenib and HFSR in patients with metastatic colorectal cancer (mCRC). METHODS: Patients who received regorafenib at 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they developed HFSR between May 2013 and October 2015. Estimates of overall survival and progression-free survival were calculated using the Kaplan-Meier method. RESULTS: Ninety-seven patients received at least one dose of regorafenib in this retrospective study. Of these patients, 81.4% (n = 79) experienced HFSR of any grade, and 34.0% (n = 33) had grade 3 HFSR. Among those patients with HFSR at any time during the study, 68.0% (n = 66) underwent the first HFSR event (any grade) during cycle 1. Both overall survival and progression-free survival were improved in patients who had HFSR grade ≥2 at any time compared with those who had HFSR grade ≤1. Multivariate logistic regression analysis revealed a history of HFSR grade ≥2 induced by capecitabine as a significant risk factor for severe HFSR (grade ≥2). CONCLUSIONS: Patients with mCRC treated using regorafenib who experienced severe HFSR showed better overall survival than patients without severe HFSR. Severe HFSR may offer an early surrogate marker for the efficacy of regorafenib in patients with mCRC.

Identificação, Prevenção e Tratamento da Síndrome Mão-Pé Induzida por Quimioterapia: Revisão Sistemática / Identification, Prevention and Treatment of Hand-Foot Syndrome Induced by Chemotherapy: Systematic Review / Identificación, Prevención y Tratamiento de la Enfermedad Mental por Quimioterapia: Revisión Sistemática

Introdução: A síndrome mão-pé é uma reação adversa experimentada por vários pacientes em tratamento para o câncer e fator preditor de morbidade e mortalidade. Objetivo: Avaliar as evidências científicas relacionadas à identificação, prevenção e tratamento da síndrome mão-pé induzida por agentes quimioterápicos, identificar os principais sinais e sintomas que possibilitam o reconhecimento da síndrome e, ainda, discutir a ocorrência de onicomicoses no contexto da síndrome mão-pé. Método: Trata-se de uma revisão sistemática na MEDLINE/PubMed, Biblioteca Virtual da Saúde e Scopus, incluindo literatura cinzenta e busca manual. Os 29 estudos incluídos na revisão foram analisados e classificados segundo a hierarquia dos níveis de evidência Grading of Recommendations Assessment, Development and Evaluations (GRADE) e a confiabilidade entre os examinadores (coeficiente Kappa) foi calculada. Resultados: Foram identificados estudos que demonstraram eficácia na prevenção da síndrome mão-pé com o uso da crioterapia e hidroterapia. Evidenciaram-se resultados satisfatórios com o uso do creme de ureia na prevenção e tratamento, e o uso de piridoxina não apresentou resultados conclusivos. Foram encontrados mecanismos para identificação da síndrome e para classificação dos agentes indutores. O grupo dos taxanos predominou entre os medicamentos indutores da síndrome mão-pé. Conclusão: Existem evidências consistentes, porém não contemplam todos os fármacos indutores da síndrome e não exploram outras manifestações relacionadas às onicólises e onicomicoses. O estudo apresentou resultados que poderão auxiliar os prescritores na identificação da síndrome mão-pé, além de alternativas para prevenção e tratamento. Contudo, vale destacar a necessidade de pesquisas futuras para elucidar a etiologia e protocolos de tratamento.

Introduction: Hand-foot syndrome is an adverse reaction experienced by many cancer patients and a predictor of morbidity and mortality. Objective:To evaluate the scientific evidence related to the identification, prevention and treatment of chemotherapeutic-induced hand-foot syndrome, to identify the main signs and symptoms that enable the recognition of the syndrome, and to discuss the occurrence of onychomycosis in the context of the hand-foot syndrome. Method: This is a systematic review at MEDLINE/PubMed, Virtual Health Library and Scopus, including gray literature and manual search. The 29 studies included in the review were analyzed and graded according to the hierarchy of evidence levels Grading of Recommendations Assessment, Development and Evaluations (GRADE) and reliability among examiners (Kappa coefficient) was calculated. Results:It were identified studies that demonstrated efficacy in preventing hand-foot syndrome using cryotherapy and hydrotherapy. Satisfactory results were evidenced with the use of urea cream for prevention and treatment, and the use of pyridoxine showed inconclusive results. Mechanisms for identification of the syndrome and classification of inducing agents were found. The taxane group predominated among hand-foot syndrome inducing drugs. Conclusion: There are consistent evidences but do not include all drugs inducing the syndrome and do not explore other manifestations related to onycholysis and onychomycosis. The study presented results that may help prescribers to identify hand-foot syndrome, as well as alternatives for prevention and treatment. However, it is worth highlighting the need for future studies to elucidate the etiology and treatment protocols.

Introducción: El síndrome de pies y manos es una reacción adversa experimentada por muchos pacientes con cáncer y un predictor de morbilidad y mortalidad. Objetivo: Evaluar la evidencia científica relacionada con la identificación, prevención y tratamiento del síndrome de pies y manos inducido por quimioterapia, identificar los principales signos y síntomas que permiten el reconocimiento del síndrome y analizar la aparición de onicomicosis en el contexto del síndrome mano-pie. Método:Esta es una revisión sistemática en MEDLINE/PubMed, Virtual Health Library y Scopus, que incluye literatura gris y búsqueda manual. Los 29 estudios incluidos en la revisión se analizaron y clasificaron de acuerdo con la jerarquía de los niveles de evidencia Grading of Recommendations Assessment, Development and Evaluations (GRADE). Resultados: Identificamos estudios que demostraron eficacia en la prevención del síndrome mano-pie usando crioterapia e hidroterapia. También mostraron resultados satisfactorios con el uso de crema de urea en la prevención y el tratamiento, y el uso de piridoxina no mostró resultados concluyentes. Se encontraron mecanismos para la identificación del síndrome y la clasificación de los agentes inductores. El grupo de taxanos predominó entre los fármacos inductores del síndrome mano-pie. Conclusión: Existe evidencia consistente pero no incluye todas las drogas que inducen el síndrome y no explora otras manifestaciones relacionadas con la onicólisis y la onicomicosis. El estudio presentó resultados que pueden ayudar a los prescriptores a identificar el síndrome de manos y pies, así como alternativas para la prevención y el tratamiento. Sin embargo, vale la pena destacar la necesidad de futuras investigaciones para dilucidar la etiología y los protocolos de tratamiento.