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.
To assess if topical silymarin is active in the prevention of capecitabine-induced hand-foot syndrome (HFS)
Pilot, randomized, double-blinded, placebo-controlled clinical trial
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.
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
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.
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.
Milk thistle is best known for its hepatoprotective effects, making its topical use for the amelioration of HFS a novel idea.
As noted in a recent NMJ review,6 measures to effectively manage and prevent HFS in medical oncology are without consensus and clinical trials are lacking. To date, the most effective way to manage HFS is to interrupt treatment and/or reduce the dose of agents known to induce this toxicity. Pharmacological agents such as dimethylsulfoxide (DMSO) and oral and topical steroids have been reported to ameliorate symptoms. However, these have not been evaluated in randomized clinical trials.7,2,8,9 In addition, the side effects associated with aforementioned agents are not without risks.
Milk thistle is best known for its hepatoprotective effects, making its topical use for the amelioration of HFS a novel idea.
Milk thistle (Silybum marianum) has held its place in the apothecary for human ailments for over 2,000 years.10 Silybum derives from the Greek “sillybon” or “silybos,” meaning “tassel” or “tuft,” and marianum refers to the white veins on the plant’s spiked leaves. Historically, milk thistle was fabled to carry the milk of the Virgin Mary and, subsequently, was used to treat nearly all ailments during the Middle Ages.13
The applicable parts of milk thistle are those above ground. The seed is most commonly used, with a content of 4% to 6% silymarin. Silymarin itself is a mixture of flavonolignans, composed predominantly of the following: silybum A, silybum B, isosilybin B, silidianin, and silychristin.11-13 Some postulate that silybin (known interchangeably as silybum) is the most active component, providing strong antioxidant and free radical–scavenging affects.14-16
Although milk thistle is most commonly indicated for liver disorders, specifically those related to liver damage, its effectiveness in these conditions is not consistent in studies.17-23 Similarly, milk thistle has mixed results in studies on the resolution of hepatic injury due to viral pathogens, medications, or environmental toxins.17,24-28 Discrepancies in the data may be associated with the effect of milk thistle on differences in drug metabolism. Depending on the metabolic pathways involved, milk thistle may be more protective in some cases and less in others. (Milk thistle’s drug metabolizing enzyme effects are discussed in more detail below.) As with many studies of natural therapies, these conflicting findings may also be due to the low methodological quality of some of the studies. Whatever the case, milk thistle remains a well-known hepatic therapy, and studies will continue to determine its role in liver health and drug metabolism.
Additional and notable attributes of silymarin include its capacity to inhibit lipid peroxidation, promote RNA and protein synthesis in the facilitation of tissue repair, and act as an anti-inflammatory.29-31 In human leukocytes, silymarin has been shown to protect against DNA damage caused by hydrogen peroxide.34,35 In rats, silymarin prevented chemically induced tumor promotion via inhibition of tumor necrosis factor (TNF)-alpha.32 Silymarin was also shown to possess antifibrotic properties via the downregulation of transforming growth factor beta and to decrease NF-kappa B activity, resulting in production of TNF-alpha and interleukin (IL)-1 in humans.33,34 Perhaps most notably, silymarin has the ability to downregulate inflammatory mediators via decreased prostaglandin and leukotriene production through inhibition of cyclooxygenase (COX)-2.35,36,41 The latter mechanism is notable, as celecoxib, a COX-2–inhibiting drug, reduced the rate of Grade 2 HFS in 50% of patients when compared to placebo.37
Milk thistle possesses well-known effects on drug metabolizing enzymes; therefore its use as a topical therapeutic to disrupt pharmacological agents at the site of toxicity makes good sense. In animal studies, silymarin has been shown to inhibit cytochrome P450 2C9 and cytochrome P450 3A4, 2 major hepatic phase 1 enzymes.38 Additionally, it has been shown to inhibit P-glycoprotein and breast cancer resistance protein (BCRP), consequently affecting drug efflux.46 Specific medications potentially affected by the use of silymarin include but are not limited to rapamycin, raloxifen, and tamoxifen.39-41 Theoretically, milk thistle does not alter capecitabine metabolism via P450 metabolism. However, the data regarding drug transporter proteins such as P-glycoprotein is less clear.
A questionable aspect of the present study worth mentioning regards the timing and observational follow-through of silymarin application in given patients. As was noted, at the end of the third and sixth weeks, the difference in HFS severity between the placebo and milk thistle groups was not significant but trended in favor of the silymarin group. At the end of the ninth week, the difference in severity was significant. Based on previous studies, the use of oral capecitabine may induce HFS from 11 to 360 days once initiated at a sustained pharmacologic dose.42,43 Given that the median time to HFS onset is 11 weeks, would a difference between groups have been more appreciable if data had been collected past 9 weeks? Or, would the application of milk thistle ointment 1 to 2 weeks before the initiation of chemotherapy have provided significant differences between treatment and placebo groups at 3 and 6 weeks? These are questions that certainly need further study.
The concept of a topical treatment to ameliorate HFS is not new. In fact, topical therapies studied in the management of HFS were reviewed in a previous NMJ article.6 Notable mentions include henna and sildenafil.44-46 Henna, also known as Lawsonia inermis, may have anti-inflammatory, antipyretic, and analgesic effects, while sildenafil (Viagra) increases the production of nitric oxide, which has been hypothesized to mitigate the mechanisms underlying PPE via improved wound healing.47-51 Curcumin, while not used topically, may offer amelioration of HFS when used orally, via anti-inflammatory mechanisms.52
Prophylactic use of a compounded ointment containing silymarin, curcumin, and henna is an intriguing thought. Given that these therapies have few to no side effects, hypothetically no interference with capecitabine, and offer high benefit potential, this topical combination is one that deserves consideration. It is also possible that application of a topical preparation weeks before the initiation of cytotoxic therapies known to induce HFS may help prevent its onset altogether. Further studies on dose, appropriate start and duration of application, and formulation of these topical therapeutics are needed. However, given the promise and safety profiles of these agents when used topically, the detrimental effects of HFS on quality of life, and the risk of discontinuing otherwise efficacious therapy because of HFS, our largest obstacle may be the creation of a specially compounded ointment for practitioners and patients in need. This is a small obstacle when measured against the many obstacles for patients in cancer treatment.
- Hoesly FJ, Baker SG, Gunawardane ND. Capecitabine-induced hand-foot syndrome complicated by pseudomonal superinfection resulting in bacterial sepsis and death; case report and review of the literature. Arch Dermatol. 2011;147(12):1418-1423.
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- Degen A, Alter M, Schenck F, et al. The hand-foot-syndrome associated with medical tumor therapy- classification and management. J Dtsch Dermatol Ges J Ger Soc Dermatol JDDG. 2010; 8(9):652-661.
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- Milano G, Etienne-Grimaldi M-C, Mari M, et al. Candidate mechanisms for capecitabine-related hand-foot syndrome. Br J Clin Pharmacol. 2008;66(1):88-95.
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- Farr KP, Safwat A. Palmar-plantar erythrodysesthesia associated with chemotherapy and its treatment. Case Rep Oncol. 2011;4(1):229-235.
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