The clinical uses of oral isotretinoin (13-cis-retinoic acid) are many. They include treatment of acneiform eruptions, diseases of cornification, inflammatory disorders, and neoplastic processes. Isotretinoin has shown greater efficacy in the chemoprevention of squamous cell carcinoma, rather than in the treatment. High-dose isotretinoin has mainly been utilized in those patients at high-risk for multiple new skin cancers where the risk of morbidity from side effects is overshadowed by the benefit to the patient.
Cutaneous squamous cell carcinoma (SCC) is the second most common cancer in the United States, afflicting approximately 200,000 Americans each year (1). In the United States, more than 90% of patients with cutaneous SCC are cured by local therapy alone (surgery and/or radiotherapy), leaving 10% of patients requiring a new therapeutic approach (2). Retinoic acid (vitamin A1) is a naturally occurring metabolite of retinol (vitamin A). The term retinoid refers to retinoic acid and any of its derivatives, both naturally occurring and synthetic. Some common retinoids include tretinoin (all-trans retinoic acid), isotretinoin (13-cis-retinoic acid), alitretinoin (9-cis-retinoic acid), etretinate (trimethyl-methoxyphenyl ethyl ester derivate of all-trans retinoic acid), acitretin (trimethyl-methoxypheny carboxylic acid), fenretinide (4-hydroxyphenyl retinamide), and bexarotene (analog of 9-cis-retinoic acid). In the U.S., etretinate is no longer available and has been replaced by acitretin (3). Retinoids have been shown to play a role in the visual cycle, reproduction, embryonic development, and the growth and differentiation of epithelial tissues. They also have an anti-proliferative effect against many animal and human malignant cell lines (4). From the early 1900s dermatologists have recognized the association between vitamin A deficiency and cancer (3). Since neoplastic transformation involves the loss of cellular differentiation, it naturally follows that retinoids are promising candidates in the treatment and prevention of cancer (5).
Mechanism of Action
Retinoids exert their anti-neoplastic effects by regulating the expression of genes involved in cell growth, differentiation, apoptosis, tumor-associated angiogenesis, and host immune functions (2,5). Retinoids mediate the transcription of genes through retinoid nuclear receptors. Retinoid nuclear receptors are ligand-inducible trans-acting transcription factors that belong to a superfamily which includes steroid, vitamin D, and thyroid hormone receptors. There are two types of retinoid nuclear receptors--retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RARs ([alpha],[beta],[gamma]) are nuclear receptors that bind specifically to both all-trans-RA and 9-cis-RA, whereas RXRs ([alpha],[beta],[gamma]) are specific for only 9-cis-RA. Retinoid X receptors act as cofactors for RARs and increase their binding and transcription rates (5).
Retinoids are thought to inhibit carcinogenesis by interfering with tumor promotion rather than tumor initiation. Promotion can be blocked by a variety of different mechanisms including inhibition of proliferation, stimulation of differentiation, and induction of apoptosis. These multiple mechanisms have been described via numerous in vitro studies (6). The antineoplastic effect of retinoids has also been studied extensively in preclinical mouse skin models (5). More than 25 years ago Bollag first demonstrated that retinoids prevented the formation of carcinomas induced by the addition of skin cancer promoters (7). Retinoids were shown to decrease mouse skin tumor promotion by inhibiting the induction of ornithine decarboxylase (ODC) by the tumor promoter agent 12-O-tetrade-canoylphorbol-13-acetate. Retinoids may mediate this action by inhibiting the protein kinase C-mediated transcription of ODC mRNA. A number of retinoids were found to inhibit tumor promotion but none more potent than all-trans retinoic acid (5). Xu et al. found that the expression of nuclear retinoid receptors is altered in both pre-malignant and malignant skin cancers. These investigators found five receptors (RAR-[alpha] and -[gamma] and RXR-[alpha], -[beta], and -[gamma]) that were suppressed progressively from normal skin to actinic keratoses to cutaneous SCC (8). Other possible anti-neoplastic mechanisms include the induction of epidermal growth factor receptors and transforming growth factor B2 resulting in growth inhibition (2,9).
Systemic isotretinoin has been shown to be efficacious in a variety of dermatologic and non-dermatologic diseases. The dermatologic applications of isotretinoin are many. One of the most common uses of isotretinoin is in the treatment of acneiform eruptions such as severe nodulocystic acne, rosacea, drug-induced steroid acne, chloracne, folliculitis, and hidradenitis suppurativa. Isotretinoin has also been show to be effective in treatment of disorders of cornification. These disorders include ichthyoses, keratodermas, Papillon-Lefevre syndrome. Darier's disease, pityriasis rubra pilaris, and psoriasis. Isotretinoin has been used to treat an assortment of inflammatory and immunodermatoses such as atrophoderma vermiculatum, lupus erythematosus, lichen planus, sarcoidosis, and granuloma annulare. Various disorders of epidermal differentiation such as epidermodysplasia verruciformis, confluent and reticulated papillomatosis, and axillary granular parakeratosis have also been treated with isotretinoin. Isotretinoin has been found to be effective in reversing cutaneous damage from chronic sun exposure. Other cosmetic applications of isotretinoin include treatment of liver spots, melasma, postinflammatory hyperpigmentation, and stretch marks. Neoplastic processes (including sebaceous hyperplasia, Muir-Torre syndrome, leukoplakia, recurrent condyloma accuminata, Langerhans' cell histiocytosis, follicular mucinosis, and cutaneous T-cell lymphoma) have also been treated effectively with isotretinoin. Isotretinoin has been used to treat HIV-dermatoses including papular mucinosis, and eosinophilic folliculitis (10).
Other specialties have placed systemic isotretinoin in their treatment armamentarium. Isotretinoin in combination with interferon-2[alpha] has been used to treat renal cell carcinoma, metastatic prostate cancer, unresectable recurrent head and neck cancer, and recurrent squamous cell carcinoma of the cervix. Furthermore, isotretinoin was found to be effective in the treatment of recurrent malignant gliomas, spinal cord astrocytomas, undifferentiated thyroid carcinomas, refractory lymphomas, and myelodysplastic syndrome. Finally, isotretinoin is curative in thrombotic thrombocytopenic purpura refractory to plasma exchange (10).
As a chemoprevention agent systemic isotretinoin appears beneficial. Retinoids are effective in the reduction of premalignant human epithelial cancers such as actinic keratosis, dysplastic nevi, oral premalignant lesions, bronchial metaplasia, laryngeal dysplasia, and cervical dysplasia (5). Systemic isotretinoin has shown efficacy in inhibiting eruptive keratoacanthomas (10). Retinoids have also been shown to prevent second primary tumors such as the skin cancers of xeroderma pigmentosum, basal cell carcinoma in basal cell nevus syndrome, breast cancer, head and neck cancer, non-small cell lung cancer, ovarian cancer, bladder cancer, and hepatocellular carcinoma (5). Isotretinoin and other retinoids are not useful in the treatment of isolated cutaneous carcinomas (10).
Chemoprevention of SCC
Systemic isotretinoin therapy has been shown to be protective in conditions that confer a high risk of developing cutaneous SCC. The conditions most widely studied include xeroderma pigmentosum and immunocompromised post-transplantation patients. Unfortunately the chemopreventive effect of systemic isotretinoin therapy in these conditions does not persist after the discontinuation of treatment. Therefore, long term therapy is required and is often complicated by the systemic toxicities associated with isotretinoin. Nevertheless, in conditions where patient are continually developing new skin cancers the benefit of preventing skin cancer may outweigh the risk of systemic toxicity. Oral isotretinoin therapy may also be of benefit in patients with other conditions that confer a high skin cancer risk. This subset includes patients exposed to agents that cause DNA damage, such as radiation therapy, and patients with immunosuppression from other causes (11).
Oral isotretinoin was shown to be efficacious in the chemoprevention of cutaneous SCC in xeroderma pigmentosum patients. Xeroderma pigmentosum is an autosomal recessive disorder in which there is abnormal repair of UV induced DNA damage (11). These patients exhibit UV light photosensitivity and develop new skin cancers at a frequency of 1000 fold greater than the general population (12). This disorder is also characterized by the development of skin cancer an average of 50 years earlier than the general population (11).
Kraemer et al. demonstrated the benefit of high dose oral isotretinoin in a three year controlled prospective study consisting of five patients with xeroderma pigmentosum (12). Patients were treated with oral isotretinoin at 2 mg/kg of body weight per day for two years, and then followed for a year without treatment. During the treatment period there was an average reduction of 63% in the total number of tumors (both SCC and BCC) when compared to a two year interval before treatment (P=0.019). In the year post-treatment the tumor frequency increased at a mean rate of 8.5 fold greater than the frequency during treatment, and was at least as high as the frequency observed in the pretreatment interval (P=0.007). The best response to therapy was found in patients with the highest frequency of skin cancers during the pretreatment period. It was noted that the high dosage used resulted in moderate to severe short-term systemic side effects, most commonly mucocutaneous. The chemopreventive effect of isotretinoin was apparent within two months of onset of treatment and subsequently disappeared three months after the withdrawal of treatment. As a result the authors theorized that isotretinoin therapy may be beneficial in the chemoprevention of cancer in patients who do not have XP (12).
Somos et al. demonstrated the benefit of oral isotretinoin therapy in the chemoprevention of SCC with a case report of a 29 year old female diagnosed with xeroderma pigmentosum variant (XPV) (13). The patient was treated with oral isotretinoin at 2 mg/kg of body weight per day for one year. During that treatment period the frequency new skin cancer was observed to decrease to 25% of the pretreatment frequency. The dosage of oral isotretinoin was then decreased to 1 mg/kg of body weight per day for the last two years of the study. Again tumor frequency was observed to decrease to 25% of the pretreatment frequency. The authors concluded that low dose isotretinoin therapy (1 mg/kg/day) has a similar efficacy as high dose (2 mg/kg/day) isotretinoin therapy in the chemoprevention of nonmelanoma skin cancers in XPV (13).
Oral isotretinoin was shown to be efficacious in the chemoprevention of cutaneous SCC in immunocompromised post-transplantation patients. The risk of skin cancer development in this population has been estimated to be 250 times that of the normal population. Furthermore these patients more frequently develop SCCs that are more aggressive in nature (11). In a case study of one post renal transplant patient on chronic immunosuppression, Bellman et al. found that oral isotretinoin at 0.5 mg/kg/day reduced the number of non-melanoma skin cancers by 50% within two months (14). The safety of oral isotretinoin therapy in renal transplant patients has also been well documented. Moreover, systemic isotretinoin therapy has been shown to reduce the cell number and activity of natural killer cells, the same cells that are involved in the initial phase of transplant rejection. Low dose systemic isotretinoin has also shown benefit in cardiac transplant patients (14).
A randomized, double-blind, controlled clinical trail of 525 patients with a history of at least four BCCs and/or SCCs demonstrated that low dose isotretinoin was not efficacious in the chemoprevention of cutaneous SCC (15). In this study patients were randomly treated with either 25,000 units/day of retinol, 5-10 mg/day of isotretinoin, or placebo for a total of three years. The investigators found no significant differences between the three arms in either the time to first occurrence of a BCC or SCC, or total number of tumors. This data is contradictory to earlier reports citing the benefit of isotretinoin in the chemoprevention of SCCs. However it should be noted that this trial used a substantially lower dose of isotretinoin and also excluded patients with either xeroderma pigmentosum or chronic immunosuppression. This study also demonstrated that patients who received the low dose isotretinoin treatment experienced only modest side effects, an observation that demonstrates the dose related toxicity of the drug (15).
Treatment of SCC
Systemic isotretinoin monotherapy has been shown to be efficacious in the treatment of squamous cell carcinoma of the skin, however its inability to induce complete resolution has limited its utility. Meyskens et al. investigated the effects of oral isotretinoin therapy on advanced SCCs and pre-neoplastic lesions (4). Patients with advanced SCC were treated with 3 mg/kg/day and patients with pre-neoplastic lesions were treated with 2 mg/kg/day for at least one month. The results of the study showed that six of 24 patients with advanced SCC and that three of five patients with pre-neoplastic squamous cell lesions responded to the isotretinoin therapy. In a pilot study of 16 patients with advanced SCC doses were increased by 0.5 mg/kg/day increments every one to two weeks until the toxicity became intolerable. It was found that most patients could not tolerate greater than 4 mg/kg/day for longer than three to four weeks. The major dose limiting toxicities were dermatitis, emotional labiality, and headaches (4).
Lippman et al. used oral isotretinoin at 1 mg/kg/day to treat four patients with refractory cutaneous SCC for a duration of at least four weeks (9). The results of this case series showed that two of the four patients achieved complete resolution and the remaining two patients showed partial resolution of their disease. All four patients had a clinical response within four weeks of onset of therapy and response durations ranged from two to more than 23 months. Furthermore, only moderate mucocutaneous side effects and asymptomatic laboratory abnormalities were reported (9).
Systemic isotretinoin when used in combination therapy has shown promise in the treatment of advanced cutaneous SCC. Studies on systemic therapy in advanced cutaneous SCC are few due to the high cure rates found with standard local therapy and the small number of patients with advanced disease (2). Cisplatin-based combination regimens have shown benefit, but currently no standard chemotherapy for cutaneous SCC exists (2,16,17). As a result studies on the efficacy of retinoids combined with other chemotherapeutic agents have intensified over the years (2).
A large number of preclinical studies have shown that isotretinoin and IFN-[alpha] have different mechanisms of action and that they exhibit synergism when used in combination against a variety of human tumor cell lines (2). Moreover, there is a wealth of data that demonstrates the efficacy of each agent when used alone at both the chemopreventive and therapeutic levels. The toxicities of both agents do not overlap and are reversible. In a report by Lippman et al. 28 patients with refractory advanced cutaneous SCC were given a combination of oral isotretinoin (1 mg/kg/day) and subcutaneous recombinant human IFN [alpha]-2a (3 million units/day) for at least two months (2). Overall the results showed that 19 of 28 patients (68%) responded to treatment, with seven patients (25%) having complete responses. The median time to response was 1.5 months and the median response duration was greater than five months. The data also showed a statistically significant relationship between decreased response rate and increased extent of disease. The major limiting side effects of isotretinoin in the study were xerosis, conjunctivitis, and hypertrigylceridemia, whereas the major limiting side effects of IFN [alpha]-2a were fatigue and a flu-like syndrome. It should be noted that the combined toxicity of these drugs resulted in dose reductions in 18 patients (56%). The results of this study showed that the response rate to combined systemic isotretinoin and IFN [alpha]-2a in locally advanced disease was two fold greater than that seen with higher doses of either agent used alone. As well when compared with the cisplatin-based combination chemotherapies this combination achieved a similar proportion of complete responders (2).
Shin et al. demonstrated the efficacy of the combination of isotretinoin (1 mg/kg/day), IFN-[alpha] (five million units three times per week), and cisplatin (20 mg/[m.sup.2] intravenous injection once per week) in a phase II trial of 39 patients with advanced cutaneous SCC (16). The overall and complete response rates to treatment were 34% and 17% respectively. The median duration of those patients that responded to treatment was nine months. The response rate of patients with locally advanced disease was significantly higher than that of patients with metastatic disease (67% vs. 17%). The one, two, and five year survival rates were estimated at 58%, 32%, and 21% respectively. The major toxicities associated with this regimen included mild to moderate fatigue, flu-like syndrome, mucocutaneous xerosis, moderate to severe neutropenia, and neutropenic fever. The authors noted that the response rates of their treatment regimen were not as high as those reported by Lippman et al. in their study of isotretinoin and IFN-[alpha]. Shin et al. attributed this to the more advanced SCC found in their patient population. Another important finding was that the nine month response duration observed with isotretinoin, IFN-[alpha], and cisplatin in more advanced SCC patients nearly doubled that of isotretinoin and IFN-[alpha] in less advanced SCC patients, a finding likely explained by the effects of cisplatin (16).
Combination therapy with oral isotretinoin and calcitriol has also shown promise in the treatment of cutaneous SCC. Preclinical data suggests that the combination of retinoids and 1.25-dihydroxy vitamin D3 inhibits the proliferation and differentiation of tumor cells. It has also been suggested that the synergistic action of these two agents results from the ability of retinoid and vitamin D nuclear receptors to form heterodimers, leading to enhanced transcription and other biological effects (18). Majewski et al. presented a case series of four patients with multiple precancerous and cancerous (SCC and BCC) skin lesions treated with a combination of oral isotretinoin (0.4-0.5 mg/kg/day) and calcitriol (0.5-1.0 ug/day) for up to one year. These investigators reported that all four patients clinically responded, with one patient achieving complete clearance of lesions (18).
Systemic retinoid therapy is often complicated by multiple side effects. The toxicity of retinoid therapy often fits the clinical picture of hypervitaminosis A. The clinical findings include mucocutaneous, ophthalmic, gastrointestinal, neuromuscular, psychiatric, rheumatologic, and laboratory abnormalities. The side effect profiles for the various retinoids differ. Many of the side effects associated with isotretinoin are dose dependent. Isotretinoin has a half-life of 22 hours, a bioavailability of approximately 25% (increased one to two fold with food), and peak blood concentrations one to four hours after ingestion. It has been suggested that twice daily dosing regimens may decrease the toxicity of isotretinoin (10).
Mucocutaneous side effects are the most commonly observed toxicity of isotretinoin. These symptoms include cheilitis (nearly universal), dry nasal mucosae, and epistaxis. Xerosis, pruritus, desquamation of the palms and soles, skin atrophy, skin fragility, alopecia, brittle nails, increased granulation tissue in sites of minor trauma, and rarely acne fulminans are other common cutaneous side effects. These symptoms are usually tolerable, treatable, and dose-dependent. Patients should be encouraged to use topical emollients on a consistent basis. It has been reported that vitamin E ([alpha]-tocopherol) at 800 IU daily inhibited mucocutaneous side effects during high dose oral isotretinoin therapy in myelodysplastic syndrome (19,20). The ophthalmologic side effects associated with oral isotretinoin use include xerophthalmia leading to exposure keratitis and corneal ulceration, corneal opacities, nyctalopia, blepharitis, papilledema, and blurry vision. Artificial tears and caution in using contact lenses should be encouraged. The gastrointestinal side effects of isotretinoin include hepatitis, and the non-specific complaints of nausea, diarrhea, and abdominal pain. There is an association of isotretinoin with cirrhosis and inflammatory bowel disease but a causal relationship has not been established. Neuromuscular side effects include headache, pseudotumor cerebri, fatigue, lethargy, and myalgias with elevated creatine phosphokinase levels. Concomitant use of drugs associated with pseudotumor cerebri and intensive physical activity should be avoided. Psychiatric complaints include irritability, depression, suicidal ideation and attempts, and psychosis (10). All patients with skin disorders are at risk for mood disorders and should be closely monitored (3). Rheumatologic side effects include arthralgias, bone pain, hyperostosis, and osteoporosis with chronic use of isotretinoin (10). High dose oral isotretinoin therapy in children rarely is complicated by premature epiphyseal closure (3). Finally, laboratory abnormalities associated with isotretinoin include elevated triglycerides, cholesterol, and elevated liver function tests (10). Baseline lab measurements of these values should be employed to identify those patients at increased risk for toxicity. Furthermore, hepatotoxins such as alcohol should be avoided (3). All systemic retinoids are potent teratogens and produce retinoic acid embryopathy in approximately 25% of fetuses. There is also an increased risk for spontaneous abortions. Isotretinoin is cleared from the body after approximately one month and once cleared there is no longer a risk of teratogenicity. Patients wishing to conceive should consult the guidelines found in the Pregnancy Prevention Program promoted by Roche Pharmaceuticals (10).
The management of patients with an increased risk of skin cancer should include patient education, sun protection, and close clinical surveillance by both patient and physician. Chemoprevention and treatment of new SCCs should be undertaken as one weighs the risks and benefits of oral isotretinoin. Isotretinoin seems most effective as a chemopreventative method as compared to a treatment modality. Future therapies include receptor-selective retinoids which would have a higher therapeutic index, retinoids combined with agents that can mediate signal transduction pathways and gene therapies that alter retinoid receptor expression.
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EVAN JONES MD (1), ADAM KORZENKO BS (1), DAVID KRIEGEL MD (2)
1. DEPARTMENT OF DERMATOLOGY, SUNY STONY BROOK SCHOOL OF MEDICINE STONY BROOK, NEW YORK
2. DEPARTMENT OF DERMATOLOGY, MOUNT SINAI SCHOOL OF MEDICINE NEW YORK CITY, NEW YORK
ADDRESS FOR CORRESPONDENCE:
David Kriegel MD
Director, Division of Dermatologic Surgery
The Mount Sinai Medical Center
5 East 98th Street, 5th Floor
New York, NY 10029
Phone: (212) 489-6669
Fax: (212) 765-0601
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