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

Keywords:

Breast neoplasms - Capecitabine - Colorectal neoplasms - Glucocorticoids - Hand-foot syndrome - Dexpanthenol

Descritores:

Neoplasias mamárias - Capecitabina - Neoplasias colorretais - Glicocorticóides - Síndrome mão-pé - Dexpantenol

INTRODUCTION

Capecitabine is an important component of various regimens that are currently used to treat advanced breast cancer, as well as of the adjuvant and palliative treatment of colorectal cancer.[1] [2] [3] [4] [5] [6] [7] [8] Although generally safe, the use of capecitabine is associated with hand-foot syndrome (HFS), a distinct adverse event that is often managed clinically by dose-reductions and delays and through the use of topical measures, such as emollient creams and corticosteroids.[9] [10] Lanolin is a natural yellow fat obtained from the wool of sheep that has been used for skin care purposes.[11] There is anecdotal evidence that lanolin-based creams are useful for the treatment of established HFS.[12] However, no definitive data are available in the literature to suggest that either lanolin-based creams or topical corticosteroids are useful for the prevention of HFS.

Moreover, various interventions have been used in the past to prevent or ameliorate HFS, including corticosteroids, pyridoxine (vitamin B₆), cycloxygenase-2 inhibitors, and vitamin E.[13] [14] However, the efficacy of these strategies remains controversial, as most randomized clinical trials assessing these interventions to date have either been negative[15] [16] [17] or relatively small,[18] [19] [21] with a few exceptions showing a positive impact in HFS prevention or/and treatment.[14] [15] [16] [17] [18] [19] [20] [21] [22] [23] Despite the accumulated clinical experience with such topical and systemic measures, there are not enough data in the literature to guide the use of any of these interventions for the prevention of HFS. Given the prevailing uncertainties about preventive measures for HFS and the current role played by capecitabine as a chemotherapeutic agent, we conducted a phase III trial to assess the worth of a lanolin-based cream with dexpanthenol (the D enantiomer of panthenol, the alcohol analog of pantothenic acid or vitamin B₅), and a topical corticosteroid, hydrocortisone, in the prevention of HFS.

MATERIAL AND METHODS

Eligibility criteria

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.

Study design and treatment plan

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.

Patient evaluation

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]

Statistical analysis

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.

RESULTS

Patient characteristics

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).

Figure 1 Patient flow during the study. Abbreviations: HFS = Hand-foot syndrome; ITT = Intention-to-treat.

Table 1 Baseline characteristics of patients

Characteristic	Observation n=205	Lanolin-based dexpanthenol cream n=209	Hydrocortisone cream n=181	p-value
Age, years (mean ± SD)	57.4 ± 13.9	58.5 ± 13.4	58.5 ± 14.0	0.65
Gender (%)				0.39
Female	69.8	66.0	72.4
Male	30.2	34.0	27.6
Performance status (%)				0.89
0	46.3	47.6	49.2
1	39.5	38.0	37.6
2	12.2	11.1	8.8
3	2.0	3.4	4.5[*]
Primary diagnosis (%)				0.91
Advanced breast cancer	36.3	35.1	39.2
Colorectal cancer, adjuvant therapy	21.5	24.0	21.5
Advanced colorectal cancer	42.0	40.9	39.2
Capecitabine use (%)				0.65
Single agent	64.4	68.3	68.0
Combination	35.6	31.7	32.0
Capecitabine dose at cycle 1, mg/m2/day (mean ± SD)	2060 ± 556	2051 ± 548	2030 ± 536	0.86
Treatment line (%[**])				0.96
First	44.9	43.1	46.4
Second	33.7	32.5	32.0

^* One patient in this group was coded as having performance status of 4.

^** Only applies to metastatic disease, but percentages refer to total number of patients in each arm.

Abbreviations: HRQoL = Health-related quality of life; SD = Standard deviation.

Frequency and severity of HFS

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.

Table 2 Frequency of hand-foot syndrome along the study (see text for timing of visits)

Assessment visit	Observation n=205	Lanolin-based dexpanthenol cream n=209	Hydrocortisone cream n=181	p-value
First	20.5%	12.4%	13.8%	0.057
Second	8.8%	9.2%	11.4%	0.721
Third	19.1%	9.9%	17.4%	0.142
Final	1.7%	0	7.9%	0.011
Overall	35.6%	24.9%	34.3%	0.039

Table 3 Mean doses of capecitabine along the study (mg/m²/day)

Study period	Observation n=205	Lanolin-based dexpanthenol cream n=209	Hydrocortisone cream n=181	p-value
At second visit	2005 ± 557	2000 ± 517	1967 ± 515	0.813
At third visit	1978 ± 568	1929 ± 451	2003 ± 536	0.577
At final visit	1976 ± 496	1832 ± 342	1838 ± 355	0.808
Overall[*]	2064 ± 558	2040 ± 535	2018 ± 522	0.704

^* Computation of overall dose includes data on dose at cycle 1 shown in Table 1.

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.

HRQoL and performance status results

[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.

Table 4 Health-related quality of life scores at baseline and follow-up visits assessed using the validated Brazilian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)

EORTCQLQ-C30 scores	Observation				Lanolin-based dexpanthenol cream				Hydrocortisone cream
	Visit 1 Mean ± SD	Visit 2 Mean ± SD	Visit 3 Mean ± SD	Visit 4 Mean ± SD	Visit 1 Mean ± SD	Visit 2 Mean ± SD	Visit 3 Mean ± SD	Visit 4 Mean ± SD	Visit 1 Mean ± SD	Visit 2 Mean ± SD	Visit 3 Mean ± SD	Visit 4 Mean ± SD
Global health and QoL scale	64.4 ± 25.5	65.3 ± 247	66 ± 24.9	68.2 ± 23.4	63.1 ± 27.4	65.7 ± 26.3	66.5 ± 27.5	73.8 ± 24	67.3 ± 22.5	67.1 ± 23.7	68.9 ± 25.6	73 ± 22.8
Physical function	69.5 ± 26.3	694 ± 25.7	65.6 ± 304	69.6 ± 27.5	67.3 ± 28	67.5 ± 28.2	68.9 ± 29.4	76 ± 26.6	714 ± 26.2	67.1 ± 27.8	71.7 ± 25.5	73 ± 26.1
Role function	646 ± 345	68.7 ± 34	62.9 ± 36.6	67.5 ± 35.5	60.3 ± 38	66.4 ± 35	68.2 ± 35.1	73.1 ± 31.9	67 ± 35.3	66.7 ± 36.3	69.7 ± 35.9	71.1 ± 34.5
Emotional function	63 ± 29.7	66.2 ± 29	62.9 ± 31.6	71.6 ± 28.9	59.7 ± 30.8	62.8 ± 30.7	68.2 ± 29.6	67.1 ± 33.3	63.3 ± 31.7	649 ± 29.9	64.1 ± 31	68 ± 29.4
Cognitive function	70.7 ± 30.6	73.5 ± 28.8	68.1 ± 32.2	73.7 ± 28.6	73.9 ± 27.1	746 ± 29.6	72.7 ± 31.1	74.6 ± 31.6	78.1 ± 26.5	75 ± 27	69.9 ± 30.5	70.6 ± 28.9
Social function	71.3 ± 32.2	77.2 ± 28.1	73.8 ± 34.3	743 ± 31.5	68.5 ± 33.9	72.7 ± 34.1	749 ± 32.6	794 ± 32.3	76.1 ± 30	76.4 ± 29.5	80.5 ± 28.6	77.9 ± 294
Fatigue	35.5 ± 30.1	29.7 ± 28	28.5 ± 29.2	29.2 ± 28.1	36.4 ± 30.6	30.4 ± 29.1	27.1±29.4	24.9 ± 25.9	33.9 ± 30.1	31.4 ± 29.6	26.8 ± 25.9	25 ± 26.9
Nausea/vomiting	13.3 ± 22.8	13.5 ± 21.8	12.6 ± 17.7	141 ± 21.8	12.4 ± 20.6	15.1 ± 21	11.4 ± 17.8	9.8 ± 17.3	13.1 ± 21.8	15.2 ± 23.2	14 ± 18.4	10.4 ± 19.8
Pain	36.5 ± 35.2	30.1 ± 33.6	31 ± 33.1	31.1 ± 31	38.9 ± 37.6	31.8 ± 31.1	26.9 ± 32.7	26.5 ± 324	34.3 ± 35.2	27.6 ± 31.8	249 ± 30.9	25.3 ± 304
Dyspnea	15 ± 27.1	144 ± 28.5	11.6 ± 24.2	14.9 ± 28	16.3 ± 28.6	148 ± 27.3	13.5 ± 23.8	11.5 ± 22	12.3 ± 26.1	10 ± 20.8	8.4 ± 18.3	6.9 ± 16
Insomnia	33.3 ± 36.8	23.6 ± 31.9	28.5 ± 35	28.7 ± 34.5	35.7 ± 38	28.7 ± 35.4	27.7 ± 35.2	26.9 ± 37.2	33.1 ± 36.1	32.1 ± 35.8	28.2 ± 35.8	20.6 ± 30.8
Appetite loss	26.2 ± 35.7	224 ± 31.6	21 ± 30.3	27 ± 34.5	26.9 ± 37.4	28 ± 35.8	23.6 ± 33.5	154 ± 27.2	24.7 ± 35.2	26.3 ± 37.6	20.1 ± 31.4	20.1 ± 35.7
Constipation	15.4 ± 29.5	8.2 ± 19.4	13.5 ± 26	15.5 ± 28.8	18.2 ± 31.6	12.7 ± 24.6	11.3 ± 21.5	10.8 ± 22.6	17.1 ± 30.9	16.3 ± 27.7	13.2 ± 25.8	13.8 ± 30.3
Diarrhea	8.6 ± 20.5	12.2 ± 247	11.6 ± 19.5	7.5 ± 15.3	9.5 ± 23.2	15.2 ± 25.7	13.2 ± 23.3	13.7 ± 24.3	8.1 ± 20.1	13.1 ± 26.3	11.4 ± 22.9	11.6 ± 20.9
Financial difficulties	33 ± 37.2	274 ± 33.7	31.5 ± 37.7	31 ± 35.6	343 ± 37.9	30.6 ± 37.1	25.5 ± 36.4	23.1 ± 324	31.3 ± 38	30.7 ± 39.2	26.7 ± 35.6	26.4 ± 35

Abbreviations: EORTC-QLQ C30 = European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire; QoL = Quality of Life; SD = Standard deviation.

Table 5 Changes in health related quality of life scores at visits 2, 3 and 4 as compared with baseline, using the validated Brazilian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)

	Observation			Lanolin-based dexpanthenol cream			Hydrocortisone cream
Change in EORTC QLQ-C30 from visit 1	Visit 2 Mean ±SE [95%CI]	Visit 3 Mean ± SE [95%CI]	Visit 4 Mean ± SE [95%CI]	Visit 2 Mean ± SE 95%CI]	Visit 3 Mean ± SE [95%CI]	Visit 4 Mean ± SE [95%CI]	Visit 2 Mean ± SE [95%CI]	Visit 3 Mean ± SE [95%CI]	Visit 4 Mean ± SE [95%CI]
Global health and QoL scale	-1.5 ± 2	0.8 ± 3.2	2 ± 3.7	-1.2 ± 2.2	-0.6 ± 2.6	5 ± 3.1	-0.4 ± 2.2	1.4 ± 2.6	5.6 ± 3.3
	[-5.4 ; 2.5]	[-5.5; 7.1]	[-5.4 ; 9.4]	[-5.5; 3.1]	[-5.8 ; 4.6]	[-1.2; 11.1]	[-4.8 ; 3.9]	[-3.8 ; 6.7]	[-1 ; 122]
Physical function	-2.5 ± 1.7	-4.8 ± 2.8	-1.6 ± 3.1	-2.4±1.5	-3 ± 2.4	1.6 ± 2.4	-4.2 ± 1.9	-2.7 ± 2.5	-4.1 ± 3.4
	[-5.8 ; 0.9]	[-10.3; 0.7]	[-7.8 ; 4.7]	[-5.4 ; 0.6]	[-7.7; 1.6]	[-3.2 ; 6.4]	[-8.1 ; -0.4]	[-7.7 ; 2.3]	[-10.8 ; 2.7]
Role function	1.8 ± 2.9	-1.2 ± 4.1	2.8 ± 4.7	2.5 ± 2.3	3.6 ± 3.5	5 ± 3.3	0.7 ± 2.5	2.7 ± 3.5	5.2 ± 5.1
	[-4; 7.6]	[-9.4 ; 6.9]	[-6.6 ; 12.2]	[-2.1 ; 7]	[-3.2; 10.5]	[-1.5 ; 11.5]	[-4.2 ; 5.7]	[-4.3 ; 9.6]	[-5 ; 15.4]
Emotional function	1.2 ± 2.3	-1.8 ± 3.3	7.8 ± 3.9	1.8 ± 2	3.6 ± 2.5	3 ± 3.2	1.5 ± 2.4	-0.9 ± 2.9	4.8 ± 2.8
	[-3.5 ; 5.8]	[-8.3 ; 4.8]	[-0.1 ; 15.6]	[-2.2 ; 5.8]	[-1.4 ; 8.6]	[-3.4 ; 9.5]	[-3.2 ; 6.2]	[-6.7 ; 4.9]	[-0.8; 10.5]
Cognitive function	1.5 ± 2.3	-5 ± 2.9	1.7 ± 3.7	-2.6 ± 1.8	-6.5 ± 2.2	-6 ± 3	-2.6 ± 2.2	-7.9 ± 2.7	-5.5 ± 4
	[-3 ; 5.9]	[-10.7 ; 0.8]	[-5.6 ; 9]	[-6.1; 1]	[-10.8;-2.1]	[-12;-0.1]	[-7; 1.7]	[-13.2;-2.5]	[-13.5; 2.5]
Social function	2.4 ± 2.6	-0.9 ± 3.7	-2.5 ± 4.8	1.3 ± 2.1	-2 ± 3.2	-0.2 ± 3.2	-0.6 ± 2.2	1.1 ±2.8	-1.3 ± 3.5
	[-2.7 ; 7.6]	[-8.3 ; 6.5]	[-12.2; 7.1]	[-2.9 ; 5.5]	[-8.3 ; 4.3]	[-6.6 ; 6.2]	[-4.9 ; 3.7]	[-4.5 ; 6.6]	[-8.3 ; 5.8]
Fatigue	-2.3 ± 2.4	-5.8 ± 3.1	-4.9 ± 3.9	-2.1 ±1.6	-1.8 ± 2.4	-3.7 ± 2.6	-1.3 ± 2.5	-2 ± 2.8	-4.9 ± 3.9
	[-6.9 ; 2.4]	[-11.9 ; 0.2]	[-12.7; 3]	[-5.3; 1.1]	[-6.4 ; 2.9]	[-8.9 ; 1.4]	[-6.1 ; 3.6]	[-7.6 ; 3.6]	[-12.7; 3]
Nausea/vomiting	1.1 ±2.2	-0.5 ± 2.8	1.7 ± 3.5	5.5 ± 1.6	4.1 ±1.5	2.9 ± 1.7	2.3 ± 2	3 ± 2.1	-0.8 ± 3.2
	[-3.3 ; 5.5]	[-6.1; 5.1]	[-5.3 ; 8.7]	[2.4 ; 8.7]	[1.1; 7]	[-0.5 ; 6.4]	[-1.7; 6.2]	[-1 ; 7.1]	[-7.3 ; 5.7]
Pain	-2.7 ± 2.8	-4.4 ± 3.2	-3.7 ± 4.5	-4 ± 2.4	-4.4 ± 2.9	-1.1 ±3.3	-6.2 ± 2.6	-9.1 ±3.5	-8.6 ± 4.8
	[-8.2 ; 2.8]	[-10.8 ; 1.9]	[-12.7 ; 5.3]	[-8.7 ; 0.6]	[-10; 1.3]	[-7.7 ; 5.6]	[-11.4;-1]	[-16.1;-2.2]	[18.2; 1]
Dyspnea	-1 ±2.2	-3.7 ± 2.8	0.6 ± 4.2	1.3 ± 2	1.3 ± 2.4	-0.9 ± 2.9	-0.2 ± 1.8	-1.1 ± 2	-1.6 ± 3
	[-5.3 ; 3.3]	[-9.3 ; 1.8]	[-7.9 ; 9]	[-2.6; 5.1]	[-3.4 ; 5.9]	[-6.7 ; 4.9]	[-3.8 ; 3.3]	[-5.2 ; 3]	[-7.5 ; 4.3]
Insomnia	-5.3 ± 2.6	0.8 ± 3.7	2.3 ± 5.6	-3.8 ± 2.2	-0.3 ± 2.8	-1.3 ± 4.4	-0.7 ± 2.5	-5.9 ± 3.5	-12.2 ± 4.5
	[-10.5;-0.1]	[-6.6; 8.1]	[-8.9; 13.5]	[-8.2 ; 0.6]	[-5.9 ; 5.3]	[-10; 7.4]	[-5.7 ; 4.2]	[-12.8; 1.1]	[-21.3;-3.1]
Appetite loss	1.7 ± 2.6	0.4 ± 3.6	8 ± 5.5	6.4 ± 2.8	4.7 ± 3.2	-0.4 ± 3.4	3.9 ± 3.1	-3.7 ± 3.5	-4.8 ± 5.1
	[-3.4 ; 6.9]	[-6.8 ; 7.5]	[-2.9; 19]	[0.9 ; 11.9]	[-1.7; 11.1]	[-7.2 ; 6.4]	[-2.3; 10.1]	[-10.6; 3.3]	[-15 ; 5.4]
Constipation	-4.5 ± 2.4	-1.1 ±3.3	3.4 ± 4.4	-3.4 ± 2.1	-3.1 ± 2.7	-0.9 ± 3.3	-2 ± 2.3	-5.6 ± 3.3	-3.8 ± 4.5
	[-9.2; 0.1]	[-7.7 ; 5.4]	[-5.3 ; 12.2]	[-7.5 ; 0.7]	[-8.6 ; 2.3]	[-7.4 ; 5.6]	[-6.6 ; 2.6]	[-12.1 ; 1]	[-12.8; 5.3]
Diarrhea	2.5 ± 2.5	0.7 ± 2.5	-2.3 ± 3.1	5.3 ± 2.1	2.5 ± 2.2	1.3 ± 3.2	5.4 ± 2.5	2.9 ± 3	4.8 ± 3.3
	[-2.4 ; 7.4]	[-4.2 ; 5.7]	[-8.4 ; 3.8]	[1.1; 9.5]	[-1.8 ; 6.8]	[-5.2 ; 7.7]	[0.4 ; 10.3]	[-3 ; 8.8]	[-1.8 ; 11.3]
Financial difficulties	-5.7 ± 2.4	-6.4 ± 4.1	-7 ± 5.7	-3.8 ± 2.5	-3.5 ± 2.9	-3 ± 3	-3.4 ± 2.4	-4.4 ± 3	-2.1 ± 4.3
	[-10.5 ;-1]	[-14.6; 1.8]	[-18.4; 4.4]	[-8.8; 1.2]	[-9.1 ; 2.2]	[-9.1 ; 3]	[-8.2; 1.4]	[-10.4 ; 1.7]	[-10.8; 6.5]

Abbreviations: EORTC-QLQ C30 = European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire; QoL = Quality of Life; SE = Standard error.

Safety

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).

Table 6 Frequency of adverse events along the study

Category	Observation n=205	Lanolin-based dexpanthenol cream n=209	Hydrocortisone cream n=181	p-value
Any adverse event	59%	56.5%	63.0%	0.42
Treatment-related adverse event	1.0%	1.0%	2.8%	0.29
Serious adverse event	15.1%	16.7%	17.1%	0.85
Severity of adverse event[*]
Grade 1	40.0%	40.7%	46.4%	0.38
Grade 2	33.7%	28.7%	32.6%	0.52
Grade 3	17.1%	12.0%	17.7%	0.22
Grade 4	3.4%	1.4%	2.8%	0.43
Grade 5	8.3%	12.0%	7.7%	0.29
Unknown	0.5%	0.5%	1.7%	0.39

^* Considering the worst grade recorded in each patient.

DISCUSSION

HFS is the most common reason for dose reductions and delays among patients treated with capecitabine.[28] [29] [30] The current phase III trial has shown that a lanolin-based cream with dexpanthenol is effective in the prevention of capecitabine-induced HFS, when compared with observation and a hydrocortisone cream. Interestingly, we found no beneficial effect from the topical corticosteroid analyzed in the study. In relative terms, the frequency of HFS was reduced by 40% with the use of lanolin-based cream with dexpanthenol, in comparison with observation. No notable adverse events were recorded from either this topical therapy or from the use of hydrocortisone cream, and no significant differences were found among treatment arms in secondary efficacy endpoints, including HRQoL parameters. Therefore, a lanolin-based cream with dexpanthenol could be considered a standard measure in the attempt to prevent capecitabine-induced HFS.

Previous phase III trials have failed to demonstrate the efficacy of preventive measures for HFS. On behalf of the North Central Cancer Treatment Group Study, Wolf et al. (2010)[16] reported negative results for a urea/lactic acid-based topical keratolytic agent that was compared with placebo in 137 patients. As a matter of fact, the active-treatment arm of that study had a higher frequency of HFS than the placebo arm, thus leading the authors to suggest possible skin toxicity from the urea/lactic acid-based topical keratolytic agent. Likewise, Kang et al. (2011)[15] reported negative results for oral pyridoxine (200mg/day), in comparison with placebo, in the prevention of grade 2 or higher HFS among 389 patients from South Korea. In a randomized trial of smaller size (n=106), Corrie et al. (2012)[20] could not find statistically significant reductions in the frequency of HFS or of capecitabine dose adjustments, when pyridoxine (50mg/day) was compared with placebo, despite nominal improvements in both endpoints. In a second randomized trial of small size (n=56), Chalermchai et al. (2010)[18] found a possible dose-response relationship for this agent, as patients treated with a daily dose of 400mg had a lower frequency of grade 3 HFS than those treated with 200mg/day. However, the former patients also had a lower tumor response rate and a decreased time to tumor progression, thus raising questions as to the safety of this systemic agent. Moreover, the absence of a placebo or observation group precludes further conclusions about the efficacy of pyridoxine in that trial. More recently, pyridoxine also failed to prevent or delay the onset of grade 2 or higher HFS in a larger placebo-controlled phase III trial including 210 patients receiving capecitabine as a single-agent in a center in Singapore.[17] Serum and red-blood-cell folate levels were identified as independent predictors of HFS in a multivariate analysis.[17] In a recent meta-analysis of 14 studies involving 1,570 patients, no robust evidence that pyridoxine can prevent HFS and reduce the incidence of grade ≥2 was reported.[31]

Contrasting with the negative results reported for pyridoxine and uric-acid-based cream, celecoxib has been suggested to be effective at preventing capecitabine-induced HFS.[19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] The first trial with a positive result for celecoxib was conducted by Chinese investigators, who reported a decreased frequency of HFS by the use of oral celecoxib, in comparison with observation in 110 patients enrolled in a randomized phase II trial.[19] The potential of celecoxib for prevention of capecitabine-induced HFS was later confirmed by the same group in a phase III trial in patients with stage II colorectal cancer.[32] However, concerns about the cardiovascular safety of celecoxib may limit the applicability of these results.

Positive-results were also reported for urea cream as Hofheinz et al. (2015)[33] found that a 10% urea cream was superior to a new ointment containing antioxidants (Mapisal) for prevention of HFS in patients with gastrointestinal tumors or breast cancer treated with capecitabine. In addition to the lower incidence of HFS, a significant longer time to any-grade HFS was observed for patients using urea cream in this study.[33] Importantly, in the study conducted by Wolf et al. (2010),[16] a mixture of urea and lactic acid was used. More recently, a randomized double-blind study reported that the prophylactic use of EVOSKIN^®Palm and sole moisturizing cream (PSMC) reduced the incidence of severe HFS in patients with colorectal cancer receiving capecitabine chemotherapy.[23]

The efficacy of different strategies (pyridoxine, topical urea/lactic acid, celecoxib, and other approaches of interest) versus placebo for prevention and treatment of capecitabine-induced HFS were assessed in a meta-analysis recently published.[14] A total of 17 eligible studies published from 2012 to 2017 and involving 2081 patients were included in the analysis. Using the risk ratio with the corresponding 95% confidence interval as an effect measure, the authors found a significant association between celecoxib and a lower incidence of grade ≥2 HFS. Confirming previous findings, the meta-analysis suggested that pyridoxine and topical urea/lactic acid are not effective in preventing capecitabine-induced grade 1, 2, and 3 HFS. Regarding other potential strategies for prevention of capecitabine evaluated in this meta-analysis, moisturizing cream, neurotropin, topical silymarin and Fuzheng Jiedusan were evaluated in independent studies, with results suggesting a positive impact of the latter two.[14] [21] [34] [35] [36] Prophylactic administration of silymarin topical formulation was suggested to promote a significant decrease of the severity of capecitabine-induced HFS and a delay in its occurrence in patients with gastrointestinal cancer.[21] Similarly, Zhou et al. (2017)[36] reported favorable results for the use of a modified prescription of Fuzheng Jiedusan in combination with capecitabine in reducing adverse reactions such as HFS.[36] In addition to the studies included in the meta-analysis published by Huang et al. (2018),[14] a pilot study conducted in 40 patients suggested that administration of turmeric, a plant used in Ayurvedic medicine, may decrease the rate of HFS induced by capecitabine, especially grade 2 or higher.[37] Overall, these findings need confirmation in larger controlled studies to provide more conclusive data.

One limitation of the current study is the lack of use of placebo due to ethical and logistic constraints in Brazil; as a result, neither patients nor investigators were blinded during the assessment of HFS. Another limitation could be the lack of endpoints pertaining to antitumor efficacy. Due to the topical nature of the treatments for HFS prevention, in principle, this measure was considered appropriate. The use of a higher initial dose of capecitabine in monotherapy (based on the local label recommendations), but known to be higher than the most commonly used dose in clinical practice may also represent a limitation, as one could speculate what would be the study results if a lower dose of capecitabine was used. In the present study, capecitabine was administrated at doses routinely used in the clinical practice. The study results showed that the mean dose of capecitabine prescribed for all three study arms and at all visits (1, 2, 3, and 4) was 2,000mg/m²/day, and there were no significant difference between arms at all visits.

Although it is not possible to anticipate the results in scenarios using different doses of capecitabine, we could expect that the relative effect of the treatments would not depend on the initial dose of capecitabine. In other words, a lower or higher dose of capecitabine would probably result in a lower or higher frequency of HFS onset in all study arms, respectively, but the relative difference between treatment arms would be maintained. The frequency of HFS of any grade in the observation arm of the current study (35.6%) was lower than that used for sample-size calculation (53%), probably as a result of lower mean doses of capecitabine currently used more often in clinical practice, when compared with the original starting dose of 2,500mg/m²/day administered in the pivotal study of this agent.[1] On the other hand, the frequency of HFS noted in the observation arm is in the range of those reported by other investigators when lower starting doses of capecitabine were used.[16] [38] [39] Even though this study was powered to detect a difference of at least 15% in the frequency of HFS between any of the active-treatment arms and the observation arm, an absolute difference of 10.7% between the frequencies of HFS with lanolin-based cream with dexpanthenol and observation was enough to provide statistical significance for the overall comparison among arms. Moreover, the relatively low frequency of HFS in the observation arm provided additional power to detect a 15% difference between the frequencies of HFS with hydrocortisone cream and observation. However, no significant differences were found between these two arms. Thus, we believe that the lower than expected frequency of HFS does not affect our conclusions about the efficacy of the lanolin-based cream with dexpanthenol, and the inefficacy of the hydrocortisone cream.

CONCLUSION

The reduced frequency of HFS with the use of lanolin-based cream with dexpanthenol found in the current study is noteworthy and can be considered a novel preventive option as an adjunct to therapy in patients treated with capecitabine. The impact of this preventive strategy in other capecitabine dosage context remains to be determined.

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