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Objective To assess the safety and efficacy of a 0.005% mixture of solasodine glycosides (Zycure) in the treatment of basal cell carcinoma.
Design Double-blind, randomized, and vehicle-controlled, parallel group study.
Setting Ten centers in the United Kingdom.
Participants Male, n = 50; female, n = 44; age range, 32–95 years (Table 1).
Table 1. Demographics
|Zycure n = 62||Vehicle n = 32|
|Age (in years): mean||68.9||70.0|
Intervention Ninety-four patients were randomized on a 2 : 1 ratio (n = 62, Zycure; n = 32, vehicle). Histologically confirmed lesions were treated double blinded, twice daily under occlusion with Zycure or vehicle for 8 weeks. Patients were reviewed fortnightly for adverse effects and overall response. Successfully treated patients were followed up at six-month intervals for a year.
Main outcome measures The primary efficacy endpoint was histologically confirmed clearance of the basal cell carcinoma (2-mm punch biopsy) at the end of 8-week treatment.
Results Efficacy (intention-to-treat population) at 8 weeks was 66% (41/62) in the Zycure group, compared to 25% (8/32) in the vehicle group (P < 0.001; Cochran–Mantel–Haenszel test). Ninety percent (37/41) of the Zycure group completed follow-up at six-month intervals for 1 year, of whom 78% (29/37) had no recurrence. There were no major treatment-related adverse effects, although 10 patients in Zycure group did not complete the treatment protocol for various reasons.
Conclusion We conclude that the solasodine glycoside cream Zycure is a safe therapy for basal cell carcinoma, with a cure rate of 66% at 8 weeks and 78% at 1 year follow-up.
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Nonmelanoma skin cancer is the most common malignancy worldwide among Caucasians, and accounts for over 90% of all skin cancers.1 Eighty percent of nonmelanocytic skin cancers are basal cell carcinomas (BCC), with an estimated 2 million new cases reported by the World Health Organization annually. In the United Kingdom, there has been a 50% increase in the number of diagnoses of skin cancer in the past decade.2 Furthermore, a patient with a primary BCC has a 40% increased risk of further diagnosis of primary BCC.
Treatments include surgery, curettage and cautery, cryotherapy, and radiotherapy depending on the site, size, and morphology of the tumors.3 Topical therapy has been suggested for multiple superficial tumors at low-risk sites (limbs and trunk). The topical treatment 5% fluorouracil cream (5FU) has been used to treat superficial BCC.4
A mixture of naturally occurring glycoalkaloids has been shown to be highly effective in treating human skin cancers. This mixture consists of solasodine glycosides (Fig. 1). These compounds are found in plants of the nightshade family like aubergine.5
A cream containing solasodine glycosides has been formulated and tested in Australia (licensed in 1991 and marketed as “Curaderm”) for solar keratosis. In an open controlled clinical trial of 28 patients with 62 lesions, complete regression was observed in 20 of 24 BCCs, 5 of 6 squamous cell carcinomas (SCC), and all 23 cases of solar keratoses. There were no systemic adverse effects and no recurrence in patients followed for 5 years.6
These observations motivated a subsequent open study in Australia of 72 patients, including cases of actinic keratoses (56 cases), BCC (39 cases), and SCC (29 cases) of skin, using treatment with a lower concentration (0.005%) of solasodine glycosides in a different cream formulation. This open study demonstrated regression of all treated lesions within 1–3 weeks of treatment, confirming efficacy.7 However, a review of the literature revealed that no data from an International Conference on Harmenisation–compliant, randomized, controlled study of glycoalkaloids exist.
We investigated the efficacy and safety of Zycure cream, containing 0.005% of solasodine glycosides (mainly solasonine and solamargine) in the treatment of BCCs.
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The ever-increasing prevalence of BCCs forms a significant impact on clinical practice not only in dermatology but also in plastic surgery and radiotherapy/oncology. Topical therapy for superficial BCCs is predominantly 5FU, although on review of literature there is lack of convincing evidence-based trial data and little information regarding clearance, clinical and/or pathological relapse rate.
An interesting observation was made in the paper by Moragas et al. in 1970. It was found that an intact epidermis impairs and in some cases prevents the absorption of 5FU explaining the poor results in nodular variants (up to 50% recurrence).7
Reymann in 19798 has shown that using a combination of curettage and subsequent 5FU treatments for nodular variants showed high recurrences on 10-year follow-up study.
Although systemic side-effects have not been reported, a review of topical therapy of 5FU by Goette et al. in 19819 outlines allergic contact dermatitis and photosensitization as local side-effects besides the irritation and soreness.
The more recent topical treatment tried has been 5% imiquimod cream. To date, preliminary data show encouraging treatment benefit for only with superficial lesions at low-risk sites after at least 4 weeks of therapy. Moreover redness and irritation are an inevitable side-effect.10
This study on the local cytotoxic activity of solasodine glycosides was primarily concerned with efficacy and safety in BCCs. The mode of action of glycoalkaloids is still not clearly understood. There are two hypotheses in the literature. The first11 suggests that steroidal glycosides interact with and disrupt the cell membrane, resulting in lysis of the cell. It is supposed that initial interaction is mediated either by specific receptors on the walls of the cell binding to the glycoside (sugar moiety) or through the binding of the compound to free sterols within the cell walls. The second hypothesis12 suggests that the glycoside diffuses within the cancer cell, causing the expression of tissue necrosis factor (TNF) receptors by activation of the relevant genes. TNF receptors bind to TNF, commencing a cascade of reactions that cause cell death by apoptosis. Such diffusion is consistent with the suggestion that these compounds initially interact with free sterols (and in particular cholesterol) within the cell wall. Such interaction and diffusion is also consistent with the knowledge that the aglycone (steroid moiety) is highly lipophilic (although inactive).11
In any case, either explanation as to the initial interaction of the compound with cells is compatible with our clinical observations that some patients had regeneration of new epidermis at the application site within the first 4–5 weeks of treatment, despite continued twice daily application of Zycure; and that histological examination showed acanthosis of the regenerated epidermis on 8-week posttreatment biopsy.
These observations suggest that Zycure is at least partially preferential in its application to transformed cells.
Our findings favor the hypothesis of cell death by apoptosis (20% of ITT cases). Furthermore, these results clinically support the hypothesis that these compounds act preferentially in the lysis of transformed as opposed to normal cells.
We feel that this novel agent, Zycure, has overall efficacy, patient acceptance, low incidence of local adverse events and no systemic side-effects. While surgery may remain a more appropriate treatment for many patients, we feel treatment with Zycure may prove advantageous if there are multiple small tumors of recent onset and perhaps in these patients where the location of the tumor makes other therapeutic approaches difficult.
It would be interesting and informative to undertake some comparative studies with existing treatments to establish the practical use of Zycure in dermatology by case selection.