Hand-foot syndrome induced by chemotherapy drug: Case series study and literature review.

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.

Long-Term Safety Data on S-1 Administered After Previous Intolerance to Capecitabine-Containing Systemic Treatment for Metastatic Colorectal Cancer.

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.

Hand-foot syndrome and nail disorders secondary to treatment with paclitaxel: Is there a relationship with the presence of fungi?

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.

Real-world safety and effectiveness of regorafenib in metastatic colorectal cancer: the French CORRELATE cohort.

Aim: We report real-world evidence with regorafenib in previously treated metastatic colorectal cancer from the French cohort of the international, prospective, observational CORRELATE study. Patients & methods: Patients receiving regorafenib according to French health authority approval were included. The primary end point was treatment-emergent adverse events. Overall survival and progression-free survival were secondary end points. Results: Two hundred and forty-two patients (61% male, median age: 66 years) were enrolled. The most common grade ≥3 drug-related treatment-emergent adverse events were hand-foot skin reaction (10.3%), asthenia/fatigue (9.9/1.2%) and hypertension (6.2%). Median overall survival and progression-free survival were 6.8 (95% CI: 6.3-7.6) and 2.8 months (95% CI: 2.6-3.0), respectively. Conclusion: The real-world safety and effectiveness data of regorafenib in metastatic colorectal cancer in France align with findings from Phase III clinical trials and the global CORRELATE population.

Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer.

PURPOSE: Capecitabine is an extensively used oral prodrug of 5-fluorouracil in treatment of colon cancer and is known to cause hand-foot syndrome (HFS). As the target enzyme for capecitabine, thymidylate synthase (TYMS) plays a key role for 5-fluorouracil metabolism and has been associated with some side effects caused by capecitabine. The aim of our study is to identify the possible genetic predictors of capecitabine-induced HFS (CAP-HFS) in Chinese colorectal cancer patients. MATERIALS AND METHODS: Whole exons of TYMS were sequenced for 288 extreme phenotype HFS patients, including 144 severe or early-onset (first 2 cycles) moderate HFS extreme cases and 144 extreme controls with no reported HFS. The associations between polymorphisms and CAP-HFS were analyzed using logistic regression under an additive model. RESULTS: We identified a novel risk mutation (c.1A>G, chr18:657743), was associated with severe HFS in an extreme case who was affected during the first cycle of treatment. Moreover, we identified three new variants, rs3786362, rs699517, rs2790, and two previously reported variants, 5'VNTR 2R/3R and 3'-untranslated region 6-bp ins-del, which were significantly associated with CAP-HFS (p < 0.05). In silico analysis revealed that the effect of these polymorphisms in the TYMS region on the development of HFS might not be restricted solely to the regulation of TYMS expression, but also the TYMS catalytic activity through the indirect effect on ENOSF1 expression. CONCLUSION: This study identified new polymorphisms in TYMS gene significantly associated with CAP-HFS, which may serve as useful genetic predictors for CAP-HFS and help to elucidate the underlying mechanism of HFS.

Toxicities of axitinib, sunitinib and temsirolimus: implications for progression-free and overall survival in metastatic renal cell cancer.

The aim of this study was to evaluate the association between axitinib, sunitinib and temsirolimus toxicities and patient survival in metastatic renal cell cancer patients. Overall survival (OS) and progression-free survival (PFS) of metastatic renal cell cancer patients from the prospective multicenter STAR-TOR study were assessed using multivariable Cox models. A total of 1195 patients were included (n = 149 axitinib; n = 546 sunitinib; n = 500 temsirolimus). The following toxicities significantly predicted outcomes: hand-foot skin reaction (hazard ratio [HR] = 0.29) for PFS with axitinib; stomatitis (HR = 0.62) and pneumonitis (HR = 0.23) for PFS with temsirolimus; stomatitis (HR = 0.52) and thrombocytopenia (HR = 0.6) for OS with temsirolimus; fatigue (HR = 0.71) for PFS with sunitinib; hand-foot skin reaction (HR = 0.56) and fatigue (HR = 0.58) for OS with sunitinib. In conclusion, in metastatic renal cell cancer, axitinib, sunitinib and temsirolimus demonstrate specific toxicities that are protective OS/PFS predictors.

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.

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

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

SNPs in the COX-2/PGES/EP signaling pathway are associated with risk of severe capecitabine-induced hand-foot syndrome.

PURPOSE: Capecitabine is a widely used 5-fluorouracil oral prodrug. Hand-foot syndrome (HFS), one of the most common adverse events of capecitabine, impacts patients' quality of life seriously. The pathogenesis of HFS remains unclear but was usually considered as a type of inflammation conducted by cyclooxygenase-2 (COX-2). The COX-2/PGES/EP signaling pathway plays an important role in the inflammatory reaction. We hypothesized that the single nucleotide polymorphisms (SNPs) in this pathway may be associated with the risk of HFS induced by capecitabine. PATIENTS AND METHODS: Using DNA from blood samples of 225 patients, we genotyped 19 SNPs in 6 core genes (COX-2, PGES, EP1, EP2, EP3, and EP4). Common Terminology Criteria for Adverse Events version 3.0 was used to grade hand-foot syndrome. We used logistic regression analysis to evaluate the correlations between genotype variants and occurrence of HFS. The cumulative incidence of HFS was assessed by Kaplan-Meier analysis. RESULTS: Among the 225 participants, 58.6% (132/225) patients developed into HFS, including 41.3% (93/225) grade 1 HFS, 10.2% (23/225) grade 2 HFS and 7.1% (16/225) grade 3 HFS. Multivariate logistic regression analysis showed the AG/GG genotype of rs3810255 to be associated with a significantly higher risk of grade 2/3 HFS, while the AG/AA genotype of rs17131450 to be associated with a significantly lower risk of grade 2/3 HFS (OR = 3.646, P = 0.011; and OR = 0.266, P = 0.036; respectively). CONCLUSION: Our study showed that rs3810255 AG/GG genotypes and rs17131450 GG genotypes to be associated with high risk of capecitabine-induced HFS.

Capecitabine-Based Chemoendocrine Combination as First-Line Treatment for Metastatic Hormone-Positive Metastatic Breast Cancer: Phase 2 Study.

BACKGROUND: Preclinical studies have suggested a synergistic effect of tamoxifen and capecitabine in estrogen receptor-positive cell lines. We evaluated the safety and efficacy of first-line chemoendocrine treatment in patients with metastatic breast cancer. Biochemical assessment was performed of serum levels of thymidine phosphorylase enzyme (TP), serum tamoxifen, hydroxytamoxifen, and 5-fluorouracil in relationship to efficacy. PATIENTS AND METHODS: This prospective phase 2 interventional study studied patients with estrogen receptor-positive, HER2- metastatic breast cancer who received either tamoxifen/capecitabine or letrozole/capecitabine as first-line treatment. The dose of capecitabine provided at 2000 mg per day continuously as a fixed dose. RESULTS: Forty women with a median age of 49.3 years were enrolled. For the whole study group, median progression-free survival (PFS) was 10 months and median overall survival (OS) was 23.3 months. The overall response rate was 60% and the clinical benefit rate 82.5%. Progesterone receptor positivity was associated with significantly longer PFS (12 vs. 7 months, P = .021). The most frequent adverse events were palmar-plantar erythrodysesthesia (62.5%), fatigue (62.5%), diarrhea (30%), abdominal pain (12.5%), and constipation (10%). Changes in serum level of TP were not correlated to response to treatment, PFS, or OS. Higher serum levels of tamoxifen and hydroxytamoxifen were correlated with higher response rates and longer PFS but not OS. CONCLUSION: Chemoendocrine treatment is well tolerated, with no evidence of contradictory effects between the combination components. However, the efficacy data need more validation.

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.

[Clinical study of apatinib combined with chemotherapy for advanced non-small cell lung cancer with negative driving genes].

Objective: To evaluate the efficacy and safety of apatinib combined with chemotherapy in the first-line treatment of advanced non-small cell lung cancer (NSCLC) with negative driving genes. Methods: From January 2016 to March 2018, 62 advanced NSCLC patients with negative driving genes diagnosed at Xuzhou Cancer Hospital were randomly divided into study group (30 cases) and control group (32 cases), respectively. The patients in the study group were treated with standard first-line chemotherapy combined with apatinib, while those in control group were treated with chemotherapy alone. Results: The disease control rate (DCR) and objective remission rate (ORR) in the study group were 60.0% and 16.7%, respectively, higher than 46.9% and 9.3% in the control group, but without statistical difference (P>0.05). The median progression-free survival (PFS) of study group and control group were 6.4 months and 4.9 months, respectively (P=0.004), and the median overall survival (OS) were 11.3 months and 9.2 months, respectively (P=0.006). Multivariate survival analysis indicated that treatment regimen (P=0.001) was the independent prognostic factor of PFS, and PS score (P=0.002), clinical stage (P=0.02) and treatment regimen (P<0.001) were the independent prognostic factors of OS. After treatment, the incidence of hypertension and hand-foot syndrome in the study group were 46.7% and 53.3%, respectively, significantly higher than 3.3% and 0 in the control group, respectively (P<0.05). The incidence of grade 3-4 adverse drug reactions (ADRs) in the study group was 26.7% (8/30), mainly including hypertension, hand-foot syndrome and bone marrow suppression. The incidence of grade 3-4 ADRs in the control group was 15.6% (5/32), all of which were bone marrow suppression, without significant difference (P=0.286). There was no difference in serum levels of VEGF and CEA between the two groups before treatment. After treatment, the serum level of VEGF in the study group was (169.3±10.1) pg/ml, lower than (211.8±16.7) pg/ml of the control group (P<0.05). Conclusion: Apatinib combined with first-line chemotherapy for advanced NSCLC patients with negative driving genes is safe and beneficial for survival. This therapeutic strategy can significantly prolong the PFS and OS, and further improvement and application can be considered as a choice in the clinical treatment.

A two centers study of postoperative adjuvant chemotherapy with S-1 versus SOX/XELOX regimens for gastric cancer after D2 resection: a cohort study.

OBJECTIVE: Currently, radical surgery with D2 lymphadenectomy has become the standard operation mode of patients in East Asian countries who suffer from resectable gastric cancer. Our target is to compare the efficacy of postoperative adjuvant chemotherapy with S-1 versus SOX/XELOX regimens for gastric cancer after D2 resection. METHODS: We selected 186 patients with gastric cancer who underwent D2 resection in Hangzhou First People's Hospital and Hangzhou Cancer Hospital from June 2014 to June 2017. All patients were followed up for more than 3 years. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were overall survival (OS) and toxicity. RESULTS: The 3-year DFS of monotherapy group and combined group were, respectively, 50.7% and 64.0%, while the 3-year OS were, respectively, 62.7% and 71.2%. The 3-year DFS and OS of the combined group were higher than the monotherapy group, but the differences had no statistical significance (3-year DFS: P = 0.071; 3-year OS: P = 0.224). Subgroup analysis showed that the DFS of patients with stage III gastric cancer in monotherapy group was significantly lower than the combined group, with the difference that had statistical significance (P = 0.030), while there was no significant difference in OS (P = 0.186). Most toxic and side effects seen in both groups had no significant differences, while the incidence of hand-foot syndrome and peripheral neurotoxicity in combined group was significantly higher than that in the monotherapy group (P < 0.001). CONCLUSION: For patients with advanced gastric cancer who underwent D2 resection, compared with S-1 regimen, there is prolonged disease-free survival trend with SOX/XELOX regimen, while there is no significant overall survival benefit.

Apatinib for chemotherapy-refractory extensive-stage SCLC: a retrospective study.

PURPOSE: There is no standard treatment strategy for patients with extensive-stage small cell lung cancer (SCLC) who have failed two or more prior chemotherapeutic regimens. In this study, we retrospectively evaluated the efficacy and safety of apatinib in patients with extensive-stage SCLC after failure of more than second-line chemotherapy. METHODS: A study group comprised of 22 patients with extensive-stage SCLC after failure of more than two prior chemotherapeutic regimens was given apatinib orally at an initial dose of 500 mg daily until disease progression or unacceptable toxicity. This study was analyzed according to the National Cancer Institute Common Toxicity Criteria for adverse events (AEs) and Response Evaluation Criteria in Solid Tumors (RECIST) for response assessment. RESULTS: Between August 30, 2015, and May 26, 2017, 22 patients were enrolled for evaluating the efficacy and safety of apatinib. Among them, 12/22 (54.5%) underwent dose reduction during treatment. Up to July 31, 2018, the median progression-free survival rate was 135.0 days [95% confidence interval (CI) 63.8-206.2]. According to the RECIST criteria, the disease control rate (DCR) was 86.4%, 19/22 [comprised of partial response (PR) 18.2%, 4/22; and stable disease (SD) 68.2%, 15/22 patients]. The most frequent AEs were hand-foot syndrome (45.5%, 10/22), secondary hypertension (45.5%, 10/22) and fatigue (40.9%, 9/22). The primary grade 3 or 4 toxicities were hypertension (22.7%, 5/22), hand-foot syndrome (13.6%, 3/22), and proteinuria (9.1%, 2/22). CONCLUSIONS: Apatinib exhibits modest activity and acceptable toxicity for patients with heavily pretreated extensive-stage SCLC.

Safety and efficacy of trastuzumab administered as a 30-min infusion in patients with HER2-positive advanced gastric cancer.

PURPOSE: To investigate the safety and efficacy of 30-min maintenance infusions of trastuzumab in advanced gastric cancer positive for human epidermal growth factor receptor 2 (HER2). METHODS: This was a retrospective study conducted across five Korean hospitals in patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with first-line, 3-weekly trastuzumab plus chemotherapy. The first dose of trastuzumab (8 mg/kg) was administered as a 90-min infusion, with all subsequent maintenance infusions (6 mg/kg) given over 30 min. The primary aim was to investigate infusion-related reactions and cardiac events with 30-min infusions of trastuzumab. Objective response rate, progression-free survival, and overall survival were secondary endpoints. RESULTS: The study included 128 patients (efficacy population), of whom 123 received both induction and maintenance infusions and formed the safety population. The median age was 63 years; 80% were presenting for the first time with metastatic disease, and 94% were treated with trastuzumab plus capecitabine/cisplatin. Infusion-related reactions were observed in 32 of 123 patients (26%). There were no cardiac events. The most frequent adverse events were anorexia and nausea, followed by vomiting, fatigue, mucositis, sensory neuropathy, and hand-foot syndrome. Most events were grade 1-2 and were manageable. No patient discontinued study treatment due to adverse events. The objective response rate was 63%, and included 6 complete responses. CONCLUSIONS: Trastuzumab 30-min maintenance infusions were well tolerated with a good safety profile, and resulted in sustained efficacy in patients with HER2-positive advanced gastric cancer.

A phase II trial of the effect of perindopril on hand-foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC.

PURPOSE: Regorafenib is an oral multi-kinase inhibitor that offers an OS benefit to patients with mCRC refractory to standard therapy (Grothey et al., in Lancet 381:303-312, 2013), but comes with potential significant toxicities including grade 3 hand-foot skin reaction (HFSR). The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. We hypothesized that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, indicated for the treatment of hypertension (Ceconi et al., in Cardiovasc Res 73:237-246, 2007), and which plays a role in preventing endothelial dysfunction, may help to prevent or reduce the severity of regorafenib-induced HFSR. PATIENTS AND METHODS: In this single-center phase II open-label trial, patients with refractory mCRC were treated with both regorafenib (160 mg/day) and perindopril (4 mg/day) for 21 days per 28-day cycle. The primary end point was to assess the proportion of patients with any grade HFSR toxicity. Secondary end points included time to development of worst (grade 3) HFSR, reduction of all grades of hypertension and all grade toxicities, as well as progression-free survival. All toxicities were evaluated using CTCAE v4.03. RESULTS: A planned interim analysis was performed after ten evaluable patients had completed their first cycle of study treatment. As 50% (5/10) experienced grade 3 HFSR, enrolment was stopped as the addition of perindopril did not lead to a reduced level of HFSR compared with regorafenib alone. Other grade 3 toxicities included hypertension (16.7%) and increased AST (16.7%). CONCLUSION: The addition of an ACE inhibitor perindopril to regorafenib did not reduce HFSR incidence or severity in patients with refractory mCRC.

Systematic review and meta-analysis of prevalence of dermatological toxicities associated with vemurafenib treatment in patients with melanoma.

BACKGROUND: Vemurafenib has been linked to dermatological adverse events in patients with melanoma, including an increased risk of rash, cutaneous squamous cell carcinoma, photosensitivity reaction and keratoacanthoma. However, there has been no systematic attempt to assess the dermatological toxicity data of vemurafenib associated with melanoma treatment. AIM: To evaluate the point prevalence of dermatological toxicities associated with vemurafenib treatment in patients with melanoma. METHODS: Searches were conducted of the electronic databases PubMed and EMBASE and of conference abstracts published by the American Society of Clinical Oncology. Eligible studies included prospective clinical trials and expanded-access programmes (i.e. outside a clinical trial) of patients with melanoma assigned to vemurafenib treatment. Outcomes included prevalence of dermatological toxicities treated with vemurafenib. Statistical analyses were performed using the R2.8.1 meta package. RESULTS: In total, 11 studies comprising 4197 patients were included in the meta-analysis. For patients assigned to vemurafenib, the overall prevalence of all-grade cutaneous squamous cell carcinoma (cSCC) was 18.00% (95% CI 12.00-26.00%), rash 45.00% (95% CI 34.00-57.00%), photosensitivity reaction (PR) 30.00% (95% CI 23.00-38.00%), keratoacanthoma (KA) 10.00% (95% CI 6.00-15.00%) and hand-foot skin reaction (HFSR) 9.00% (95% CI 4.00-20.00%), while the prevalence of high-grade events was: cSCC 16.00% (95% CI 11.00-23.00%), rash 12.00% (95% CI 3.00-38.00%), PR 4% (95% CI 2.00-8.00%) and KA 6.00% (95% CI 5.00-7.00%). CONCLUSION: The most frequent dermatological toxicities associated with vemurafenib treatment in patients with melanoma were cSCC, rash, PR and KA. These data may be useful for estimation of the efficacy and safety of the drug during clinical treatment and for reducing the prevalence of adverse reactions to vemurafenib treatment in patients with melanoma.

Regorafenib-Induced Hand-Foot Skin Reaction Is More Severe on the Feet Than on the Hands.

Regorafenib is a multikinase inhibitor for the treatment of metastatic colorectal cancer. Regorafenib-induced hand-foot skin reaction (HFSR) is a common side effect during treatment. The reported frequency of HFSR was 80% (grade 3: 28%) in the Japanese subpopulation in the CORRECT trial; however, more detailed data regarding HFSR in terms of onset and sites of susceptibility are unclear. Additionally, the risk factors for regorafenib-induced severe HFSR are unknown. The aim of this study was to compare HFSR between the hands and feet and identify preexisting risk factors for severe HFSR in Japanese patients receiving regorafenib. We retrospectively examined the onset and severity of HFSR on the hands and feet of patients with metastatic colorectal cancer treated with regorafenib from May 2013 to October 2015 in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. In addition, we examined the possible association between preexisting clinical factors and severe HFSR. Our results showed that no significant difference in the incidence of HFSR of any grade was observed between the hands (71%) and feet (74%) (p = 0.63). The incidence of grade 3 HFSR was more frequent on the feet (33%) than on the hands (8%) (p < 0.01). The onset of grade 3 HFSR was earlier on the feet than on the hands (p < 0.001). No preexisting risk factor was identified. Our findings indicate that severe HFSR was more prevalent on the feet than on the hands, suggesting the need for appropriate screening for early detection and treatment of regorafenib-induced HSFR.

Síndrome Mão-Pé Induzida por Quimioterapia: Abordagem Clínica e Epidemiológica de Pacientes com Câncer / Chemotherapy-Induced Hand-Foot Syndrome: Clinical and Epidemiological Approach to Cancer Patients / Síndrome Mano-Pie Inducida por Quimioterapia: Enfoque Cínico y Epidemiológico de Pacientes con Cáncer

Introdução: A síndrome mão-pé (SMP) ou eritrodisestesia palmopalmar é uma reação cutânea tóxica decorrente da quimioterapia antineoplásica, que ocorre com frequência e constitui importante problema clínico ao indivíduo com neoplasia maligna. O desenvolvimento da SMP pode levar à interrupção do tratamento e, com frequência, à redução da dose do quimioterápico. Objetivo: Analisar os dados clínicos e epidemiológicos de pacientes com SMP tratados com quimioterapia. Método: Estudo descritivo e retrospectivo, com coleta de dados realizada entre janeiro de 2013 e janeiro de 2014 em prontuários utilizando-se do registro de toxicidades dos antineoplásicos e da Escala de Performance Status do Eastern Cooperative Oncology Group. Resultados: Foram analisados 250 prontuários. Destes, 70 realizaram tratamento quimioterápicos e 15 (21,4%) apresentaram SMP, com toxicidade grau 1 após uso de dois ciclos de capecitabina (13,3%); grau 2 após dois, quatro e até 12 ciclos de tratamento (40%); grau 3 após cinco e 11 ciclos de capecitabina (20%); e, em grau 4, um paciente apresentou toxicidade após dois ciclos de capecitabina e outro, apresentou SMP após dois ciclos de doxorrubicina lipossomal (13,3%). Conclusão: O tratamento com quimioterapia causa alto risco de apresentar SMP. No entanto, mostrou baixa incidência dessa síndrome em pacientes com câncer que fazem tratamento com capecitabina, doxorrubicina e citarabina.

Introduction:Hand-foot syndrome (HFS) or palmar-plantar erythrodysesthesia is a toxic skin reaction resulting from antineoplastic chemotherapy, which occurs frequently and is an important clinical problem for individuals with malignant neoplasm. The development of HFS may lead to treatment discontinuation and, often, a reduction of the chemotherapy dose. Objective: To analyze the clinical and epidemiological data of patients with HFS treated with chemotherapy. Method: A descriptive and retrospective study, with data collected from January 2013 to January 2014 in medical charts using the register of antineoplastic toxicities and the Eastern Cooperative Oncology Group Performance Status scale. Results: It were analyzed 250 charts. Of these, 70 underwent chemotherapy treatment, and 15 (21.4%) presented HFS, with grade 1 toxicity after 2 cycles of capecitabine (13.3%); grade 2 after two, four and up to 12 treatment cycles (40%); grade 3, after five and 11 cycles of capecitabine (20%) and with grade 4, one patient presented such toxicity after two cycles of capecitabine and another patient presented HFS after two cycles of liposomal doxorubicin (13.3%). Conclusion: Chemotherapy treatment causes high risk of presenting HFS. However, this syndrome showed low incidence in cancer patients receiving treatment with capecitabine, doxorubicin and cytarabine.

Introducción: El síndrome de manos y pies (SMP) o la eritrodistesia palmopalmar es una reacción cutánea tóxica resultante de la quimioterapia antineoplásica, que ocurre con frecuencia y es un problema clínico importante para las personas con neoplasia maligna. El desarrollo del SMP puede conducir a la interrupción del tratamiento y, a menudo, a una reducción de la dosis de quimioterapia. Objetivo: Analizar los datos clínicos y epidemiológicos de pacientes con SPM tratados con quimioterapia. Método:Estudio descriptivo y retrospectivo, con recopilación de datos realizada entre enero de 2013 y enero de 2014 en registros médicos utilizando el registro de toxicidad antineoplásica y la Escala de estado de rendimiento del Grupo de Oncología Cooperativa del Este. Resultados: Se analizaron 250 registros médicos. De estos, 70 se sometieron a tratamiento de quimioterapia y 15 (21,4%) presentaron SMP. Con toxicidad de grado 1 después del uso de 2 ciclos de capecitabina (13,3%); grado 2 después de dos, cuatro y hasta doce ciclos de tratamiento (40%); grado 3 después de cinco y 11 ciclos de capecitabina (20%); grado 4, y un paciente presentó dicha toxicidad después de dos ciclos de capecitabina y otro paciente presentó SMP después de dos ciclos de doxorrubicina liposomal (13,3%). Conclusión: El tratamiento con quimioterapia causa un alto riesgo de presentar SMP. Sin embargo, ha mostrado una baja incidencia de este síndrome en pacientes con cáncer que reciben capecitabina, doxorrubicina y citarabina.