Clinical Trials With Retinoids

Acute promyelocytic leukemia (APL) shows the most spectacular response to retinoid treatment, consistent with results in the cultured human APL cell line HL60.35 Combined therapy with RA and conventional chemotherapy produces 70% long-term remission.36 A few cases of APL develop resistance to RA therapy. In contrast, although RA alone has spectacular initial effects on patients with the form of APL that involves the t(15,17)-translocation, which produces the fusion protein PML-RARa, many of these patients relapse and become resistant to further RA therapy, for reasons still debated.

Oral retinol (25,000 nmol/day) reduces by 32% the development of squamous cell carcinomas of the skin in high-risk patients, with no apparent toxicity, as shown in a study that involved 5 years of treatment and nearly 4 years of follow-up.37 In contrast, oral retinol had no effect on basal cell carcinoma, and neither retinol nor isotretinoin (13-ds-RA) affected the incidence of nonmelanoma skin cancers. An extension of this work demonstrated the safety and enhanced efficacy of using 50,000 and 75,000 nmol/day of vitamin A for 1 year in patients with sun-damaged skin.38

Organ transplant patients suffer from an increased incidence of premalignant skin lesions and from nonmelanoma skin cancers. The synthetic aromatic retinoid acitretin — Soriatane or all-irans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid) — is effective systemically as a chemopre-ventive agent for skin premalignant lesions and cancer, but only during treatment. Like fenretinide, discontinuation of acitretin treatment results in complete loss of chemopreventive effects, indicating need for lifetime therapy.39,40

The RAR ligands RA, isotretinoin, etretinate, and acitretin have been used to treat disorders in which malignant T cells accumulate in skin, known as cutaneous T-cell lymphomas.41 Depending on the retinoid used, the response rate with RAR agonists was as high as 85% and the complete response rate was as high as 33%. The RXR ligand bexarotene has been approved recently for clinical use for the same indication. Higher oral doses (650 mg/m2) provide response rates as high as 67% and complete responses as high as 54%.41-43 Lower toxicity compared to RAR ligands has been suggested as an anticipated benefit of bex-oretine, because bexoretine produces only "laboratory abnormalities," such as hypertriglyceridemia, hypercholesterolemia, hypothyroidism, and leukopenia, which may be addressed with other drugs without discontinuing retinoid therapy.41 In contrast, RAR ligands commonly produce side effects of dry skin, conjunctivitis, alopecia, headache, and bone changes. Not unexpectedly, the RAR ligands demonstrate vitamin A excess symptoms, whereas RXR ligands demonstrate consequences of activating nuclear receptors that heterodimerize with RXR, such as PPAR and LXR. Long-term studies should eventually determine the relative therapeutic indices of these two approaches.

Fenretinide represents one of the most promising cancer chemopreventive agents because of its activity in model systems, its lower toxicity compared to many other retinoids, and its tendency to show some tissue-specific uptake.

Disappointingly, in several Phase III clinical trials, fenretinide has not shown broad-based chemoprevention activity against cancer of the sites predicted as responders from studies in models, including breast, bladder, cervix, and head and neck. Two groups have concluded, however, that fenretinide may show an effect in reducing ovarian cancer, as long as treatment is continued, but not after, and possibly a reduction in second malignancies of the breast in premenopausal women, but not for second breast cancers in postmenopausal women.44-46 Currently, there is hope for fenretinide, but final evaluation must await the outcome of further clinical investigation.

Isotretinoin has been evaluated fairly extensively for its ability to suppress second primary tumors in patients with head and neck squamous cell carcinoma.47-49 High doses (50 to 100 mg/m2/day) reduced by nearly fivefold the rate of second primary tumor occurrence over a 55 month period. The impact of isotretinoin continued for 2 years beyond cessation of dosing. Unfortunately, the majority of patients suffered from conjunctivitis, skin toxicities, and cheilitis and required dose reduction.48 A trial to evaluate lower-dose use of isotretinoin (30 mg/day) for 3 years followed by another 4 years of appraisal in the absence of dosing reported no obvious anticancer effects.49 Consistent with other studies, which often reveal retinoid-specific results, etretinate did not reduce the incidence of second primary tumors.50 Treatment with retinyl palmitate for 2 years did not affect survival and second primary tumors formation in patients with head and neck cancer.51

Retinoids have been among the most widely tested agents for prevention of nonsmall cell lung cancer, reversal of premalignant lesions, and prevention of additional cancer in former lung cancer patients.52-54 No large-scale, reproducible, randomized clinical trial has shown positive results, i.e., no impact of retinoids, including isotretinoin, fenretinide, etretinate, retinol, or retinyl palmitate, has been observed with respect to any of these three outcomes. In the Physician's Health, CARET, and ATBC studies, P-carotene alone had no impact or, in conjunction with a-tocopherol or retinol, was harmful. These data seem to indicate total gloom, but recent work relating RAR to lung tissue changes suggests continued studies might be warranted.55 RAR, especially RARP2, has been proposed as a tumor suppressor gene, because it is lost in squamous cell carcinomas and ade-nocarcinomas, is epigenetically silenced by hypermethylation in the early stages of lung cancer, and is not expressed in tumor samples of the esophagus, prostate, breast, and lung.56 The effect of upregulating and activating RAR on the development of second primary lung cancers, however, seems related to whether the patients are current or former smokers. Only in former smokers was RAR upreg-ulation and activation (unmethylated form) protective, through inhibiting carcino-genesis and inducing apoptosis. In current smokers, activation of RAR may enhance carcinogenesis.

Bladder cancer clinical trials with isotretinoin had too much toxicity to continue, whereas a double-blind trial with etretinate showed a modest overall impact, and has supported a call for large-scale trials with retinoids in superficial bladder cancer.57

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