Concepts in Onychomycosis Treatment and Recurrence Prevention: An Update.

In considering therapy for onychomycosis, the most important factor to take into account is patient selection rather than treatment selection. Patients should be screened and evaluated for the extent of nail involvement, the amount of subungual debris, the degree of dystrophy, their ability and willingness to follow the regimen, and whether comorbidities are present that may affect the efficacy and/or safety of one or more therapies. Onychomycosis is a chronic disease with a high recurrence rate. Commonsense measures to reduce the risk for reinfection include patient education and a clinician-patient team approach to long-term management.

[Main treatment and preventive measures for hand-foot syndrome, a dermatologic side effect of cancer therapy]. / A daganatterápia egyik dermatológiai mellékhatása, a kéz-láb szindróma fõbb kezelési és megelõzési elvei.

Hand-foot syndrome is a highly unpleasant adverse reaction caused by treatment protocols containing capecitabine (an orally administered drug), docetaxel, liposomal doxorubicin infusions or continuously infused 5-fluorouracil. It affects the skin of the palms and soles manifesting characteristic symptoms like erythema, inflammation, dysesthesia, pain, thickening, desquamation and cracking of the skin that may progress to cause wounds and ulceration, negatively influencing quality of life, psychological state and belief in recovery, which often result in the need of permanent or temporary interruption of the oncologic treatment and are potential sources of danger to the completion of the therapy. Adequate provision of the syndrome is of particular importance since a decline in adherence due to adverse events endangers precise maintenance of the self-sufficient oral treatment at home. Early recognition of symptoms, regular oncologic checkups and patient education on how to prevent or soothe the unpleasant skin toxicities could ensure a more successful treatment.

Management of tyrosine kinase inhibitor-induced hand-foot skin reaction: viewpoints from the medical oncologist, dermatologist, and oncology nurse.

One significant toxicity associated with the anticancer tyrosine kinase inhibitors (TKIs) is hand-foot skin reaction (HFSR). We provide an overview of HFSR, emphasizing experience-based prevention techniques and nursing management strategies from the viewpoints of a medical oncologist, a dermatologist, and an oncology nurse. Supporting data include (1) published preclinical and phase I-III clinical studies and (2) published abstracts of phase II-III clinical trials of sorafenib and sunitinib. HFSR has been reported in up to 60% of patients treated with sorafenib or sunitinib. TKI-induced HFSR may lead to dose reductions or treatment interruptions and reduced quality of life. Symptoms of TKI-associated HFSR can be managed by implementing supportive measures and aggressive dose modification. Patients educated about HFSR can work with their health-care teams to proactively detect and help manage this cutaneous toxicity, thus preventing or reducing the severity of TKI-associated HFSR. Successful prevention and management of TKI-associated HFSR can help to ensure that patients achieve optimal therapeutic outcomes. Implementation of such measures may increase the likelihood that therapy is continued for the appropriate interval at an appropriate dose for each patient. Optimal management of TKI-associated HFSR is predicated on establishing appropriate partnerships amongmedical oncologists, dermatologists, oncology nurses, and patients.

Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5.

PURPOSE: Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine for which no effective preventative treatment has been definitively demonstrated. This trial was conducted on the basis of preliminary data that a urea/lactic acid-based topical keratolytic agent (ULABTKA) may prevent HFS. PATIENTS AND METHODS: A randomized, double-blind phase III trial evaluated 137 patients receiving their first ever cycle of capecitabine at a dose of either 2,000 or 2,500 mg/m(2) per day for 14 days. Patients were randomly assigned to a ULABTKA versus a placebo cream, which was applied to the hands and feet twice per day for 21 days after the start of capecitabine. Patients completed an HFS diary (HFSD) daily. HFS toxicity grade (Common Terminology Criteria for Adverse Events [CTCAE] v3.0) was also collected at baseline and at the end of each cycle. The primary end point was the incidence of moderate/severe HFS symptoms in the first treatment cycle, based on the patient-reported HFSD. RESULTS: The percentage of patients with moderate/severe HFS symptoms was not different between groups, being 13.6% in the ULABTKA arm and 10.2% in the placebo arm (P = .768 by Fisher's exact test). The odds ratio was 1.37 (95% CI, 0.37 to 5.76). Cycle 1 CTCAE skin toxicity was higher in the ULABTKA arm but not significantly so (33% v 27%; P = .82). No significant differences were observed in other toxicities between groups. CONCLUSION: These data do not support the efficacy of a ULABTKA cream for preventing HFS symptoms in patients receiving capecitabine.

Randomized trial of two different doses of pyridoxine in the prevention of capecitabine-associated palmar-plantar erythrodysesthesia.

AIM: The aim of the present study was to compare the efficacy of 200 mg versus 400 mg daily of pyridoxine in preventing or delaying the onset of palmar-plantar erythrodysesthesia (PPE) in capecitabine-treated patients. METHODS: Patients with histologically confirmed breast cancer or colorectal cancer receiving single agent capecitabine started at 2000 to 2500 mg/m(2) daily from day 1 to 14 every 3 weeks were randomly assigned to receive 200 mg or 400 mg daily of pyridoxine for PPE prophylaxis. The primary endpoint was the reduction of incidence of grade 2 or greater PPE. Secondary endpoints were reduction of severe PPE and prolongation of time to development of grade 2 or greater PPE. RESULTS: There were 56 patients in this study. The baseline characteristics were generally similar in both groups. The high dose arm had less PPE than the low dose arm (11 of 28 or 39% vs 20 of 28 or 71%, relative risk = 0.26 [0.08, 0.79], P = 0.031). Grade III PPE developed in 3 of 28 (10.7%) versus none in patients receiving 200 mg versus 400 mg pyridoxine, respectively (relative risk 2.12 [1.594, 2.819], P = 0.24). High dose pyridoxine had a longer time to development of grade 2 or greater PPE compared to the low dose arm, 87 days versus 62 days. The 400 mg pyridoxine group had, however, a worsened tumor response and tended to have greater tumor treatment failure and shorter time to treatment failure. CONCLUSION: With the limitation of sample size in this study, there was a trend to improve PPE incidence and time to event with a higher dose of pyridoxine. Further validation of these results in a larger population is warranted.

Pyridoxine is not effective to prevent hand-foot syndrome associated with capecitabine therapy: results of a randomized, double-blind, placebo-controlled study.

PURPOSE: To determine whether concurrent pyridoxine therapy can prevent the development of hand-foot syndrome (HFS) in patients being treated with capecitabine. METHODS: Chemotherapy-naive patients with GI tract cancers scheduled for capecitabine-containing chemotherapy were randomly assigned to concurrent oral pyridoxine (200 mg/d) or placebo. Patients were stratified by chemotherapy regimen and monitored until development of National Cancer Institute Common Toxicity Criteria grade 2 or worse HFS or capecitabine-containing chemotherapy ended. Patients in the placebo group who developed grade 2 or worse HFS were randomly assigned again to receive pyridoxine or placebo in the next chemotherapy cycle to determine whether pyridoxine could improve HFS. RESULTS: The median number of chemotherapy cycles to grade 2 or worse HFS was three in both groups. Grade 2 or worse HFS developed in 55 (30.6%) of 180 placebo-treated patients and in 57 (31.7%) of 180 pyridoxine patients. The cumulative dose of capecitabine to grade 2 or worse HFS was not different between the two groups (median not reached in either group; hazard ratio [HR] = 0.95; P = .788). Randomization of the 44 patients in the placebo group with grade 2 or worse HFS to placebo or pyridoxine for the next cycle resulted in no significant difference in the proportion showing improvement of HFS (42.9% v 47.8%; HR = 1.12; P = .94). By multivariate analysis, age > or = 56 years (HR = 1.768; 95% CI, 1.190 to 2.628; P = .005) was an independent risk factor for grade 2 or worse HFS, and combined use of docetaxel (HR = 2.046; 95% CI, 0.880 to 4.755; P = .096) was of borderline significance. CONCLUSION: Pyridoxine is not effective in prevention of capecitabine-associated HFS.

[Use of sorafenib in patients with hepatocellular or renal carcinoma]. / Bon usage du sorafénib chez les patients pris en charge pour un carcinome hépatocellulaire ou un cancer du rein.

Therapeutic approaches of cancers have been recently improved by the development of targeted therapies. Amongst these new drugs, some anti-angiogenic molecules have been approved by either the EMEA or the Food and Drug Administration. Sorafenib, one of these inhibitors of angiogenesis, has been established as the standard of care for advanced hepatocellular and renal carcinoma. This paper reviews the safety profile of sorafenib and presents guidelines for the prevention and the treatment of the main side effects associated with this molecule.

Impact of prophylactic pyridoxine on occurrence of hand-foot syndrome in patients receiving capecitabine for advanced or metastatic breast cancer.

BACKGROUND: Capecitabine, an oral fluoropyrimidine, has shown consistently high efficacy in anthracycline- and/or taxane-pretreated advanced and metastatic breast cancer. The safety profile of capecitabine is characterized by hand-foot syndrome (HFS), which, although not life threatening, can impair patients' quality of life if it is not managed promptly and effectively. We conducted a study to assess the impact of prophylactic pyridoxine on HFS. METHODS: Prophylactic pyridoxine was given to 38 patients receiving capecitabine (alone or in combination with cyclophosphamide) for metastatic breast cancer and compared with historical data from 40 patients receiving capecitabine without pyridoxine in our clinic. The impact of urea ointment on HFS was also assessed. RESULTS: HFS developed in 20 patients (52.6%) receiving pyridoxine compared with historical data showing an 82.5% rate in patients receiving no pyridoxine prophylaxis (p < 0.01). A nonsignificant trend towards less severe HFS was seen among patients who received urea ointment at first appearance of symptoms. In addition, nonsignificant trends towards higher rates of HFS were seen among those who were ≥61 years and those who derived clinical benefit (clinical response or stable disease). CONCLUSIONS: Prophylactic pyridoxine and urea ointment at first appearance of symptoms appears to reduce the risk of severe capecitabine-induced HFS. However, randomized data are required to determine the true effect of these measures.

The use of cod liver oil by patients receiving pegylated liposomal doxorubicin is associated with a lack of severe palmar-plantar erythrodysesthesia.

Pegylated liposomal doxorubicin (PLD) is an effective and tolerable agent in the treatment of recurrent and refractory ovarian carcinoma. One of the most common dose-limiting toxicities of PLD is palmar-plantar erythrodysesthesia (PPE). We report a retrospective review of patients who took cod liver oil (CLO) while being treated with PLD at Roswell Park Cancer Institute. None of the patients required dose reduction, treatment interruption or discontinuation secondary to skin toxicity. No patient experienced grade 2 or greater PPE. The mechanism for the development of PLD-induced PPE is unknown. CLO may possibly mitigate it via decreased extravasation of PLD and/or by a blunting of the local inflammatory response. The effects of CLO should be further evaluated in a prospective, randomized trial, and attempts to elucidate the mechanism by which CLO may exert its effects should be pursued.

[Phalanges necrosis--a rare manifestation of "hand-foot" syndrome induced by gemcitabine used in the second--line therapy for progressive ovarian cancer. A case report]. / Zespól dloniowo-podeszwowy pod postacia martwicy palców rak. Przypadek rzadkiego powiklania w nastepstwie zastosowania gemcytabiny u chorej z zaawansowanym rakiem jajnika.

"Hand-foot" syndrome is a well-documented, dermatologic reaction after several chemotherapeutic agents with wild spectrum of symptoms. To the best of our knowledge, palmar-plantar erythrodysesthesia syndrome--presented as irreversible cytotoxic side effect induced by gemcitabine alone--has not been reported so far. We present a case of a patient with a history of peripheral sensory neuropathy who developed a painless finger necrosis caused by gemcitabine used in the second-line therapy for progressive ovary cancer.

Search for evidence-based approaches for the prevention and palliation of hand-foot skin reaction (HFSR) caused by the multikinase inhibitors (MKIs).

BACKGROUND: The anticancer multikinase inhibitors (MKIs) are associated with cutaneous adverse events, including hand-foot skin reaction (HFSR), a condition affecting 20%-40% of patients. Symptoms are usually mild, but can evolve into a painful condition that limits function and impacts quality of life (QoL), resulting in shortened cancer treatment duration or intensity. The goal of this study was to systematically review the literature on the prevention and palliation of MKI-associated HFSR, to identify areas for further clinical study, and to provide a foundation for evidence-based guidelines for HFSR management. METHODS: Systematic searches of the National Library of Medicine's PubMed database, Cochrane Reviews, BIOSIS, CancerLit, and the American Society of Clinical Oncology website were conducted using search terms for cutaneous toxicities associated with chemotherapeutic agents. Articles were categorized (C) based on type of agent and cutaneous reaction as: C1 (MKI and HFSR); C2 (MKI and other cutaneous toxicity); C3 (other antineoplastic agents and HFSR); and C4, other. RESULTS: Of the 2,069 abstracts screened, 350 (17%) met the criteria for C1-C4, with 56 (16%) coded as C1 with details of HFSR histology, pathogenesis, clinical outcome, QoL impact, and/or prevention and treatment approaches in MKI-treated patients. No randomized, controlled trials (RCTs) on prevention/palliation of HFSR were identified. Anecdotal evidence or expert opinion advocated protective measures, preventive and therapeutic skin care, systemic analgesics for pain, vitamin B(6), and MKI dose modification. CONCLUSION: No articles containing evidence from RCTs on preventive/palliative approaches to MKI-associated HFSR have been published. Systematic study of optimal treatment strategies for HFSR is needed to advance development of evidence-based treatment guidelines.

Influence of microparticles on the homogeneity of distribution of topically applied substances.

The uppermost layer of the skin--the stratum corneum--represents a barrier of the human organism to the environment. It prevents the penetration of substances coming into contact with the skin into the human body. In cases of strong exposure, the skin has to be protected additionally by barrier creams. In the present study, the influence of microparticles on the homogeneity of distribution of the protection cream on the skin was investigated by laser scanning microscopy. The protection cream contained antioxidant substances with a high radical protection factor for the prevention of palmar-plantar erythema often occurring during chemotherapy with doxorubicin. In this case, the chemotherapeutic substance comes out with the sweat onto the skin surface, from which it penetrates into the skin like topically applied. It was found that particles increase the homogeneity of distribution and, thus, the protection efficacy is significantly increased. The obtained results are important, not only for the prevention of side effects during chemotherapy, but also for the development and application of sunscreens and all types of topically applied drugs and cosmetics, which should form an efficient protection film on the skin.

["Hand-foot" syndrome--after liposomal pegylated doxorubicin in patients with the ovarian cancer recurrence (own experiences)]. / Zespól "reka-stopa" w nastepstwie stosowania liposomalnej pegylowanej doksorubicyny u chorych na raka jajnika w fazie nawrotu choroby (doswiadczenie wlasne).

AIM: To present our own experience with pegylated liposomal doxorubicin applied in ovarian cancer patients. MATERIAL AND METHODS: The group of 32 patients with ovarian cancer was treated with pegylated liposomal doxorubicin (LPD) in Klinika Onkologii Klinicznej Centrum Onkologii Branch Gliwice between the years 2004 and 2007. Median age was 47 years. The histoclinical variables potentially influencing the occurrence of the hand-foot syndrome were analyzed. RESULTS: Hand-foot syndrome has been observed in 11 patients (34.4%) treated with the LPD. The lesions have been present on the skin of hands, feet, elbow and knee joints and armpits. In the analyzed group of patients, the risk of the hand-foot syndrome occurrence increased, however non-significantly, with the increase of number of cycles including LPD (p=0.069) and the number of previous lines of chemotherapy (p=0.067). Other analyzed factors had no negative influence on the hand-foot syndrome occurrence. CONCLUSIONS: It is important to inform the patients about the risk of the hand-foot syndrome occurrence and its management. Early diagnosis allows to prevent the worsening of the hand-foot syndrome and makes it possible to continue the chemotherapy without the necessity of dose reduction and breaking from the therapy.

Can inhibiting dihydropyrimidine dehydrogenase limit hand-foot syndrome caused by fluoropyrimidines?

Hand-foot syndrome (HFS) is a cutaneous adverse event that occurs in some patients treated with fluoropyrimidines. Although it is not life threatening, HFS can severely disrupt the daily lives of patients. HFS appears more frequently with 5-fluorouracil (5-FU) delivered by continuous infusion or with the 5-FU oral derivative capecitabine than with bolus 5-FU therapy. HFS is a leading cause of treatment interruption, dosage reduction, or, even, therapy discontinuation for patients on a capecitabine regimen. Interestingly, addition of a dihydropyrimidine dehydrogenase (DPD) inhibitor, such as uracil, 5-chloro-2,4-dihydroxypyridine, or eniluracil, to the fluoropyrimidine treatment regimen significantly diminishes the incidence of HFS. DPD inhibitors were initially combined with fluoropyrimidines to increase the efficacy of the drugs by impairing the DPD-mediated catabolism of 5-FU. However, with the accumulating findings from clinical trials that show the benefits of DPD inhibition on decreasing the risk of HFS, consideration should be given to changing the recommendations for the treatment of cancer patients with fluoropyrimidines to include DPD inhibitor components as standard therapy.

Prevention strategies in palmar-plantar erythrodysesthesia onset: the role of regional cooling.

OBJECTIVE: Palmar-plantar erythrodysesthesia (PPE) is a characteristic cutaneous toxicity associated with pegylated liposomal doxirubicin (PLD). Different therapies have been proposed to alleviate PPE onset. We performed a prospective study to evaluate preventive strategies to reduce PPE incidence in patients treated for gynecologic cancers. METHODS: Fifty-three patients were treated from 2001 to 2006 with PLD as single agent therapy or in combination with carboplatin or paclitaxel. PLD dosages were in the range of 30-50 mg/m2 every 21-28 days. All patients received premedication with dexamethasone and pyridoxine. Twenty-eight patients received application of ice packs on extremities during PLD infusion. RESULTS: PPE was observed in 11 patients (20.8%). PLD administration as single agent or in combination and schedule of PLD therapy did not affect PPE incidence. A significant reduction in PPE onset was observed if PLD dosage was 30-35 mg/m2 (p=0.03) and when patients were submitted to regional cooling protocol (p=0.0097). CONCLUSIONS: The use of ice packs around wrists and ankles is a simple and well tolerated prevention strategy and its efficacy is demonstrated in this study.