Leukoplakia

Abstract

Retinoids, a group of compounds encompassing Vitamin A and its analogs, have been shown to inhibit tumor growth in laboratory studies. Based on these findings, a number of clinical trials have been conducted to investigate the chemoprotective and chemotherapeutic effects of retinoids. This paper reviews the current database regarding the use of oral and topical retinoids in the prevention and treatment of cutaneous and internal malignancies. Clinical studies have shown that retinoids have beneficial effects in the prevention and treatment of certain neoplasms. In view of the heightened concern of malignancy associated with the use of biologic agents in the treatment of psoriasis, retinoids may be an attractive option for combination therapy with the biologic agents. Future clinical investigations are needed to precisely define how this combination will fit into the treatment algorithm for moderate-to-severe psoriasis.

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Introduction

Psoriasis is a chronic, inflammatory disease of the skin affecting approximately 2.6% of the United States population. (1) Traditionally, treatment modalities for moderate-to-severe psoriasis have included phototherapy and systemic agents such as methotrexate, cyclosporine, and retinoids, either as monotherapy or combination therapy. Recently, biologic agents, which interact with very specific targets within the immune system, have been used with increasing frequency in the treatment of psoriasis. At a molecular level, the biologic agents are known to downregulate the immune system, and thus, there is concern about their long-term risk of malignancy. The maker of one of the biologic agents, namely infliximab (Remicade[R]), in conjunction with the Food and Drug Administration (FDA) advisory committee, has issued a warning to healthcare providers and patients regarding the risk of malignancy associated with infliximab. In patients with both rheumatoid arthritis and Crohn's disease treated with infliximab, the risk of lymphoma was increased six-fold greater than the risk of the general population and was double that of the control arm that received placebo. (2) Thus, a warning concerning malignancy has been added not only to the labeling of infliximab but to that of all biologic agents that block TNF-[alpha], including etanercept (Enbrel[R]) and adalimumab (Humira[R]).

The term retinoid encompasses a group of naturally occurring and synthetic derivatives of Vitamin A. (3) Retinoids play an important role in controlling the growth, differentiation, and cell death during embryonic and adult life. While retinoids have been used in the treatment of acne, psoriasis, and disorders of cornification for decades, their use in cancer prevention and treatment may not be as well known. The association between retinoids and cancer prevention dates back to a study in 1925 demonstrating that vitamin-A deficient rats developed squamous metaplasia at several epithelial sites. (4) Retinoids were later shown to inhibit chemically induced cancers of the breast and genitourinary tract in animal studies. (5) However, high doses of vitamin A were associated with significant toxicity. Thus, over the past 40 years, more than 1,500 synthetic retinoids have been created, and the protective and therapeutic effects of retinoids in skin and internal malignancies have been studied in both laboratory and clinical trials. (6) In the laboratory, in vitro studies have demonstrated that retinoids can inhibit tumor growth by several mechanisms including suppression of cell proliferation, promotion of cell maturation and differentiation, and induction of apoptotic cell death. (6)

Retinoids are the only systemic agents used in the treatment of psoriasis that are not immunosuppressive or cytotoxic, and in fact, may be chemoprotective. Acitretin (Soriatane[R]) has been used in conjunction with phototherapy to decrease the risk of skin cancer in psoriasis patients. (7) Questions are now being raised as to whether retinoids may be chemoprotective against malignancy when combined with biologic agents in the treatment of moderate-to-severe psoriasis. The objective of this paper is to review the current database regarding the use of retinoids in the prevention and treatment of cutaneous and internal malignancies.

Methods

A Medline literature search for cohort studies, clinical trials, randomized controlled trials, and review articles between 1984 and 2004 was performed. The key word retinoid combined with malignancy, neoplasm, cancer, chemoprevention, and chemotherapy was used. The search yielded over 8,000 articles, of which we chose 85 for this review. The focus of the search included the use of retinoids in the prevention and treatment of skin cancer and internal malignancies including Kaposi's sarcoma, hematological malignancies, oral leukoplakia, head and neck cancer, hepatocellular carcinoma, cervical cancer, breast cancer, neuroblastoma, prostate cancer, and pancreatic cancer. Due to the vast amount of information on these topics, selected clinical trials were chosen which demonstrated or failed to demonstrate efficacy of retinoids in cancer.

Results

Cancers for Which Retinoids Have Been Shown to be Chemoprotective or Chemotherapeutic

Skin Cancer: Chemoprevention

The results from laboratory and clinical trials suggest that retinoids have chemoprotective effects in skin cancer. A review of the studies on skin cancer chemoprevention in high, moderate, and low risk patient populations will be presented.

High Risk Patients

Inherited Predisposition

In a 3-year controlled prospective study, Kraemer et al (8) investigated the use of isotretinoin (13-cis retinoic acid, Accutane[R]) as a chemoprotective agent in 5 patients with xeroderma pigmentosum, a disorder characterized by a DNA repair defect, resulting in a predisposition to develop skin cancers. After preexisting skin cancers were removed surgically, patients were treated with high dose oral isotretinoin 2 mg/kg/day for 2 years. During the treatment period, there was a 63% reduction in non-melanoma skin cancers compared to the pre-treatment period (p = .019). In their article, the authors did not make the distinction between squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs). The chemoprotective effect of isotretinoin was lost after the discontinuation of the drug. While taking the drug, many patients experienced significant mucocutaneous side effects, and some developed triglyceride, liver function, or skeletal abnormalities. A subsequent study treated patients using lower doses of isotretinoin 0.5 to 1.5 mg/kg/day, which resulted in similar efficacy with significantly less toxicity. (9)

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder, which results from a defect in the PTCH gene. As the name implies, affected patients are at an increased risk for developing basal cell carcinomas, in addition to cancers of the skeletal system, genitourinary system, and central nervous system. (10) In one case report, a patient with NBCCS was treated with oral etretinate (Tigason[R]) 1 mg/kg/day for 5 months. This resulted in a reduction of 83% of these basal cell carcinomas, especially those situated on the eyelids and in the axillae. In addition, etretinate proved beneficial in preventing new cancers from developing. (10)

In addition to oral retinoids, researchers have assessed the efficacy of topical retinoids in the chemoprevention of skin cancers. In a recent randomized control trial, So et al (11) investigated the effect of 0.1% tazarotene cream in mice engineered to be susceptible to developing skin cancer (PTCH +/- mice). The animals were exposed to ultraviolet and ionizing radiation. It was found that the number and size of basal cell carcinomas in the group of mice treated with tazarotene were significantly lower than in the control group at 5, 7, and 9 months (p < .05 at all time intervals). These findings suggest that topical tazarotene is effective in inhibiting tumor initiation and progression. The relevance of topical tazarotene for prophylaxis in PICH +/- humans has yet to be studied. Clinical studies in humans are warranted as the use of topical retinoids instead of systemic agents could have profound effects on reducing toxicity in patients.

Organ Transplant Patients

Given the necessity of immunosuppressive drugs postoperatively, organ transplant recipients are at high risk for developing skin cancers. (12) One particular survey reported that by 9 years post transplantation, 44% of renal transplant recipients develop nonmelanoma skin cancer. (13) In addition, the cancers tend to be aggressive with a greater potential for recurrences and metastases than in the non-immunosuppressed population. (14)

The use of retinoids as skin cancer chemoprotective agents for renal transplant recipients has been well-documented in clinical studies. In a prospective study, McKenna at al (15) followed 16 renal transplant recipients with a previous history of skin cancer who were treated with acitretin 0.3 mg/kg over a 5-year period. The study found that there was a 72% reduction in the total number of skin cancers during the period of retinoid therapy (21 total: 18 SCC, 3 BCC) compared with the pretreatment period (77 total: 64 SCC, 13 BCC) (p = .007). In addition, there were fewer tumors each year over the first 4 years of treatment, suggesting a chemoprophylactic effect. Six patients withdrew from the study after the fourth year secondary to side effects of acitretin.

Another study demonstrated that the beneficial effects of acitretin are not limited to kidney transplant recipients. In a retrospective study of 5 cardiac transplant recipients receiving acitretin 10 or 25 mg/day for 10 to 24 months, it was found that all patients showed an 80% reduction in the number of non-melanoma skin cancers compared to the pre-treatment period. (16) The authors noted that in the post-treatment period, the number of SCCs removed was far greater than the number of BCCs. In addition, all patients had an objective decrease in the number of actinic keratoses. Although these 2 studies showed chemoprotective effects in kidney and cardiac transplant patients, they lacked a control group to account for confounding variables.

In an attempt to increase the scientific rigor of prior studies, George et al (17) recently conducted a similar study with a prospective, open randomized crossover design. Twenty-three renal transplant patients with a history of skin cancer were randomized to receive acitretin 25 mg daily or placebo; they crossed-over after 1 year. The average number of squamous cell carcinomas was decreased by 42% during the acitretin-treatment period compared to the untreated period (p = .002). Although there were fewer basal cell carcinomas during the acitretin-period, this result was not statistically significant. The major limitation of the study was the high drop out rate (~50%) secondary to side effects.

Topical retinoids are associated with fewer adverse effects than their systemic counterparts; however, a review of the literature reveals no studies investigating the protective effect of topical retinoids against skin cancer development in transplant recipients. Clinical studies investigated topical retinoids in the treatment of actinic keratoses in transplant recipients. (18) Two of the three studies demonstrated a statistically significant reduction in the number of actinic keratoses with topical tretinoin (Retin-A[R]) and adapalene (Differin[R]) respectively.

Psoriatic Patients with History of Psoralen with Ultraviolet A (PUVA) Photochemotherapy

Tamar and Stern (19) recently reported the results of a nested cohort study of psoriasis patients who had participated in the PUVA Follow-up Study. Ten percent of the initial 1,380 patients were treated with oral retinoids (isotretinoin, etretinate, or acitretin) between 1985 and 2000. The retinoid dose varied from 25 to 50 mg daily, and the duration of treatment was at least 26 weeks in all patients. A multivariate analysis, which compared patients' tumor incidence while using and not using retinoids over a 15-year period reveled that retinoid use was associated with a 20% reduction in squamous cell carcinomas. Consistent with other studies, it was found that upon discontinuation of the retinoid, the incidence of squamous cell carcinomas increased back to pretreatment levels. In contrast to squamous cell carcinomas, no significant association between retinoid use and basal cell carcinoma incidence was found.

A recent case repot describes a 40-year-old patient with severe psoriasis who, after receiving 345 psoralen plus UVA (PUVA) treatment sessions, developed 14 SCCs. The patient was then started on acitretin 25 mg daily. Over the following 25 months, he developed only 6 SCCs, 2 of them developing within the first 5 months of starting acitretin, 4 over the next 13 months, and none in the last 6 months. The suppressive effect of the retinoid continued as long as the patient was taking the medication. Upon discontinuation, the patient experienced a flare of psoriasis and recurrence of squamous cell carcinomas. The authors suggest that retinoids may be useful in patients who develop squamous cell carcinomas secondary to exposure to numerous PUVA treatments. (20)

Moderate Risk Patients

Patients with History of Premalignant/Malignant Skin Lesions

Patients with actinic keratoses and/or a history of skin cancers can be considered at moderate-risk for developing future skin cancers. Moon et al (21) examined the usefulness of retinoids in chemoprevention in this moderate risk population. In a randomized, double-blind, controlled trial of 2,297 subjects treated with either 25,000 IU of retinol daily or placebo for a median of 3.8 years, it was found that retinol was effective in the prevention of squamous cell carcinomas (p = .04) but not basal cell carcinomas (p = .36).

Low Risk, Otherwise Healthy Patients

In a large, prospective cohort study of more than 85,000 healthy nurses, Fung et al (22) found that higher levels of vitamin A in the diet played no protective role in the development of basal cell carcinomas in a 12-year follow-up period. A similar prospective cohort study (23) of 128,811 men and women with no prior history of cancer found no protective effect of dietary vitamin A and beta-carotene in the development of squamous cell carcinomas over a 10- to 14-year follow-up period. The results of these studies suggest that in non-immunosuppressed patients, natural dietary retinoids do not appear to have a beneficial effect in preventing non-melanoma skin cancer. To our knowledge, there are no studies investigating the effects of synthetic retinoids in preventing skin cancer in low-risk, healthy individuals.

Skin Cancer: Chemotherapy

Levine et al (24) described an 83-year-old woman with more than 20 keratoacanthomas and squamous cell carcinomas who was treated with oral isotretinoin 2 mg/kg/day for 6 months. These tumors regressed in the 6-month treatment period and did not recur in the 3-year follow-up period after the oral retinoid was discontinued. Only 4 new tumors (3 SCCs and 1 keratoacanthoma) developed in the follow-up period, suggesting the retinoid had both chemoprotective and chemotherapeutic effects. Thus, although surgery remains the first line treatment for squamous cell carcinoma, oral retinoids may be considered when surgery is refused or deemed not feasible.

Rosenthal and Oratz (25) conducted a phase II clinical trial in which 13 patients with metastatic malignant melanoma were treated with interferon-[alpha] and isotretinoin 1 mg/kg/day for a median of 2 months. Only one patient demonstrated a partial response, and all patients experienced significant side effects. Thus, the authors concluded that the combination of 13-cis retinoic acid and IFN-[alpha] is not helpful in the treatment of patients with malignant melanoma.

Kaposi's Sarcoma (KS)

Kaposi's sarcoma is the most common acquired immunodeficiency syndrome (AIDS)-associated malignancy. It is caused by an abnormal proliferation of spindle cells, resulting in tumors that may involve the skin, oral mucosa, lymph nodes, and visceral organs. (26) Until recently, therapeutic options for severe cutaneous KS involved cryotherapy with liquid nitrogen, intralesional vinblastine, and radiation therapy. Although effective, these treatment modalities are painful and often result in scarring. (27-29) In 1999, the FDA approved 0.1% alitretinoin (9-cis-retinoic acid, Pangretin[R]) for the treatment of cutaneous lesions in AIDS-related Kapsoi's sarcoma. (30)

The recently reported results of open-label, within-patient, dose-escalating, phase I and II clinical trials confirmed the efficacy and safety of topical alitretinoin in cutaneous Kaposi's sarcoma. (31) In one study, 115 patients applied alitretinoin 0.1% gel to at least one cutaneous lesion for up to 16 weeks. At least 2 other lesions on each patient served as untreated controls. Clinically significant responses were observed in 37% of treated lesions compared with 11% of untreated lesions (p < .001). The incidence of disease progression was lower for treated lesions versus untreated lesions (34% versus 46%, p = .02). Treatment with topical alitretinoin was well-tolerated.

In a phase III, multicenter, randomized, double-blind, vehicle-controlled trial, Walmsley et al (32) evaluated the efficacy and tolerability of 0.1% topical alitretinoin gel in 268 patients with biopsy-proven cutaneous Kaposi's sarcoma. Patients were treated with 0.1% topical alitretinoin gel or vehicle gel applied 3 to 4 times daily to 6 lesions for 12 weeks. The overall response rate (complete and partial responders) was 35% in the treatment group compared with 18% in the vehicle group as measured by the AIDS Clinical Trials Group (ACTG) response criteria (p = .002). The statistically significant difference was maintained when the data were adjusted for age, race, baseline CD4+ lymphocyte counts, number and area of cutaneous lesions, and number of concurrent antiretroviral therapies taken by the patient. Topical alitretinoin was well-tolerated, and the most common adverse effect was mild to moderate dermal irritation (erythema, pain, pruritus, and swelling) limited to the site of application and reversible with reduction in the frequency of application. Based on the results of prior molecular studies, the authors speculated that alitretinoin's beneficial effects in the treatment of KS may be secondary to downregulation of interleukin-6, an autocrine growth factor in KS cells, or antiviral activity against human herpes 8 virus, an organism that appears to be related to the development of Kaposi's sarcoma. In another randomized, double-blind, vehicle-controlled, phase III trial by Bodsworth et al (33) 134 KS patients were treated with either alitretinoin gel 0.1% or vehicle gel twice daily for 12 weeks. The overall response rate was 37% for alitretinoin-treated patients and 7% for the vehicle-treated patients. The most frequent adverse event was skin irritation seen in 32% of patients.

In a phase II, open-label, clinical trial of 57 HIV-seropositive men with early or advanced-stage KS, Aboulafia et al (34) investigated the safety and efficacy of oral alitretinoin. Patients were treated with oral doses of alitretinoin increasing in 40-mg increments every 2 weeks from 60 mg/[m.sup.2] to a maximum of 140 mg/[m.sup.2] per day. Six lesions on each patient were followed for clinical improvement according to the AIDS Clinical Trials Group (ACTG) criteria. At 15 weeks, the response rate for overall KS disease severity was 19%. The highest dose 140 mg/[m.sup.2] per day was not well-tolerated by patients. Ninety-three percent of patients experienced at least one adverse event (headache, exfoliative dermatitis, cheilitis, and hyperlipidemia) causing 37% of patients to withdraw from the study. The study demonstrated that oral alitretinoin had moderate activity and provided durable responses in patients with KS; how-ever, the substantial toxicities at higher doses limit its suitability in the treatment of this disease.

Bower et al (35) conducted a phase II clinical study of 15 patients with advanced AIDS-related KS. Oral administration of isotretinoin was found to have an overall response rate of only 7% by the AIDS Clinical Trials Group (ACTG) criteria. The authors concluded that the low overall activity, considerable toxicity, and limited cosmetic benefit even in responding patients limit the value of oral isotretinoin in KS. The FDA has approved no oral formulation for Kaposi's sarcoma.

Internal Malignancies

Hematological Malignancies

Cutaneous T Cell Lymphoma (CTCL)

Bexarotene (Targretin[R]) is a synthetic retinoid analogue that selectively binds to retinoid X receptors (RXRs), which have biological activity that is distinct from retinoic acid receptors (RARs). In December 1999, bexarotene became the first oral retinoid to be formally approved for the treatment of CTCL that is refractory to at least one systemic medication. One year later, the topical gel formulation was approved for the treatment of cutaneous lesions. (36) A recent, phase II to III multicenter, open-label trial was conducted on 58 patients with refractory or persistent, early stage CTCL who were randomized to receive bexarotene 6.5, 300, or 650 mg/[m.sup.2]/day for as long as the treatment proved safe and beneficial. (37) Patients on the 6.5-, 300-, and 650-mg/[m.sup.2]/day doses demonstrated clinical improvement in 20%, 54%, and 67% of cases respectively (p = .045). The most significant side effects of bexarotene included hypertriglyceridemia (79% of patients) and hypothyroidism (40% of patients), both of which could be controlled with medications and were reversible after discontinuation of the drug. In taking into account both efficacy and tolerability, 300 mg/[m.sup.2]/day proved to be the optimal dose.

The beneficial effects of bexarotene in the treatment of CTCL do not appear to be limited to patients with earlystage disease. This was demonstrated by a similarly conducted phase II to III multicenter trial of 94 patients with advanced CTCL randomized to receive bexarotene 300 mg/[m.sup.2]/day or 650 mg/[m.sup.2]/day. Patients receiving 300 mg/[m.sup.2]/day had a response rate of 45% compared to 55% in those receiving the higher dose. (38) Based on these 2 studies, the overall response rate (complete and partial responders) in the 300-mg/[m.sup.2]/day group was 48% (54% in early stage and 45% in advanced stage). The remission was durable with a relapse rate of 28% in patients in the 300-mg/[m.sup.2]/day group over a 17-week follow-up period.

In an effort to assess the safety and efficacy of topical bexarotene 1% gel in patients with CTCL, Heald et al (39) conducted a multinational, open-label, phase III trial of 50 patients with refractory or persistent early stage CTCL. The overall response rates for the Physician's Global Assessment of Clinical Condition, Composite Assessment of Index Lesion Disease Severity, and primary end point classification were 44%, 46%, and 54%, respectively. The gel was well-tolerated, and the most common side effects included burning, pruritus, and skin inflammation.

Tsimberidou et al (40) conducted a prospective clinical trial of 44 patients with advanced, refractory lymphoid malignancies (18 with CTCL, 6 with peripheral T-cell lymphoma, 14 with Hodgkin's disease, and 6 with other lymphoid malignancies) treated with a combination of isotretinoin 1 mg/kg/day and IFN-[alpha] 3 million units/day for a median duration of 2 months. The overall response rate was 38.6%. Five patients had a complete remission and 12 patients had a partial remission. Interestingly, one patient with non-Hodgkin's lymphoma who was previously treated with retinoid monotherapy without success responded well to the combination of isotretinoin and IFN-[alpha].

Other Lymphomas

Ong et al (41) described a 53-year-old woman with stage IV CD30+ anaplastic large cell lymphoma with brain, skin, and lung involvement who was treated with a combination of oral acitretin 50 mg daily and IFN-[alpha] 3 million units weekly. The authors tried this combination due to the mere 15% response rate of these tumors to conventional chemotherapy. The authors report that the skin and mucosal lesions resolved at 2 months while the lung and brain lesions resolved at 5 months and 7 months respectively. The authors suggest that clinical studies are needed to assess whether patients with lymphoma treated with this combination of therapies can be cured.

Acute Promyelocytic Leukemia (APL)

Acute promyelocytic leukemia is a relatively rare subset of acute leukemia, accounting for 5% to 10% of acute myeloid leukemias in the United States. (42) APL is characterized by a chromosomal translocation involving the PML gene on chromosome 15, which encodes a growth-suppressing transcription factor, and the RAR-[alpha] gene on chromosome 17, which encodes a factor regulating myeloid differentiation. (43) The PML/RAR-[alpha] fusion gene results in a chimeric protein which causes an arrest of maturation of myeloid cells, resulting in an excessive accumulation of promyelocyte leukemia cells in the bone marrow. (43) The most serious complication of APL is disseminated intravascular coagulation and fatal hemorrhage, which is caused by the release of particular tissue factors from the malignant cells. (44) The chemotherapeutic agents used in the treatment of APL, prior to the introduction of tretinoin, enhanced the killing of the malignant cells and promoted this tissue factor release. The mortality rate of APL approached 50%. (44) In contrast to traditional chemotherapeutic agents, all-trans retinoic acid does not kill the malignant cells; instead, it induces differentiation of promyelocytic leukemic cells to mature, normal functioning neutrophils. (44) After the publication of the results from the European APL 93 trial, the gold standard for the treatment of APL is the combined use of all-trans retinoic acid and anthracycline-based chemotherapy. (44) This combination has been reported to cause approximately 80% of APL patients to go into remission.

Oral Leukoplakia

Oral leukoplakia is a white-plaque mucosal lesion that may give rise to squamous cell carcinomas. (45) In a randomized control trial, Stitch et al (46) investigated the chemopreventive and chemotherapeutic effects of vitamin A in 54 betal nut chewers with leukoplakia. Subjects received either 200,000 IU vitamin A weekly or placebo for 6 months. Complete remissions occurred in 57.1% and total suppression of new lesions occurred in 100% of the treated group as compared to 3% and 21%, respectively, in the placebo group. Long-term follow-up for recurrences and development into squamous cell carcinomas was not carried out.

In addition to natural vitamin A, researchers have investigated the effect of synthetic retinoids in the treatment of oral leukoplakia. One such investigation randomized 44 patients with histologically confirmed leukoplakia to receive either isotretinoin 1 to 2 mg/kg/day or placebo for 3 months. (47) Significant side effects to isotretinoin required a dose reduction in several of the patients. However, after 6 months, there were clinically significant decreases in the size of the mucosal lesions noted in 67% of subjects given isotretinoin compared with 10% of those given placebo (p = .0002). A histological response correlated with the clinical response in 56% of cases. Importantly, 9 of 16 patients relapsed within 3 months after treatment was discontinued. The authors concluded that oral isotretinoin is useful in at least the short-term treatment of oral leukoplakia.

A few years later, Lippmann et al (48) conducted a similar randomized control trial using much lower doses of isotretinoin over a longer period of time in hope of preventing relapses and limiting adverse effects. Seventy patients with oral leukoplakia were treated with high dose isotretinoin 1.5 mg/kg/d for 3 months. The 59 subjects who demonstrated clinical regression of these lesions were then randomized to receive beta-carotene 30 mg/d or low dose isotretinoin 0.5 mg/kg/d for a 9-month maintenance phase. Ninety-two percent of patients in the low-dose isotretinoin group and 45% of patients in the beta-carotene group demonstrated either regression or stability of their lesions (p < .001). Adverse effects were mild in both groups, although somewhat fewer in the group treated with betacarotene. This study was important in demonstrating that induction with high-dose isotretinoin followed by maintenance with a lower, better-tolerated dose is effective in the treatment of oral leukoplakia.

In an effort to make long-term maintenance therapy with retinoids even more tolerable, researchers have investigated the efficacy of topical retinoids in the treatment of oral leukoplakia. Bosinic et al assessed the efficacy of retinaldehyde 0.1% gel applied twice daily for 2 months in 13 patients with oral leukoplakia. (49) Clinically, this regimen resulted in complete regression in 17% of lesions and significant improvement in 75% of lesions. In addition, his-tological and immunohistochemical studies confirmed the regression of these premalignant lesions.

Head and Neck Cancer

After the removal of a primary head and neck tumors 3% to 7% per year develop second primary tumors. (50) In a phase III, randomized control trial, Hong et al (51) investigated the effect of isotretinoin in preventing a second primary squamous cell carcinoma of the head and neck. The study randomized 103 patients with a history of stage I to IV squamous cell carcinoma of the larynx, pharynx, or oral cavity, who were clinically free of disease after surgery and/or radiation, to receive either isotretinoin 50 to 100 mg/[m.sup.2] or placebo daily for 1 year. There were no statistically significant differences in the number of recurrences of the primary tumor between the 2 groups after a median follow-up of 32 months. However, the isotretinoin group developed statistically significant fewer second primary tumors. Four percent of patients in the isotretinoin group had a second primary tumor as compared to 24% in the placebo group (p = .005). As a result of the adverse effects of isotretinoin, one-third of patients in the treatment group did not complete their 1-year course of treatment. In a follow-up of 55 months median duration, it was found that those who had been treated with isotretinoin continued to have fewer second primary tumors than the placebo group (14% versus 33%) (p = .04). (52)

Hepatocellular Carcinoma (HCC)

Therapeutic modalities for HCC include surgical resection, percutaneous ethanol injection therapy, and radiofrequency ablation therapy. Unfortunately, the recurrence rate at 5 years after curative treatment often exceeds 70%. (53) This is usually due to the development of second primary tumors. In hope of preventing post-therapeutic recurrences, Kojima et al (54) developed a synthetic acyclic retinoid, polyprenoic acid, which can induce apoptosis in human HCC cell lines. In a randomized prospective controlled trial, 89 patients who were free of HCC after conventional therapies were randomized to receive polyprenoic acid 600 mg daily or placebo for 12 months. After 38 months, 27% of patients in the treatment group compared with 49% in the placebo group had recurrent or new HCCs (p = .04). The investigators are currently conducting further research to develop potent and safe analogues of polyprenoic acid that may prevent primary HCC in high-risk individuals.

Cervical Cancer

Cervical cancer is a major health problem worldwide, especially in developing countries where it is among the most common malignancies in women. (55) In a phase III clinical trial, Meyskens et al (56) investigated the efficacy of topical retinoic acid in reversing moderate or severe cervical intraepithelial neoplasia (CIN), a precancerous condition. In the trial, 301 women with CIN were randomized to insert cervical caps containing either 1.0 mL of 0.372% beta-trans retinoic acid or placebo daily for 4 days when they entered the trial and then for 2 days at months 3 and 6. Retinoic acid increased the complete histological regression rate of moderate CIN (CIN II) from 27% in the placebo group to 43% in the retinoic acid group (p = .041). However, no difference was noted in cases of severe dysplasia (CIN III). In terms of mechanism of action, retinoids not only act to induce maturation of epithelial cells, but they have also been shown to suppress transcription of human papillomavirus type 16 (HPV16), the virus involved in the pathogenesis of cervical cancer. (57)

The previous trial demonstrated that topical trans-retinoic acid treatment of cervical intraepithelial neoplasia II and III led to a statistically significant regression of CIN II, but not CIN III. In vitro studies demonstrated that N-(4-hydroxyphenyl) retinamide (4-HPR) is effective in inducing apoptosis of cervical tumor cell lines. Thus, Follen et al (58) tested the efficacy and tolerability of 4-HPR, a synthetic vitamin A analogue that has been shown to have better tolerability than many other retinoids, against CIN II/III. In a blinded randomized trial, 4-HPR at 200 mg/day for 6 months was compared with placebo in patients with biopsy-proven CIN II or III. An interim analysis of the data showed that the 4-HPR-treatment group had lower response rates than those of the placebo group at 6 and 12 months (25 versus 44% response rates at 6 months; 14 versus 50% at 12 months). The authors concluded that 4-HPR at 200 mg/day is not efficacious compared with placebo in the treatment of CIN II or III. They speculated that the lack of efficacy of 4-HPR in their trial, despite positive results in in vitro studies, might indicate that higher doses are needed in patients to achieve comparable results.

Cancers for Which Retinoids may be Chemopreventive Breast Cancer

Fenretinide was found to successfully inhibit chemically induced mammary carcinoma in mice in 1979, leading to the proposition that this compound be tried as a chemoprotective agent in humans. Camerini et al (59) recently reported the results of such a study. In a phase II, randomized, placebo-controlled trial, 2,867 women with a history of stage I breast cancer were randomized to receive either fenretinide 200 mg daily or placebo for 5 years. At a median of 97 months, there were no statistically significant differences in the overall occurrence of contralateral breast cancer or ipsilateral breast cancer between the 2 groups. However, upon further data analysis, a possible beneficial effect was seen in premenopausal women and an opposite effect in postmenopausal women. The authors concluded that fenretinide treatment of women with breast cancer for 5 years appeared to have no statistically significant effect on reducing the incidence of second breast malignancies in the overall population; however, it may be effective in reducing the development of contralateral breast cancers and local recurrences in premenopausal women.

Neuroblastoma

Neuroblastoma, a tumor originating from the adrenal medulla or other sites of sympathetic nervous tissue, is one of the most common solid tumors in childhood. Despite complete clinical remission with chemoradiotherapy and bone marrow transplantation, relapse from minimal residual disease occurs in over 50% of patients with high-risk neuroblastoma. (60) Thus, newer therapies are needed to more effectively suppress residual disease. In vitro studies have demonstrated that all-trans retinoic acid (tretinoin) and 13-cis-retinoic acid (isotretinoin) can inhibit proliferation and induce differentiation and maturation of neuroblastoma cell lines. (61, 62)

In a phase III randomized trial, the Children's Cancer Group (CCG) (63) investigated the efficacy of isotretinoin in 539 children with advanced neuroblastoma. Patients were randomized to receive three cycles of intensive chemotherapy or myeloablative chemotherapy followed by autologous bone marrow transplantation. Patients in clinical remission, ie, without active tumor on biopsy, were then randomized to receive isotretinoin 160 mg/[m.sup.2]/day or no further therapy. The 3-year, event-free survival for patients receiving isotretinoin was 46% compared to 29% in those receiving no further therapy (p = .027).

The European Neuroblastoma Study Group (ENSG) (64) also conducted a clinical trial investigating the efficacy of isotretinoin in preventing relapse of neuroblastoma. In the study, 175 children with advanced neuroblastoma who had achieved remission with conventional therapies were randomized to receive isotretinoin 0.75 mg/kg/day or placebo for 4 years. The three-year event-free survival was 37% in those receiving isotretinoin compared with 42% of those randomized to placebo. Thus, in contrast to the above study, low dose continuous isotretinoin conferred no advantage in maintaining remission of neuroblastoma. It has been speculated that this discrepancy is due to the fact that in the ENSG study, the dose of isotretinoin was only 15% of the maximum tolerated dose in a phase I study by Villablanca et al (65) and in the CCG study. (66) In addition, there was a greater lag time between the completion of cytotoxic therapy and the initiation of isotretinoin in the ENSG study compared to the CCG study (341 days versus 290 days). Starting isotretinoin soon after cytotoxic therapy may be important in preventing tumor cells from growing again.

Cancers for which Retinoids may not be Efficacious Prostate Cancer

Because prostate cancer is the most common malignancy diagnosed in American men, there has been much interest in its prevention and treatment. A statistically significant inverse association between natural baseline serum vitamin A levels and prostate cancer was reported in a prospective, cohort study of 2,440 men followed for a period of 10 years. This relationship was independent of age, stage of disease, and time at which blood was drawn. (67) In a study of 394 patients with prostate cancer or benign prostatic hyperplasia, it was found that the mean baseline serum retinol levels in patients with prostate cancer was significantly lower than in controls (p < .05). (68) These studies led to the recommendation that men increase their vegetable and fruit consumption to reduce the risk of prostate cancer and to the investigation of retinoids in the chemoprevention and chemotherapy of prostate cancer.

In 1993, Pienta et al (69) found that N-4-Hydroxyphenylretinamide (fenretinide or 4HPR), was cytotoxic and decreased the development of prostate cancer in a rat carcinogenesis model, suggesting that 4HPR may be a potent inhibitor of early prostate cancer growth. A phase II chemoprevention trial evaluated the efficacy of oral fenretinide as a chemoprevention agent in 22 men at high risk (prostate specific antigen value [greater than or equal to] 4 ng/ml and negative prostate biopsies) for prostate cancer. (70) The patients took fenretinide 100 mg daily for twelve 28-day cycles (25 days on drug, 3 days off). Eight patients with negative pre-trial biopsies had positive prostate biopsies prior to their 12th cycle evaluation, leading to early termination of the study. The investigators suggested that some of the individuals with elevated PSAs may have had disease that could not be detected at the time of biopsy. They suggested that further studies investigating fenretinide as a chemoprotective agent in prostate cancer are warranted and should be conducted with a larger sample size.

Culine S et al (71) conducted a phase II trial of 26 patients with histologically confirmed metastatic adenocarcinoma of the prostate who failed at least one hormonal therapy. Patients received a single dose of 45 mg/m tretinoin daily for 7 days followed by 7 days of no treatment, and then resumed treatment on day 14. This schedule was continued until progression or limiting toxicity occurred. Only 4 (15%) patients demonstrated a biological response of 50% or greater decrease in serum prostate specific antigen. In addition, there was no significant reduction of pain.

Recently, Shalev et al (72) investigated the effect of isotretinoin 1 mg/kg/day on serum PSA levels in a control group (n = 14) and in patients with rising PSA levels after radical prostatectomy for prostate cancer (n = 11). The rise in PSA levels was a harbinger of local or metastatic progressive disease. At 12 weeks, no significant changes in PSA levels were noted in the control group. Three of 11 post-prostatectomy patients (27%) had PSA reductions of 28%, 15%, and 6.6%. However, in 2 of these patients, the PSA level subsequently rose exponentially. The investigators concluded that isotretinoin is unlikely to be of therapeutic benefit in prostate cancer when used as a single agent. Isotretinoin has also been investigated in combination with interferon-[alpha] (73) and/or paclitaxel. (74) However, these combinations had few, if any beneficial effects in the treatment of prostate cancer.

Pancreatic Cancer

In 1996, Bold et al (75) demonstrated the antiproliferative effects of retinoic acid on pancreatic cell lines. At around the same time, Moore et al (76) conducted a pilot phase II clinical trial in which 6 patients with advanced pancreatic adenocarcinoma were treated with isotretinoin 1 mg/kg/day and interferon-[alpha] 6 million units/day. No objective therapeutic responses occurred in these patients, and the investigators concluded that further exploration of this biological approach for pancreatic adenocarcinoma is not warranted.

Cancers for which Retinoids may be of no Benefit Lung Cancer

Lung cancer is the most common cause of cancer death in the world. (77) In a review of 8 dietary epidemiological studies, Palgi found an inverse relationship between vitamin A intake and lung cancer, after controlling for cigarette smoking and socioeconomic status. (78) The results suggested that daily consumption of green-yellow vegetables reduces the risk of lung cancer in patients, regardless of their degree of smoking. These studies led to clinical trials investigating the role of retinoids in both primary and secondary prevention. The trials in which retinoids were found to be efficacious are presented followed by studies demonstrating no benefit or possibly even harmful effects of retinoids.

In a randomized secondary prevention control trial, Pastorino et al. (79) investigated the chemopreventive properties of retinol alone. In the study, 307 patients with stage I non-small cell lung cancer who had undergone curative surgery were randomized to receive either natural vitamin A ester retinyl palmitate 300,000 IU daily or placebo. After a median of 46 months, recurrence of the primary lung cancer occurred in 37% of the treated patients and 48% of the placebo group (p = .045). This study demonstrates some efficacy for retinol as monotherapy in the chemoprevention of secondary tumors.

Based on the encouraging results of retinoids preventing second primary tumors, a large phase III clinical trial was conducted, the European Study on Chemoprevention with Vitamin A and N-acetylcysteine (EUROSCAN). (80) In the trial, 2,592 patients with a history of lung cancer or head and neck cancer were randomly assigned to receive retinyl palmitate, N-acetylcysteine, both compounds, or placebo for 2 years. EUROSCAN found that retinyl palmitate and/or N-acetylcysteine resulted in no statistically significant difference in overall or event-free survival between the 2 groups.

Synthetic retinoids have also been investigated as secondary chemopreventive agents in lung cancer. In a randomized control trial, Lippmann et al (81) randomized 1,166 patients with pathologic stage I non-small cell lung cancer who had undergone resection to receive placebo or isotretinoin 30 mg daily for 3 years. After a median follow-up of 3.5 years, there were no statistically significant differences between the 2 groups with respect to the time to development of second primary tumors, recurrences, or mortality.

Epidemiological studies served as an impetus for 2 large clinical trials investigating the chemoprotective effect of beta-carotene and alpha-tocopherol on the lung. In a randomized double-blind, placebo-controlled trial, The Alpha-Tocopherol Beta Carotene Cancer (ATBC) prevention study group randomized 29,133 male smokers to receive, beta-carotene 20 mg daily with or without 50 mg alpha tocopherol (vitamin E), or placebo for 5 to 8 years. (82) Among the 876 new cases of lung cancer diagnosed during the trial, there was no reduction in incidence among men who received alpha-tocopherol. Unexpectedly, however, lung cancer development was 18% higher and overall mortality was 8% higher in those men receiving beta-carotene compared to those in the placebo group (p < .02). The adverse effect of beta-carotene appeared stronger, although not statistically significant, among those who smoked at least 20 cigarettes daily compared to those who smoked 5 to 19 cigarettes daily. In addition, beta-carotene's detrimental effect was exacerbated by alcohol intake.

The Beta-Carotene and Retinol Efficacy Trial (CARET) found similar, disappointing results in a multicenter, randomized double-blind, placebo-controlled trial. (83) Approximately 18,000 men and women at high risk for lung cancer because of a current or past history of smoking or asbestos exposure were given beta-carotene 30 mg daily in combination with retinol 25,000 IU daily or placebo for an average of less than 4 years. The trial was terminated 21 months prematurely because researchers found a 28% increase in lung cancer incidence and 17% increase in overall mortality in the treatment group compared to placebo group (p < .02). Interestingly, there was no increase in lung cancer among the subset of former smokers. The mechanism by which beta-carotene increases the risk of lung cancer is not clear; however, it has been proposed that the supplement may have pro-oxidant effects under the oxidative stress that occur in the lungs of smokers. (84)

Discussion

A comprehensive review of the literature reveals that there have been a number of clinical trials investigating the effects of oral and topical retinoids in the chemoprevention and chemotherapy of skin and internal malignancies. The most convincing evidence for the role of retinoids in chemoprevention is seen in the suppression of skin cancers in organ transplant patients. Retinoids have also been shown to have beneficial effects in Kaposi's sarcoma, cutaneous T-cell lymphoma, acute promyelocytic leukemia, oral leukoplakia, head and neck cancer, hepatocellular carcinoma, cervical cancer, breast cancer, and neuroblastoma. Retinoids were not efficacious as single agents in the chemoprevention of prostate cancer or chemotherapy of pancreatic cancer. In addition, they may possible have harmful effects in the prevention of lung cancer in smokers. The majority of the data from these clinical trials, however, supports the chemoprotective effect of retinoids.

Due to retinoids' chemopreventive and chemotherapeutic effects, acitretin may be an ideal partner for the new biologic agents used in the treatment of moderate-to-severe psoriasis. Recently, it has been reported that infliximab (Remicade[R]) increases the risk of lymphoma approximately two-fold greater than expected in patients with rheumatoid arthritis and Crohn's disease, who are thought to already have an increased risk of lymphoma relative to the general population. (2) In addition, clinical trials revealed a five-fold increase in lymphoma rates among rheumatoid arthritis patients treated with adalimumab compared with the general population. (85) Since the other biologic agents used in the treatment of psoriasis also downregulate the immune system, there is a concern that they may increase the risk of malignancy. Acitretin, on the other hand, is the only FDA-approved systemic therapy for psoriasis that is not immunosuppressive, and in fact, possibly chemoprotective and even chemotherapeutic for some malignancies. Thus, acitretin may be a good adjunctive therapy to biologic agents to try to minimize the possible increased risk of lymphoma and other potential malignancies.

In addition, retinoids and the biologic agents work via very different mechanisms of action for the treatment of psoriasis. While retinoids act to normalize the hyperproliferative state of psoriatic lesions by enhancing the maturation and differentiation of keratinocytes, the biologic agents act by targeting one particular step within the immunogenesis of psoriasis. Theoretically, the concurrent use of retinoids and biologic agents may allow for a synergistic effect in which the combined efficacy is greater than that of either agent alone. This is especially useful given that thus far, the FDA-approved biologic agents appear to have only moderate efficacies, and many patients on these agents may require another therapeutic modality for better results. Lastly, retinoids and biologic agents have different side effect profiles, thus, avoiding the double insult on the immune system and possibly allowing lower doses of each drug to be used, minimizing acute and long-term organ toxicities.

Conclusion

Retinoids are used as both chemoprotective and chemotherapeutic agents in a number of cutaneous and internal malignancies. In addition, they are used in the treatment of moderate-to-severe psoriasis. Over the past several years, many new biologic agents have been introduced for the treatment of psoriasis; however, there is significant concern that the use of these agents downregulate the immune system and thus, increase the risk of malignancy. Retinoids are the only systemic agents used in the treatment of psoriasis that are not immunosuppressive, and in fact, are chemoprotective for certain malignancies. Thus, retinoids and biologic agents may be an attractive combination in the treatment of psoriasis. Moreover, because retinoids act via a different mechanism than the biologic agents, the drugs may act synergistically to result in greater overall efficacy. Finally, retinoids and biologic agents have non-overlapping side effect profiles, thereby minimizing the potential for additive adverse effects. The specific hypothesis that combination therapy with retinoids and biologic agents will reduce the risk of malignancy, improve efficacy, and minimize side effects remains untested. Further clinical studies are warranted to fully understand the effect and role of retinoids when combined with biologic agents in the treatment of psoriasis.

Conflict of interest: John Koo, MD has been a clinical researcher, consultant, and speaker for Allergan, Amgen, Biogen, Bristol-Myers Squibb, Centacor, Connetics, Elan, Fujisawa, Galderma, Genentech, GlaxoSmithKlein, ICN, Novartis, and Roche.

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Pooja Khera MD, (a) John Y. Koo MD (b)

a. University of Pittsburgh School of Medicine, Pittsburgh, PA

b. Director, UCSF Psoriasis Treatment Center; Vice Chairmen, Department of Dermatology, University of California, San Francisco, CA

Address for Correspondence

Pooja Khera

1173 Greenfield Drive

Erie, PA 16509

Tel: 412-498-6765

e-mail: poojakhera@gmail.com

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