Earl G. Gross

Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.

OBJECTIVE To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING Seven dermatology clinics in the eastern United States. PATIENTS A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. INTERVENTIONS Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. RESULTS After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made

Treatment and prevention of basal cell carcinoma with oral isotretinoin

Twelve patients with multiple basal cell carcinomas resulting from varying causes were treated with high-dose oral isotretinoin (mean daily dosage: 3.1 mg/kg/day) for a mean of 8 months. Of the 270 tumors monitored in these patients, only 8% underwent complete clinical and histologic regression. All patients developed moderate to severe acute toxicities, leading five patients to withdraw from the study. Retinoid skeletal toxicity was identified in two patients who were examined after long-term therapy. Lower doses of isotretinoin (0.25 to 1.5 mg/kg/day) were ineffective for chemotherapy but demonstrated a chemopreventive effect in a subset of three patients who received these lower doses for 3 to 8 years. Two of these three patients have been observed after discontinuation of therapy. In one patient with a history of arsenic exposure, only one new tumor has appeared in a 27-month posttreatment observation period; in the other patient with the nevoid basal cell carcinoma syndrome, 29 new tumors have appeared within a 13-month period. This suggests that the need for long-term maintenance therapy with isotretinoin for chemoprevention of basal cell carcinoma may depend on the underlying cause of the skin cancers.

Vertebral abnormalities associated with synthetic retinoid use

Frequent symptoms of back and neck stiffness led to a radiographic investigation of the vertebral spine in patients receiving synthetic retinoids, isotretinoin and etretinate. X-ray examination of fifty patients with various skin disorders who received retinoids for at least 2 years were compared with seventy-two age- and sex-matched untreated patients. Differences in frequencies of defined abnormalities, which included anterior spinal ligament calcification and presence of osteophyte at two or more vertebral levels in the absence of joint space narrowing, were determined for treated and untreated patients. When the entire group of treated patients was compared with the entire group of those untreated, no statistically significant differences were observed. When only patients with basal cell nevus syndrome ( BCNS ) or basal cell carcinoma (BCC) who had never received retinoid were compared with those who received isotretinoin, the frequency of the defined abnormalities was significantly higher in the treated group (P less than 0.01). This study suggests that the ingestion of isotretinoin at mean total dose of 150,060 mg for an average of 2.9 years is associated with a statistically significant increase in developing an associated ossifying diathesis in patients with BCNS or BCC, when compared with matched, untreated controls.

Chemoprevention of basal cell carcinoma with isotretinoin

Three patients with multiple basal cell carcinomas, due either to excessive sunlight exposure, the nevoid basal cell carcinoma syndrome, or arsenical insecticide exposure, were treated with oral isotretinoin for 2 1/2 to 4 years. Although higher doses were used initially, approximately 1.5 mg/kg/day was used for long-term therapy in all three patients. Therapeutic effects on existing tumors varied between each patient, and only nine of sixty-five lesions underwent complete clinical regression. No tumors enlarged in two patients; a few tumors enlarged slightly in the third patient, particularly during the later courses of therapy when isotretinoin was given at lower dosage. No new lesions have been observed in any of these three patients. With these encouraging preliminary data, it now may be appropriate to perform larger trials for longer periods of time to determine the usefulness of isotretinoin in the chemoprevention of basal cell carcinoma in patients with multiple tumors.

Influence of topical and systemic retinoids on basal cell carcinoma cell membranes.

Although much recent work suggests that retinoids can prevent the development of epithelial cancers, their mechanism of action remains unknown. Since malignancy has been associated with alterations in gap junctions, desmosomes, microfilaments, and hemidesmosomes, the authors examined freezefracture replicas and thin sections of cell membranes of: (1) 11 basal cell cancers (BCC) treated twice daily for two weeks with topical 1.0% retinoic acid (RA); (2) 21 BCC treated for 2 to 17 weeks with oral 13‐cis retinoic acid (CRA) (1.0‐8.0 mg/kg/day); and (3) 17 BCC prior to retinoid treatment and/or after applications of vehicle alone. Both thin sections and replicas were examined and photographed in a single‐blind fashion, and the density and size distribution of gap junctions and desmosomes were computed planimetrically. Topical RA treatment induced a two‐fold increase in gap junction density (P ± 0.025) over controls. In contrast, RA produced a concurrent =35% decrease in desmosome density. Systemic CRA did not significantly alter either gap junction or desmosome density or size. Finally, neither RA nor CRA treatment appeared to influence hemidesmosome or microfilament populations. Structural changes in both treatment groups did not correlate with either tumor regression or inflammation. Topical and systemic retinoids may exert their antineoplastic activity by different cellular mechanisms.