Hand-foot syndrome and its impact on daily activities in breast cancer patients receiving docetaxel-based chemotherapy.

PURPOSE: Breast cancer patients who undergo docetaxel-based chemotherapy regimens can have hand-foot syndrome (HFS), which negatively impacts their ability to perform daily activities. The purpose of the study was to assess, in breast cancer patients receiving chemotherapy: the perceived levels of HFS-related symptoms of the feet, hands or fingers; and HFS-related restrictions in daily activities; as well as to identify factors associated with these symptoms and restrictions. METHODS: This cross-sectional study examined breast cancer patients who received docetaxel-based chemotherapy from the general surgery outpatient department and oncology outpatient department of a medical center in northern Taiwan. A set of structured questionnaires were used to measure patients' HFS-related symptoms and HFS-related restrictions in daily activities. RESULTS: Of the 85 breast cancer patients studied, 41.2% reported HFS. Patients had higher level of HFS-related foot symptoms than HFS-related hand or fingers symptoms. Greater restriction in HFS-related daily activities was associated with more HFS-related hand or fingers symptoms and more HFS-related foot symptoms; these factors explained 44.7% of the variance in restriction of activities. CONCLUSION: Skin care and patient education should be provided to manage the HFS of breast cancer patients receiving chemotherapy.

Skin adverse events in recently approved targeted therapies in solid malignancies.

Targeted anticancer therapies are an important weapon in the fight against cancer. Targeted therapies interfere with specific molecules necessary for tumor growth and cancer progression. They are divided mainly to either monoclonal antibodies or small molecules inhibitors. Their primary objective is to target directly and precisely the cancer cells leading to a minimal side-effects profile. The dermatologic adverse reactions of these targeted therapies is different from those seen with classical cytotoxic chemotherapy. Rashes, xerosis, hand-foot-skin reaction and mucositis are the most frequent side effects. In this paper, we aim to present a comprehensive review of the dermatologic side effects of targeted therapies including, specific side effects related to recently, approved targeted therapies.

Palmar-plantar erythrodysesthesia syndrome following treatment with high-dose methotrexate or high-dose cytarabine.

BACKGROUND: Palmar-plantar erythrodysesthesia syndrome (PPES) is an uncommon side effect of high-dose cytarabine or methotrexate. Prior case reports of PPES have been limited, and the predisposing factors for the development of PPES remain unknown. METHODS: A review of databases identified 22 patients (1.3%) who developed 39 episodes of PPES among 1720 patients after treatment with high-dose cytarabine or methotrexate. RESULTS: Symptoms lasted a mean of 6.4 days. Hands and feet were both involved in 68% of the initial episodes. Parenteral opioids were required for pain control by 27% of the patients. In comparison with the 1698 children treated with similar therapy, the children who developed PPES were older (mean age at diagnosis, 14.3 vs 7.7 years; P = 7.5 × 10-7 ). The frequency of PPES was less common in patients receiving methotrexate alone (7 of 946 or 0.7%) versus cytarabine (7 of 205 or 3.4%; P = .005) but was not different for those receiving both high-dose methotrexate and cytarabine (8 of 569 or 1.4%; P = .32). Prolonged infusions of methotrexate were associated with less frequent PPES in comparison with rapid infusions (P = 1.5 × 10-5 ), as was the co-administration of dexamethasone with cytarabine (P = 2.5 × 10-6 ). Self-described race and sex were not associated with PPES. In a multivariate analysis, older age and high-dose cytarabine administration without dexamethasone remained associated with PPES (P = 1.1 × 10-4 and P = .038, respectively). A genome-wide association study did not identify any associations with PPES meeting the genome-wide significance threshold, but top variants were enriched for skin expression quantitative trait loci, including rs11764092 in AUTS2 (P = 6.45 × 10-5 ). CONCLUSIONS: These data provide new insight into the incidence of PPES as well as its risk factors. Cancer 2017;123:3602-8. © 2017 American Cancer Society.

The contribution of keratinocytes in capecitabine-stimulated hand-foot-syndrome.

Capecitabine, as the first-line treatment for multiple tumor types, has a serious drawback of hand-foot-syndrome (HFS) that limits its clinical use. However, the pathophysiology and mechanism of capecitabine-induced HFS is rarely known. Here we built the experimental mouse model of HFS induced by capecitabine at first and it was shown that 3 of 6 mice appeared HFS in the 5th day and 5 mice occurred HFS in the 30th day. The corneous layer was reduced in capecitabine-induced HFS in vivo. Moreover, we found that capecitabine could significantly induce keratinocytes cells death in vitro through activated apoptosis pathway and decreased mitochondrial membrane potential. In conclusion, these results suggested that HFS of capecitabine may be developed from reduction of corneous layer through stimulation of intracellular mitochondrial dysfunction following activation of caspase-dependent apoptosis pathway.

Validation of a short questionnaire to measure symptoms and functional limitations associated with hand-foot syndrome and mucositis in patients with metastatic renal cell carcinoma.

BACKGROUND: Hand-foot syndrome and mucositis/stomatitis are frequent adverse events (AEs) of treatment with tyrosine kinase inhibitors in cancer therapy. Quality-of-life instruments that measure the functional consequences of these AEs are needed to assess the impact of therapeutic interventions and to guide patient care. The Hand-Foot and Mucositis Symptom and Impact Questionnaire (HAMSIQ [formerly the Supplementary Quality of Life Questionnaire]) was used in the COMPARZ trial (Pazopanib vs Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma [national clinical trial no. NCT00720941]) and the PISCES study (Patient Preference Study of Pazopanib vs Sunitinib in Advanced or Metastatic Kidney Cancer [clinicaltrials.gov NCT01064310]) to assess mouth/throat and hand/foot soreness symptoms and subsequent limitations in patients receiving pazopanib or sunitinib for metastatic renal cell carcinoma. The objective of the current analysis was to validate the HAMSIQ using data from the PISCES study. METHODS: The HAMSIQ was administered in the PISCES study at baseline and every 2 weeks over two 10-week periods to patients who were receiving pazopanib or sunitinib. Data from the first 10-week period were used to assess the feasibility, validity, and responsiveness of the HAMSIQ. RESULTS: In total, ≥85% of 169 patients completed the HAMSIQ (excluding the item concerning days off work). Correlations among items within the same limitation subscale generally were high (Cronbach α ≥ .80). HAMSIQ limitation scores differentiated patients according to their baseline performance status and severity of soreness. Small-to-moderate correlations were observed for the symptoms/limitation scores and for changes from baseline scores between the HAMSIQ and the Functional Assessment of Chronic Illness Therapy fatigue survey. The HAMSIQ demonstrated responsiveness to changes in clinical status and the development of hand-foot syndrome AEs over time. CONCLUSIONS: The HAMSIQ is a feasible, valid, reliable, and responsive instrument for assessing the impact of hand-foot syndrome and mucositis in patients receiving tyrosine kinase inhibitors. Cancer 2016;122:287-295. © 2015 American Cancer Society.

Risk Factors Exacerbating Hand-Foot Skin Reaction Induced by Capecitabine plus Oxaliplatin with or without Bevacizumab Therapy.

BACKGROUND: Capecitabine plus oxaliplatin (CapeOx) ± bevacizumab therapy is associated with a high incidence of hand-foot skin reaction (HFSR), hindering treatment. However, timing of onset and risk factors remain unclear. OBJECTIVE: This study examined the development of HFSR and risk factors for its exacerbation to a serious condition in CapeOx ± bevacizumab therapy. METHODS: We retrospectively examined patients with colorectal cancer receiving CapeOx ± bevacizumab therapy between October 1, 2009, and March 31, 2012. The observation period was defined as lasting until completion of 8 cycles. The relationship between cumulative dose of capecitabine and cumulative proportion of patients developing HFSR was evaluated by Kaplan-Meier methods. Risk factors for exacerbation of HFSR to a serious condition were assessed by multiple logistic regression. RESULTS: Data for 203 patients were analyzed. For patients treated at cumulative capecitabine doses of 100 000 mg/m(2) and 200 000 mg/m(2), Grade 1 HFSR occurred in ≥80% and ≥90%, respectively, and moderate-to-severe HFSR (Grade 2+) occurred in ≥10% and ≥20%, respectively. Multivariate analysis showed significant associations with diabetes (odds ratio [OR] = 4.79; 95% confidence interval [CI] = 1.86-12.34; P = 0.001), concomitant use of bevacizumab (OR = 6.01; 95% CI = 2.20-16.41; P = 0.001), history of fluorinated pyrimidine administration (OR = 2.42; 95% CI = 1.10-5.33; P = 0.027), and early onset (within 21 days) of Grade 1 HFSR (OR = 3.78; 95% CI = 1.64-8.70; P = 0.001). CONCLUSIONS: HFSR in CapeOx therapy is a cumulative toxicity and risk of exacerbation to a serious condition increases with diabetes, concomitant use of bevacizumab, history of fluorinated pyrimidine administration, and onset of Grade 1 HFSR within 21 days.

Phase II gemcitabine and capecitabine combination therapy in recurrent or metastatic breast cancer patients pretreated with anthracycline and taxane.

PURPOSE: We conducted a phase II study evaluating safety and efficacy of combination gemcitabine and capecitabine therapy for metastatic breast cancer patients following anthracycline and taxane treatment in Korea. METHODS: This was a single-arm, non-randomized phase II study. Patients received 1,000 mg/m(2) gemcitabine intravenously over 30 min on days 1 and 8, and 1,250 mg/m(2) capecitabine orally twice daily on days 1-14 until disease progression or intolerable toxicity occurred. This regimen was repeated every 3 weeks. The primary outcome assessed was overall response rate [ORR, complete response (CR) + partial response (PR) as the best response], and secondary outcomes were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) [maintenance of CR + PR + stable disease (SD) for at least 3 months], drug toxicity, and predictive factors for response to this regimen. RESULTS: Of 41 patients, the ORR was 39.0% (CR 0%; PR 39.0%), and DCR was 78.0% using this chemotherapy. DCR for 6 and 12 months was 68.3 and 26.8%, respectively. Median PFS was 10.0 months [95% confidence interval (CI) 7.8-12.1], and median OS was 25.1 months (95% CI 18.2-32.1). Prominent toxicities were neutropenia and hand-foot syndrome. Most adverse events were well known, relatively moderate, and reversible. Taxane sensitivity [odds ratio (OR) 0.169; 95% CI 0.034-0.826; P = 0.028] and hepatic metastasis (OR 0.097; 95% CI 0.017-0.559; P = 0.009) were significantly predictive of response to gemcitabine and capecitabine combination. CONCLUSIONS: This study showed reproducible anticancer activity and tolerable toxicity of gemcitabine and capecitabine combination therapy in recurrent or metastatic Korean breast cancer patients previously treated with anthracycline and taxane.

Results of a phase 1, randomized study evaluating the effects of food and diurnal variation on the pharmacokinetics of linifanib.

PURPOSE: The primary objectives of this study were to evaluate the effect of food on the oral bioavailability and to evaluate the effect of diurnal variation on the pharmacokinetics of linifanib, a novel tyrosine kinase (TK) inhibitor selective for vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, in patients with advanced solid tumors. Adverse events were monitored. METHODS: This was a phase 1, open-label, randomized, crossover study. Thirty-four patients received dosing regimens to evaluate linifanib pharmacokinetic parameters under fasting and non-fasting conditions and with morning or evening dosing. Adverse events (AEs) were assessed according to National Cancer Institute Common Terminology Criteria for AEs (Version 3.0). RESULTS: The administration with food had a negligible effect on the AUC∞ of linifanib, but the Cmax of linifanib was decreased by 40 % compared to the fasting condition. Evening dosing after a 2-h fast had a negligible effect on AUC24; however, the dose-normalized Cmax of linifanib after evening dosing was 64 % of that after morning dosing following a 10-h fast. Common Grade 3/4 AEs were fatigue (24 %), hypertension (21 %), and palmar-plantar erythrodysaesthesia syndrome (15 %). CONCLUSIONS: Dosing with food or in the evening has a significant effect on the oral bioavailability of linifanib that should be taken into consideration when designing future clinical studies. The pattern of adverse advents reported in this study is similar to that seen in other studies of linifanib and other agents in the VEGF/PDGF TK receptor inhibitor class.

Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma.

PURPOSE: Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for enhanced antitumor efficacy. METHODS: Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two-stage design, after 14 of planned 21 subjects were enrolled. RESULTS: Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) ≥16 weeks was observed in 57 % patients, including three patients with SD lasting ≥1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug-related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (<300 pg/ml) experienced longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance. CONCLUSIONS: Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration.

Chemotherapy-induced hand-foot syndrome and nail changes: a review of clinical presentation, etiology, pathogenesis, and management.

Chemotherapy-induced hand-foot syndrome and nail changes are common complications of many classic chemotherapeutic agents and the newer molecular targeted therapies. They significantly impact patient quality of life, and frequently necessitate chemotherapy dose intensity modification or reduction. We aim to describe the epidemiology, pathogenesis, clinical presentation, and current evidence-based treatment options for these entities.