Trends in the incidence of nonmelanoma skin cancers in southeastern Arizona, 1985-1996.

This report describes trends in the incidence of various nonmelanoma skin cancers in a region of high ultraviolet exposure. The Southeastern Arizona Skin Cancer Registry routinely identified cases of skin cancer between 1985 and 1996 through pathology logs and reports from dermatology offices and laboratories in 3 Arizona counties. The incidence rates for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) for non-Hispanic whites were 3 to 6 times higher than the incidence rates from more northern regions. The rates for non-Hispanic whites were approximately 11 times greater than rates for Hispanics. Furthermore, there was no constant increase in the incidence of nonmelanoma skin cancers. The incidence of SCC, in particular, demonstrated a plateau or even a modest decline between 1985 and 1996. Thus the incidence rates of both SCC and BCC in Arizona, although among the highest in the world, do not appear to be increasing as rapidly as predicted elsewhere.

Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults.

Risk factors for non-melanoma skin cancer among populations with evidence of precursor damage are not well described. We examined and compared risk factors associated with the development of cutaneous basal-cell (BCC) or squamous-cell (SCC) carcinoma among a group of 918 adults with significant sun damage (> or = 10 clinically assessable actinic keratoses) but no prior history of skin cancer. These adults were participants in a 5-year skin chemoprevention trial between 1985 and 1992, who had been randomized to the placebo group and followed for occurrence of skin cancer. During the study, a total of 129 first SCC and 164 first BCC lesions were diagnosed. The overall BCC and SCC incidence rates for this group of men and women, mean age 61 years, were 4,106 and 3,198 per 100,000 person-years, respectively. Different constitutional and exposure factors were independently associated with BCC compared to SCC. Only increased age independently predicted BCC occurrence among this population. In contrast, older age along with male gender, natural red hair color and adult residence in Arizona for 10 or more years independently predicted SCC occurrence. The substantial incidence of skin cancer found among this population confirms the need for active dermatological monitoring among individuals with multiple visible actinic lesions.

Predictors of inactivation and reasons for participant inactivation during a skin cancer chemoprevention study.

Maintaining good compliance is a major challenge in long-term cancer chemoprevention trials. Minimizing the number of inactive participants during a trial is an important factor in maximizing compliance. Identifying reasons for and predictors of inactivation is the first step in being able to reduce participant inactivation. In this skin cancer chemoprevention trial, the 2,297 participants were randomized to receive 25,000 IU of retinol daily or a placebo. Median follow-up time was 3.8 years. The reason for inactivation was determined for each participant who stopped taking the study capsules. Six hundred and seventy-seven (29.7%) participants became inactive during the 5-year study. There was no significant difference between the number of participants inactivating by treatment group or sex. The most common reasons for inactivation were illness of subject, spouse, or a close relative (18.6%) and experience of a clinical symptom consistent with vitamin A ingestion (17.1%). Participants in the vitamin A group (10.1%) more frequently cited symptoms coded as "not consistent with vitamin A" as the reason for inactivation compared with those in the placebo group [5.4% (P < 0.05)]. The inactivation rate was highest in the first month of the trial and declined thereafter. A low education level (hazard ratio, 1.59) and unmarried status (hazard ratio, 1.29) were the only significant predictors of inactivation. These findings may be useful in developing targeted strategies to decrease inactivation and thereby increase compliance in future chemoprevention trials. However, these findings need to be confirmed because published research in this area is very limited.

Effects of long-term intake of retinol on selected clinical and laboratory indexes.

BACKGROUND: Chemopreventive agents developed to be used in a moderate-risk but otherwise healthy population need to be both efficacious and to have minimal adverse effects. OBJECTIVE: The objective of this study was to evaluate the adverse effects of long-term retinol intake in a skin cancer chemoprevention trial in a large population at moderate risk for skin cancer. DESIGN: Participants (n = 2297) were randomly assigned to receive retinol [7576 retinol equivalents (RE), or 25000 IU] or a placebo daily. The adverse effects of retinol intake were studied by monitoring 14 clinical symptoms and laboratory indexes. The median follow-up time was 3.8 y. RESULTS: No adverse effects concerning the 14 symptoms were observed. Significant differences in alkaline phosphatase (P < 0.0001), triacylglycerol (P < 0.0001), cholesterol (P = 0.04), and HDL (P = 0.01) were observed over time between the 2 groups. After 49 mo of follow-up, alkaline phosphatase was 7% higher, triacylglycerol was 11% higher, cholesterol was 3% higher, and HDL was 1% lower in the retinol group than in the placebo group. CONCLUSIONS: Because a 1% increase in cholesterol concentrations has been reported to be associated with a 2% increase in coronary artery disease risk, long-term ingestion of 7576 RE vitamin A/d should be considered with caution. However, further studies are needed to confirm this finding.

Prognostic factors for survival of patients treated systemically for disseminated melanoma.

PURPOSE: The current American Joint Commission on Cancer (AJCC) staging system distinguishes between soft tissue and visceral metastases in advanced (stage IV) melanoma. We sought to verify these staging criteria and to identify prognostic variables that could be used to evaluate the impact of systemic therapy on long-term survival during the prior decade. PATIENTS AND METHODS: We conducted a retrospective study of patients with advanced cutaneous melanoma enrolled in clinical trials between 1979 and 1989 at The University of Texas M.D. Anderson Cancer Center. Pretreatment age, sex, number of organs with metastases, serum levels of lactate dehydrogenase (LDH) and albumin, and period of enrollment were analyzed using a Cox proportional hazards model of survival. RESULTS: In univariate and multivariate analyses that involved 318 stage IV patients, normal serum levels of LDH and albumin, soft tissue and/or single visceral organ metastases (especially lung), female sex, and enrollment late in the decade were independent positive predictors for survival. In multivariate analyses, the current AJCC criteria did not significantly predict outcome. Systemic treatment response did not bias these results, and only 4% of patients had a complete response. Patients who lived more than 2 years (11%) had a mix of favorable prognostic characteristics and a high frequency of systemic or surgically induced complete response. CONCLUSION: This study supports the use of stratification parameters that reflect the favorable prognostic impact of soft tissue or single visceral organ metastases and normal serum levels of LDH and albumin at time of enrollment in advanced melanoma trials. Improved survival over the prior decade probably reflects advances in diagnostic and palliative interventions.

Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma.

Recently, we reported that LGD1069, a high-affinity ligand for the retinoid X receptors (RXRs), was shown to have an efficacy equivalent to that of tamoxifen (TAM) as a chemopreventive agent in the N-nitroso-N-methylurea-induced rat mammary carcinoma model. Furthermore, LGD1069 was very well tolerated during 13 weeks of chronic therapy with no classic signs of "retinoid-associated" toxicities. Due to the high efficacy and benign profile of this RXR agonist as a suppressor of carcinogenesis, we examined its role as a therapeutic agent on established mammary carcinomas. In the rat mammary carcinoma model, N-nitroso-N-methylurea was used to induce tumors, and the tumors were allowed to grow to an established size prior to initiation of treatment. LGD1069-treated animals showed complete regression in 72% of treated tumors and had a reduced tumor load compared to control. In addition, the combination of LGD1069 and TAM showed increased efficacy over either agent alone. Histopathological analysis showed a reduction of LGD1069-treated tumor malignancy, an increase in differentiation, and a sharp decrease in cellular proliferation compared to vehicle-treated control tumors. These data demonstrate that the RXR-selective ligand LGD1069 is a highly efficacious therapeutic agent for mammary carcinoma and enhances the activity of TAM.

Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group.

We conducted a randomized, double-blind, controlled trial to examine the efficacy of retinol supplementation on the incidence of first new nonmelanoma skin cancer in moderate-risk subjects. A total of 2297 free-living subjects were enrolled; subjects resided in Arizona (median age, 63 years) and had a history of more than 10 actinic keratoses and at most 2 squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) skin cancers. Subjects were randomly assigned to receive oral retinol (25,000 IU) or placebo supplementation daily for up to 5 years. The primary end points for the trial were time to first new SCC or BCC. During a median follow-up time of 3.8 years, we found that 526 subjects had a first new skin cancer. Comparing retinol-supplemented subjects with placebo-supplemented subjects showed a hazard ratio for first new SCC of 0.74 (95% confidence interval, 0.56-0.99; P = 0.04). The hazard ratio of first new BCC for the retinol-supplemented subjects compared with those receiving placebo was 1.06 (95% confidence interval, 0.86-1.32; P = 0.36). Potentially adverse symptoms that were judged to be associated with retinol were rare (approximately 1% higher in the retinol group than in the control group). Therefore, we concluded that daily supplementation with 25,000 IU of retinol was effective in preventing SCC, although it did not prevent BCC.

Trial of retinol and isotretinoin in skin cancer prevention: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group.

The objective of this study was to examine the effect of retinol and isotretinoin on the incidence of nonmelanoma skin cancer in high-risk subjects. A total of 525 participants with a history of at least four basal cell carcinomas (BCCs) and/or cutaneous squamous cell carcinomas (SCCs) were entered into a randomized, double-blind, placebo-controlled trial, performed in free-standing study clinics. Participants were randomly assigned to receive oral retinol (25,000 units), isotretinoin (5-10 mg), or placebo supplementation daily for 3 years. The time to first new occurrence of BCC or cutaneous SCC was used as the outcome measure. During the study period, 319 BCCs and 125 cutaneous SCCs were diagnosed clinically and pathologically. There were no differences between those who received retinol, isotretinoin, or the placebo, with regard to the time to first occurrence or to the total number of tumors noted. No beneficial effects were noted with regard to the prevention of nonmelanoma skin cancer with either retinol or isotretinoin.

Retinoids in prevention of skin cancer.

Two chemoprevention randomized clinical trials were begun in 1984 to evaluate retinoids in the prevention of skin cancers. Moderate risk subjects with a history of at least 10 actinic keratoses and at most two prior skin cancers were enrolled in the SKICAP-AK trial and randomized to 25,000 IU retinol or placebo daily for 5 years. High risk subjects with a history of at least four prior skin cancers were enrolled in the SKICAP-S/B trial and randomized to receive 25,000 IU retinol, 5-10 mg isotretinoin or placebo daily for 3 years. Data from the SKICAP-AK trial indicate that retinol reduces incidence of first new squamous cell skin cancers but had no effect on the incidence of first new basal cell skin cancer. The effect of retinoids had no significant benefit on squamous or basal cell skin cancers in the high risk subjects on the SKICAP-S/B trial, although intervention duration was less than planned. Daily retinol was effective in preventing squamous cell cancers in moderate risk subjects.

Attitudes and practices of primary care physicians for prostate cancer screening.

Prostate cancer screening with digital rectal examination (DRE) and prostate-specific antigen (PSA) is recommended by several professional organizations. Our objective was to assess the prostate cancer screening practices and attitudes reported by primary care physicians. We randomly surveyed 454 Arizona primary care physicians, subsequently excluding 124 ineligible subjects. Overall, 141 of 329 eligible physicians completed the survey (42.9%). Survey data included physician demographics, practice characteristics, screening and follow-up strategies, and attitudes toward screening. One hundred thirty-one physicians (93%) reported screening asymptomatic men with DRE or PSA. Respondents generally agreed that screening tests were accurate and that early detection was beneficial. Screening began at an average patient age of 45 years, though 7.8% of respondents began screening men younger than 40 years and 7.0% began screening men older than 50 years. PSA levels ranging from 3.9 to 40 ng/mL were considered abnormal, and 11.6% of respondents used a cutpoint higher than 10 ng/mL. Primary care physicians report a high rate of screening for prostate cancer and consider PSA and DRE accurate and useful tests. Screening practices, however, varied considerably between physicians. The screening of younger men reported by practitioners would tend to increase the rate of false-positive tests, while using a high cutpoint for PSA and delaying screening beyond age 50 years would decrease the chance for early detection. These screening practices may increase health care costs without necessarily leading to improved health outcomes. Medical Subject Headings (MeSH): prostatic neoplasms, prostate-specific antigen, primary health care, screening.

Design and analysis of the ESVEM Trial.

Inadequate understanding of the design and statistical approach of a clinical trial and the failure to recognize subjective aspects of the analysis often result in misinterpretation of trial results. This is exacerbated by the push to shorten publications and the wish for a simple message that summarizes the outcome of the trial. The purpose of this review is to critically review the design and statistical analyses of the results, to evaluate the assumptions underlying the statistical tests, and to examine the results of exploratory analysis on the interpretation of major findings of the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial. The trial was unusual because its primary objective was to compare testing methods instead of treatments. This necessitated using a subset of the original randomized groups for sensible analysis of the clinical question. Nevertheless, the two groups appeared to be well balanced. The absence of a difference in outcome could be verified by several analyses. In addition, confidence intervals were narrow, indicating the high precision and reliability of the findings. However, the comparison of antiarrhythmic drugs is problematic because the trial was not designed to address this issue. There were differences in the distribution of clinical characteristics between the groups who received different antiarrhythmic drugs. Nevertheless, using both univariate analyses and a variety of adjustments for important prognostic variables, treatment with sotalol appeared to be a significant predictor of reduced arrhythmia recurrence, and sotalol was consistently associated with a trend for nearly a 50% reduction in sudden death and all-cause mortality as compared with the other drugs administered in the trial. In conclusion, the ESVEM trial raises a number of interesting and instructive issues about clinical trial design and analysis.

The Myocarditis Treatment Trial: design, methods and patients enrollment.

The Myocarditis Treatment Trial was a multicentre clinical trial conducted to determine the efficacy of immunosuppressive therapy for treatment of biopsy-documented myocarditis, and to improve understanding of the immunological mechanisms in the development of myocarditis. Thirty-one centres screened 2305 patients with unexplained heart failure, and 2233 patients underwent an endomyocardial biopsy which provided adequate tissue for diagnosis. Those with a positive biopsy and a left ventricular ejection fraction (LVEF) less than 45% were randomly assigned to receive immunosuppressive therapy plus conventional drug therapy for congestive heart failure (66 patients) or conventional therapy only (45 patients) for 24 weeks. For 28 additional weeks all patients received conventional therapy only. In addition to diagnostic and clinical data, serum and myocardial tissue for immunological marker analysis and histopathologic evaluation were collected at baseline and at 12, 28 and 52 weeks after randomization. The primary analysis of efficacy was designed as a comparison of the mean increase in LVEF at week 28 between treatment limbs. Secondary objectives were to evaluate survival differences, and changes in the histopathology of the disease and immunological markers. Randomized patients were relatively young (mean age, 42.0 years +/- 13.8 standard deviation (sd) and entered the Trial with a mean LVEF percent of 24.3 +/- 10.1 sd) and mean exercise treadmill duration of 9.4 (+/- 5.3 sd) minutes. The incidence of biopsy-documented myocarditis was low (9.6%). The analyses of outcome and immunological data are reported elsewhere.

Design and recruitment for retinoid skin cancer prevention (SKICAP) trials. The Southwest Skin Cancer Prevention Study Group.

The retinoid skin cancer prevention (SKICAP) trials are a set of double-blind, randomized, placebo-controlled clinical trials. The SKICAP-actinic keratoses (AK) trial tests the hypothesis that daily supplementation of retinol (25,000 IU) for 5 years reduces the incidence of skin cancers in high-risk individuals, those with a history of greater than ten clinically or pathologically diagnosed AK and, at most, one prior pathologically confirmed cutaneous squamous cell carcinoma (SCC) or basal cell carcinoma (BCC). The SKICAP-SCC/BCC (S/B) trial tests the hypothesis that daily supplementation of retinol (25,000 IU) or 13-cis-retinoic acid (5 or 10 mg) for 3 years reduces skin cancer incidence in very high-risk individuals, those with a history of at least four pathologically confirmed SCCs or BCCs. Between 1984 and 1988, 2800 participants were enrolled at two clinics on the SKICAP-AK trial; and between 1985 and 1990, a total of 719 participants were enrolled at four clinics on the SKICAP-S/B trial. The initial recruitment strategy was referral by dermatologists, but low accrual necessitated the use of other strategies to achieve enrollment goals, which included involving additional clinics and using paid trial-specific advertisements in print and electronic media. Thirteen % of the SKICAP-AK participants and 36% of the SKICAP-S/B participants were enrolled through dermatologist referral, whereas paid advertisements resulted in enrollment of 87% of SKICAP-AK and 43% of SKICAP-S/B participants. A population-based skin cancer registry was used to identify and enroll the remaining 21% of the SKICAP-S/B participants.(ABSTRACT TRUNCATED AT 250 WORDS)

A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators.

BACKGROUND: Myocarditis is a serious disorder, and treatment options are limited. This trial was designed to determine whether immunosuppressive therapy improves left ventricular function in patients with myocarditis and to examine measures of the immune response as predictors of the severity and outcome of disease. METHODS: We randomly assigned 111 patients with a histopathological diagnosis of myocarditis and a left ventricular ejection fraction of less than 0.45 to receive conventional therapy alone or combined with a 24-week regimen of immunosuppressive therapy. Immunosuppressive therapy consisted of prednisone with either cyclosporine or azathioprine. The primary outcome measure was a change in the left ventricular ejection fraction at 28 weeks. RESULTS: In the group as a whole, the mean (+/- SE) left ventricular ejection fraction improved from 0.25 +/- 0.01 at base line to 0.34 +/- 0.02 at 28 weeks (P < 0.001). The mean change in the left ventricular ejection fraction at 28 weeks did not differ significantly between the group of patients who received immunosuppressive therapy (a gain of 0.10; 95 percent confidence interval, 0.07 to 0.12) and the control group (a gain of 0.07; 95 percent confidence interval, 0.03 to 0.12). A higher left ventricular ejection fraction at base line, less intensive conventional drug therapy at base line, and a shorter duration of disease, but not the treatment assignment, were positive independent predictors of the left ventricular ejection fraction at week 28. There was no significant difference in survival between the two groups (P = 0.96). The mortality rate for the entire group was 20 percent at 1 year and 56 percent at 4.3 years. Features suggesting an effective inflammatory response were associated with less severe initial disease. CONCLUSIONS: Our results do not support routine treatment of myocarditis with immunosuppressive drugs. Ventricular function improved regardless of whether patients received immunosuppressive therapy, but long-term mortality was high. Patients with a vigorous inflammatory response had less severe disease.

Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial.

BACKGROUND: Retinoids enhance differentiation of most epithelial tissues. Epidemiologic studies have shown an inverse relationship between dietary intake or serum levels of vitamin A and the development of cervical dysplasia and/or cervical cancer. Pilot and phase I investigations demonstrated the feasibility of the local delivery of all-trans-retinoic acid (RA) to the cervix using a collagen sponge insert and cervical cap. A phase II trial produced a clinical complete response rate of 50%. PURPOSE: This randomized phase III trial was designed to determine whether topically applied RA reversed moderate cervical intraepithelial neoplasia (CIN) II or severe CIN. METHODS: Analyses were based on 301 women with CIN (moderate dysplasia, 151 women; severe dysplasia, 150 women), evaluated by serial colposcopy, Papanicolaou cytology, and cervical biopsy. Cervical caps with sponges containing either 1.0 mL of 0.372% beta-trans-RA or a placebo were inserted daily for 4 days when women entered the trial, and for 2 days at months 3 and 6. Patients receiving treatment and those receiving placebo were similar with respect to age, ethnicity, birth-control methods, histologic features of the endocervical biopsy specimen and koilocytotic atypia, and percentage of involvement of the cervix at study. Treatment effects were compared using Fisher's exact test and logistic regression methods. Side effects were recorded, and differences were compared using Fisher's exact test. RESULTS: RA increased the complete histologic regression rate of CIN II from 27% in the placebo group to 43% in the retinoic acid treatment group (P = .041). No treatment difference between the two arms was evident in the severe dysplasia group. More vaginal and vulvar side effects were seen in the patients receiving RA, but these effects were mild and reversible. CONCLUSIONS: A short course of locally applied RA can reverse CIN II, but not more advanced dysplasia, with acceptable local side effects. IMPLICATIONS: A derivative of vitamin A can reverse or suppress an epithelial preneoplasia, lending further support to the notion that chemoprevention of human cancer is feasible.

Comparison of two physical activity questionnaires, with a diary, for assessing physical activity in an elderly population.

Measurement of physical activity in epidemiological studies is usually achieved by means of a questionnaire. Little work has been done to determine which questionnaire format has greater validity in an elderly population. In this study of elderly subjects, physical activity as reported in two self-administered questionnaires (A and B), which differed in format and length, were compared to activity reported in a 4 day diary. As compared with the diary, moderate/heavy activity was more accurately reported in Questionnaire A (mean difference 5 min), the longer more detailed questionnaire, than B (mean difference 170 min). Light activity was under reported in Questionnaire A (mean difference 68 min) and over reported in B (mean difference 88 min) as compared with the diary. In contrast, time spent sitting was more accurately reported in Questionnaire B (mean difference 40 min) than in A (mean difference 230 min) as compared with the diary. The longer more detailed questionnaire was the more accurate instrument for assessing moderate/heavy activity in this elderly population. The shorter questionnaire was more accurate for assessing time spent sitting.

Study of strategies for the recruitment of elders including the use of community volunteers.

OBJECTIVES: The primary objective was to compare study participation when first contact was made by telephone versus an unscheduled visit to the household. The secondary objective was to compare study participation when three differing modes of questionnaire presentation were used. DESIGN: The residents of 300 randomly selected households were contacted by community volunteers and asked to participate in a study of the etiology of cancer and other chronic diseases. Two methods of first contact were used, a telephone call to schedule a home visit and an unscheduled visit to the household. Three modes of questionnaire presentation were used. PARTICIPANTS: Residents of a retirement community in Arizona who were aged 50 or over. MAIN OUTCOME MEASURES: Agreement to participate, defined as acceptance of and agreement to complete the study questionnaires. Participation in the study, defined as acceptance and completion of the study questionnaires. RESULTS: No difference was observed in participation when first contact was made by telephone (46%) as compared with an unscheduled visit to the household (45%) (P = 0.83). Similarly, no difference in the participation was observed between three modes of presentation of the questionnaire to the householders (P = 0.13). Agreement to participate was, however, significantly higher when first contact was made by visiting the home (81% vs 55%) (P less than 0.001). CONCLUSIONS: Neither the strategy used for first contact nor mode of questionnaire presentation affected participation.