Lanolin-based dexpanthenol cream, topical hydrocortisone or observation in the prevention of capecitabine-induced hand-foot syndrome: a phase III trial

The protocol for the current study (ClinicalTrials.gov, NCT00661102) was approved by the research ethics committees of all participating institutions, and all patients enrolled provided their written informed consent before randomization. Eligible patients had at least 18 years of age; confirmed diagnosis of breast cancer or colorectal cancer, with indication by their primary physician of treatment with capecitabine as a single agent or in combination for any treatment line; inclusion and randomization at a maximum of 5 days since day 1 of the frst cycle of capecitabine-based chemotherapy; no evidence of HFS upon randomization; no current or previous (≥3 months) use of any pharmaceutical formulation of doxorubicin (including liposomal), or cytarabine; no history of diabetes mellitus; no current pregnancy or intention to get pregnant during the study, no known history of hypersensitivity to any of the study medications; and no use of other investigational agents within the previous 30 days.

Patients were randomized in an open-label fashion to one of three arms: observation, topical lanolin-based cream with dexpanthenol, and topical hydrocortisone cream. Before enrollment, all patients were carefully instructed about HFS and its recognition. Randomization was done through an electronic case report form and took place on the first study visit. Both creams were provided by Roche Brazil in their commercially available formulations (Bepantol^® and Berlison^®). In active-treatment arms, patients were instructed to apply a thin and uniform layer of topical medications in the palms of hands and soles of feet according to the prescribing information for each cream: lanolin-based cream with dexpanthenol was to be used three times a day, and hydrocortisone cream was to be used twice a day (approximately every 8 and 12 hours, respectively). These patients were instructed to use topical treatments continuously, even when there were chemotherapy delays between cycles. Patients in the observation arm received identical information, except that regarding the use of topical creams.

The starting dose of capecitabine in breast and colorectal cancer patients was 1,000 or 1,250mg/m², based on the investigator's discretion and clinical practice, administered every 12 hours, for 14 consecutive days followed by a 7-day resting period. Dose reduction was done according to the prescribing information for this agent in Brazil. Following the available literature, on the palliative therapy for breast cancer, patients could receive capecitabine until progression or serious adverse events. Treatment with study creams was continued until the development of HFS, discontinuation of on-study capecitabine-based chemotherapy, or consent withdrawal. For all patients discontinued prematurely from the study, further anticancer treatment was left to physician's discretion.

Patients were assessed at baseline and during follow-up using structured instruments. After the baseline visit and one planned visit before the third chemotherapy cycle, follow-up was slightly different between patients on palliative therapy for breast or colorectal cancer (a third visit before the ffth cycle and the final visit after the sixth cycle) and those on adjuvant therapy for colon cancer (a third visit before the sixth cycle and the final visit after the eight cycle), but did not vary according to the three randomization arms. HFS was assessed at each visit and classified, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, as grade 0 when absent, grade 1 when skin changes or erythema were minimal and caused no pain, grade 2 when there was pain or more pronounced skin changes (e.g., peeling, blisters, bleeding, or edema) but no interference with function, and grade 3 when skin changes led to pain and interfered with function.24 Health-related quality of life (HRQoL) was assessed at each visit using the validated Brazilian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30), version 3.0.25 26 27 This HRQoL instrument assesses five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea/vomiting); individual symptoms (dyspnea, insomnia, appetite loss, constipation, and diarrhea); the financial impact of treatment; and a global health and quality-of-life scale. Only a summary of results for the analysis of quality of life is presented herein. Adverse events other than HFS were also assessed using CTCAE, version 3.0.24

The primary endpoint was the frequency of HFS of any grade. Secondary endpoints were various HRQoL scores (for global health status, functional scales, symptom scales, individual symptoms, and financial impact of therapy), change from baseline in performance status (according to the Eastern Cooperative Oncology Group scale), and the incidence of adverse events. No assessment was made of chemotherapy efficacy, given the expected absence of systemic effect from topical creams. The required sample size for this study was estimated under the assumption that the incidence of HFS of any grade in the observation arm would be 53%. Using a one-sided type I error of 5%, the enrollment of 489 patients (163 per arm) would give the study 80% power to detect a difference of at least 15% in the frequency of HFS of any grade between any of the active-treatment arms and the observation arm, allowing for a dropout rate of 20%. Although analyses were conducted in intention-to-treat (ITT) and per-protocol (PP) populations, the primary analysis was the frequency of HFS of any grade in the ITT population, which comprised all randomized patients that received any amount of study treatment. The PP population included only patients in the ITT population that either completed the whole planned capecitabine treatment or were discontinued before completion because of the development of HFS, disease progression, adverse event or death (other reasons for discontinuation led to the removal of patients from the PP population). The frequency (and 95% confidence interval [CI]) of HFS of any grade was compared between arms using the chi-square test, and logistic regression models were used to explore the association between baseline characteristics and this outcome.

Variables showing an association with HFS at p-value ≥0.20 in the univariate analysis were included in a multivariate logistic regression analysis performed using a stepwise selection process and a maintenance level of 0.25. Numerical variables were compared between arms using t-tests and analysis of variance (ANOVA) for two and three-way comparisons, respectively, of normally distributed variables, or the Mann-Whitney and the Kruskal-Wallis tests for corresponding comparisons of variables with non-normal distribution. Moreover, repeated-measures ANOVA was used to explore time trends in HRQoL scores. Statistical analysis was conducted using SAS (version 9.1.3), and significance was considered for two- tailed p-values <0.05.

Between January 2009 and October 2010, 598 patients were randomized in 31 centers in Brazil. Of these patients, three patients were removed from the study because they did not sign the consent form (two in the control arm and one in the hydrocortisone arm). Of the remaining 595 patients, 393 were prematurely discontinued from the study, more often due to development of HFS (n=182) and disease progression (n=51). Figure 1 depicts patients' flow in the study, including the reasons for treatment discontinuation across the three study arms. Among patients withdrawn from the study, premature discontinuation due to HFS was reported for 72/146 (49.3%), 53/129 (41.1%) and 57/118 (48.3%) in the observation, lanolin-based cream with dexpanthenol, and hydrocortisone cream study arms, respectively. Selected baseline patient characteristics are shown in Table 1 and were evenly distributed among arms. Overall, the mean age was 58 years, and 69% of patients were women. The vast majority of patients had performance status of 0 or 1. Advanced breast cancer was the underlying diagnosis in 37% of patients, and 63% of individuals had colorectal cancer (22% in adjuvant therapy and 41% in palliative therapy for advanced disease). Capecitabine was used as single agent in 67% of patients; for the vast majority (82%) of the remaining 33% of patients treated with combinations, oxaliplatin was the chemotherapy partner. There were no significant differences in the mean daily dose of capecitabine prescribed in the first chemotherapy cycle among arms. Chemotherapy lines were also evenly distributed among the three arms (data not shown).

Overall, the frequency of HFS of any grade during the study was 35.6% (95%CI, 29.4% to 42.4%) with observation, 24.9% (95%CI, 19.5% to 31.2%) with lanolin-based cream with dexpanthenol, and 34.3% (95%CI, 27.7% to 41.4%) for hydrocortisone cream (p=0.039). When compared with observation, the unadjusted odds ratio for the frequency of HFS in the arm treated with the lanolin-based cream with dexpanthenol was 0.60 (95%CI, 0.39 to 0.92), indicating a 40% relative reduction in the frequency of this adverse event. Adjusting for other covariates that showed an association with HFS development at p-values ≥0.20 in the univariate analyses (i.e., cancer site, metastatic disease, treatment line, heart disease, hypertension, smoking, systolic blood pressure, and prescribed dose of capecitabine at visit 1), this odds ratio was 0.61 (p=0.047); the only other covariate significantly associated with the occurrence of HFS was the dose of capecitabine (data not shown). As shown in Table 2, differences across groups were more pronounced during the first two cycles (between the first and second visits). Such findings do not seem to be explained by dose adjustments, as the mean dose of capecitabine during the study did not vary significantly across arms (Table 3). Likewise, there were no significant differences in the distribution of the severity of HFS across the three arms, when the overall study duration was considered (p=0.694). Grade 1 HFS was noted in 53.1% of patients with this adverse event along the study in the observation arm, 61.5% of patients treated with the lanolin-based cream with dexpanthenol, and 59.0% of patients in the hydrocortisone cream arm. Corresponding figures for grade 2 HFS were 37.5%, 34.6%, and 38.5%, respectively. Only between 2.6% and 9.4% of patients in three study arms had grade 3 HFS.

Exploratory analyses conducted in the PP population corroborated the analyses conducted in the ITT population. The frequency of HFS of any grade during the study in the PP population was 47.2% (95%CI, 51.6% to 69.5%) with observation (n=142), 31.1% (95%CI, 29.1% to 45.7%) with lanolin-based cream with dexpanthenol (n=151), and 44.4% (95%CI, 41.6% to 60.2%) for hydrocortisone cream (n=124; p=0.012 for the comparison of the three arms). Once again, there were no significant differences in the distribution of the severity of HFS among the three arms in the PP population, when the overall study duration was considered; moreover, such distribution in the PP population closely mirrored the one found for the ITT population (data not shown). No exploratory analyses were conducted with regard to potential differences in treatment efficacy among subgroups of patients defined by baseline characteristics, including tumor type and treatment intent.

Table 4 shows HRQoL scores at baseline and at all follow-up visits, while Table 5 shows the mean change in HRQoL scores from baseline. Apart from a slight imbalance in cognitive function with a statistically significantly higher score in the hydrocortisone arm (p=0.038), there were no significant differences in other scores among the three study arms at baseline (all p>0.05). There were no statistically significant differences in mean change from baseline in any of the HRQoL scores among the three study arms (Table 5). However, there were statistically significant improvements across the three arms, in comparison with baseline scores, in the global health and quality-of-life scale in the last visit (p=0.033); in emotional function in the final visit (p=0.008); nausea/vomiting in the second (p=0.008) and third (p=0.076) visits; in appetite loss in the second visit (p=0.016); and in diarrhea in the second visit (p=0.002). On the other hand, in the three study arms there was statistically significant worsening of physical function in the second (p=0.002) and third (p=0.017) visits; of cognitive function in the third visit (p<0.001); of fatigue in the third (p=0.043) and final (p=0.025) visits; of pain in the second (p=0.004) and third (p=0.001) visits; of insomnia in the second visit (p=0.021); of constipation in the second visit (p=0.011); and of the financial impact of treatment in the second (p=0.003) and third (p=0.014) visits, always in comparison with baseline. There were no statistically significant differences in the distribution of performance status among the three arms during the study.

Overall, the frequency of adverse events along the study did not vary significantly among study arms (Table 6). Nearly 60% of patients in the three arms had at least one adverse event. As shown in Table 6, the frequency of serious adverse events and the severity of adverse events, as indicated by CTCAE grading, also did not vary significantly among study arms. The most frequent adverse events reported by at least five patients in any arm were nausea, diarrhea, vomiting, fatigue, and pain, with no notable differences in their distribution among study arms. Thirty-seven deaths were reported during the study; in 34 of these cases, death was attributed to disease progression (in nine patients in the observation arm, 20 in the lanolin-based cream with dexpanthenol arm, and five in the hydrocortisone cream arm).