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Topical Milk Thistle for Capecitabine-Induced Hand-Foot Syndrome

NatureMed Clinic’s Dr. Kirsten West contributed a study regarding topical milk thistle for Capecitabine-Induced Hand-Foot Syndrome to the Natural Medicine Journal.

Forty patients diagnosed with gastrointestinal malignancy, including colorectal and esophageal cancers, who had no previous exposure to capecitabine but were scheduled to receive this medication; average age was 60 years and 60% were male. Gastric cancer was the most common malignancy in both the treatment and placebo groups (75% and 60%, respectively).

Topical Milk Thistle for Capecitabine-Induced Hand-Foot Syndrome

Reference

Elyasi S, Shojaee FSR, Allahyari A, Karimi G. Topical silymarin administration for prevention of capecitabine-induced hand-foot syndrome: a randomized, double-blinded, placebo-controlled clinical trial. Phytother Res. 2017;31(9):1323-1329.

Objective

To assess if topical silymarin is active in the prevention of capecitabine-induced hand-foot syndrome (HFS)

Design

Pilot, randomized, double-blinded, placebo-controlled clinical trial

Participants

Forty patients diagnosed with gastrointestinal malignancy, including colorectal and esophageal cancers, who had no previous exposure to capecitabine but were scheduled to receive this medication; average age was 60 years and 60% were male. Gastric cancer was the most common malignancy in both the treatment and placebo groups (75% and 60%, respectively).

Study Medication and Dosage

Patients were randomly allocated to either the topical silymarin (treatment) or placebo group. Those in the treatment group received a 1% silymarin gel, which contained 80% active ingredients based on silymarin flavonolignans. The placebo gel was identical in composition and color but lacked silymarin. On day 1 of chemotherapy and for 9 weeks thereafter, a “half fingertip” was applied to the soles and “one fingertip” applied to the palms, twice a day. Patients with esophagogastric malignancy were given 1,000 mg capecitabine twice a day, 12 hours apart, with a bolus of oxaliplatin (XELOX regimen) at 130 mg/m2 starting on the first day of treatment and then at 3-week intervals for 4 cycles. Patients with colorectal cancer had the same bolus XELOX regimen but were given 1,500 mg capecitabine twice a day, 12 hours apart for 2 weeks, followed by 1 week of rest, in 3-week cycles.

Outcome Measures

To assess dermatologic toxicities, examinations were conducted at the onset of the study (prior to any chemotherapy) and every 3 weeks, for a total of 9 weeks. Assessments were made by a pharmacist and oncologist using the World Health Organization (WHO) Hand-Foot Syndrome grading scale. This scale rates the intensity of HFS as follows: grades 1 and 2, early or mild cytotoxic reactions showing isolated necrotic basal keratinocytes; grades 3 and 4, severe cytotoxic reactions in which the entire basal layer is destroyed, and a blister may form together with complete epidermal necrosis.1

Key Findings

In patients who received topical silymarin gel, HFS development and progression were significantly delayed at 9 weeks when compared to placebo group (P=0.03). Although scores were not significantly different between groups at the end of week 3 (P=0.54) and week 6 (P=0.66), a significant difference between groups was found at the end of week 9. Of patients in the silymarin group, 60% remained asymptomatic at the end of the weeks 6 and 9, a significant finding when compared to the placebo group (40%; P=0.03). Ultimately, WHO scores in both groups increased during the 9 weeks of treatment (P≤0.05). So although topical silymarin did not prevent HFS, manifestation of HFS was significantly delayed and its presentation less severe.

Practice Implications

Hand-foot syndrome, also known as palmar-plantar erythrodyesthesia (PPE), is a treatment-limiting symptom associated with several chemotherapy drugs. Capecitabine is the drug most frequently linked with this dermatologic toxicity. However, 5-fluorouracil (5-FU), doxorubicin, docetaxel, vinorelbine, gemcitabine, and multikinase inhibitors may also cause HFS.2 Diagnosis is made through clinical observation. Symptoms commonly begin to occur within 2 to 12 days after administration of chemotherapy. Among those who develop HFS, 40%-50% will show symptoms of HSF within 2 to 12 days. Hand-foot syndrome is typically heralded by dysesthesia followed by a painful palmar and/or plantar erythematous rash, which may or may not be associated with edema.3 In approximately 20% of patients, the rash may become bullous, ulcerative, and severely painful, so that it interferes with activities of daily living.4 The latter may necessitate reducing the dose of the given chemotherapeutic agent. Although the development of HFS is not life-threatening, it has been shown to affect quality of life in 90% of those with a Grade 3 manifestation.4

The pathophysiology of HFS remains unclear and is under active investigation. Capecitabine, used in the study reviewed here, is a prodrug that is metabolized into 5-FU.5 It is postulated that 5-FU metabolizing enzymes thymidine phosphorylase (TP) and dihydropyridine dehydrogenase (DPD) are concentrated in palmar tissue. Additionally, skin biopsies in humans have demonstrated a higher epidermal basal cell proliferation rate (per Ki-67 staining) in the palms as compared to the dorsum. These factors could explain the preferential and significant toxicity to palmar-plantar surfaces. Additional elements implicated in the development of HFS include gravitational forces, vascular anatomy unique to those areas with associated temperature gradients, and increased drug concentration in the eccrine glands of the palms and soles.2 Whatever the cause, the relatively common occurrence of HFS and its dose-limiting nature make it imperative that we develop management and, most importantly, preventive strategies. These strategies must not interfere with the therapeutic efficacy of the given cytotoxic therapies.

Read the full study: Topical Milk Thistle for Capecitabine-Induced Hand-Foot Syndrome