Long-Term Retinoid Therapy Is Needed for Maintenance of Cancer Chemopreventive Effect

Abstract

Two patients with multiple basal cell carcinomas, due either to the nevoid basal cell carcinoma syndrome (NBCCS) or arsenical insecticide exposure, were treated with oral isotretinoin for 7 or 8 years, respectively. Gradually decreasing dosage levels were employed. During the initial courses of therapy, high doses (2.0–3.0 mg/kg/day) were intended as chemotherapy. In these patients only 6 of 40 (15%) lesions underwent complete clinical regression. In subsequent courses aimed at chemoprevention, the dose was progressively reduced from 1.5 to 0.25 mg/kg/day. During therapy, no new lesions were observed in the patient with the arsenical exposure. The NBCCS patient developed 1 new lesion during therapy at 1.0 mg/kg/day, 1 new lesion at 0.5 mg/kg/day and 5 new lesions at 0.25 mg/kg/day. Treatment was discontinued and the patient with the arsenic exposure developed his first new tumor 17 months afterwards; in contrast, the NBCCS patient developed 29 tumors within 13 months. These findings suggest that long-term therapy with isotretinoin is needed for the continuation of the cancer chemopreventive effect. However, the need for continuous rather than intermittent maintenance therapy, and the determination of the optimal dose for this purpose may depend on the etiology of the multiple carcinomas and on the tolerability of the lowest effective dose by the individual patient. With these encouraging data, it now appears appropriate to expand this pilot study and perform larger trials to dertermine the usefulness of isotretinoin in the chemoprevention of basal cell carcinoma in patients with multiple tumors.

Topical Tazarotene Chemoprevention Reduces Basal Cell Carcinoma Number and Size in Ptch1 +/− Mice Exposed to Ultraviolet or Ionizing Radiation

“…Human studies in which withdrawal of oral retinoids generally resulted in a rapid recurrence of tumors are consistent with an inhibitory effect on promotion and progression rather than on initiation (14). Tazarotene inhibited the formation of the majority of microscopic BCCs and reduced BCC size, suggesting that it is effi- Fig.…”

Analysis of 1,25-Dihydroxyvitamin D3 Receptors (VDR. in Basal Cell Carcinomas

“…A great deal of work has been done evaluating the chemotherapeutic and/or chemopreventive effects of retinoids on BCCs. 40,41 These effects are thought to be mediated via binding to the corresponding intranuclear receptors, retinoic acid receptors (RAR) -␣, -␤, and -␥. Recently, it has been demonstrated that VDR require heterodimerization with auxiliary proteins for effective DNA interaction.…”

Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis

“…Also, long-term therapy with low doses of systemic retinoids such as isotretinoin/ATRA and 13-cis retinoic acid, was not effective in reducing the occurrence of BCCs at new sites in patients with previously reported small numbers (1, 2) of BCCs (31). The differences between our observations and those observed for skin cancer patients treated with systemic retinoids may be (a) mode of delivery: topical tazarotene application may result in more retinoid reaching the tumor cells; (b) type of retinoid: the human studies were carried out using other pan-RAR agonists (that is, 13-cis retinoic acid and ATRA); from our observations, the outcome of activating different RARs in the skin may be quite different; (c) there may be a species difference in the response to retinoids; and/or (d) the sustained and curative effects of tazarotene applied topically may be specific to microscopic BCCs; previous observations showed that systemic retinoids prevented the occurrence of new BCCs in BCNS patients during therapy but had no effect against the majority of existing BCCs in these patients (10). However, reports that topical tazarotene application cures 30% to 50% of visible human BCCs (13) and our data suggest that topical tazarotene effectively cures both microscopic and macroscopic BCCs in contrast to the above-mentioned systemically used retinoids.…”

“…to human studies in which new BCCs promptly appear after systemic retinoids are stopped in BCNS and XP patients (10,11). Also, long-term therapy with low doses of systemic retinoids such as isotretinoin/ATRA and 13-cis retinoic acid, was not effective in reducing the occurrence of BCCs at new sites in patients with previously reported small numbers (1, 2) of BCCs (31).…”

“…Endogenous retinoid signaling mediated by the bioactive retinoid, all-trans retinoic acid (ATRA), is essential for many cellular processes including cell specification, differentiation, and apoptosis (9). Although systemic retinoic acids have been used with some success to treat cancers including leukemia and nonmelanoma skin cancers, they cause significant toxicities and are often discontinued (10,11). Long-term topical treatment with the synthetic retinoid ''prodrug'' tazarotene (Tazorac; Allergan) can cure one-fourth to one-half of sporadic visible human BCCs without significant toxicity (12,13).…”