A Grant-Based Experiment to Train Clinical Investigators: The AACR/ASCO Methods in Clinical Cancer Research Workshop.

To address the need for clinical investigators in oncology, American Association for Cancer Research (AACR) and American Society for Clinical Oncology (ASCO) established the Methods in Clinical Cancer Research Workshop (MCCRW). The workshop's objectives were to: (i) provide training in the methods, design, and conduct of clinical trials; (ii) ensure that clinical trials met federal and international ethical guidelines; (iii) evaluate the effectiveness of the workshop; and (iv) create networking opportunities for young investigators with mentoring senior faculty. Educational methods included: (i) didactic lectures, (ii) Small Group Discussion Sessions, (iii) Protocol Development Groups, and (iv) one-on-one mentoring. Learning focused on the development of an Institutional Review Board (IRB)-ready protocol, which was submitted on the last day of the workshop. Evaluation methods included: (i) pre- and postworkshop tests, (ii) students' workshop evaluations, (iii) faculty's ratings of protocol development, (iv) students' productivity in clinical research after the workshop, and (v) an independent assessment of the workshop. From 1996 to 2014, 1,932 students from diverse backgrounds attended the workshop. There was a significant improvement in the students' level of knowledge from the pre- to the postworkshop exams (P < 0.001). Across the classes, student evaluations were very favorable. At the end of the workshop, faculty rated 92% to 100% of the students' protocols as ready for IRB submission. Intermediate and long-term follow-ups indicated that more than 92% of students were actively involved in patient-related research, and 66% had implemented five or more protocols. This NCI-sponsored MCCRW has had a major impact on the training of clinicians in their ability to design and implement clinical trials in cancer research.

Racial disparities in cancer survival among randomized clinical trials patients of the Southwest Oncology Group.

BACKGROUND: Racial disparities in cancer outcomes have been observed in several malignancies. However, it is unclear if survival differences persist after adjusting for clinical, demographic, and treatment variables. Our objective was to determine whether racial disparities in survival exist among patients enrolled in consecutive trials conducted by the Southwest Oncology Group (SWOG). METHODS: We identified 19 457 adult cancer patients (6676 with breast, 2699 with lung, 1244 with colon, 1429 with ovarian, and 1843 with prostate cancers; 1291 with lymphoma; 2067 with leukemia; and 2208 with multiple myeloma) who were treated on 35 SWOG randomized phase III clinical trials from October 1, 1974, through November 29, 2001. Patients were grouped according to studies of diseases with similar histology and stage. Cox regression was used to evaluate the association between race and overall survival within each disease site grouping, controlling for available prognostic factors plus education and income, which are surrogates for socioeconomic status. Median and ten-year overall survival estimates were derived by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: Of 19 457 patients registered, 2308 (11.9%, range = 3.9%-21.6%) were African American. After adjustment for prognostic factors, African American race was associated with increased mortality in patients with early-stage premenopausal breast cancer (hazard ratio [HR] for death = 1.41, 95% confidence interval [CI] = 1.10 to 1.82; P = .007), early-stage postmenopausal breast cancer (HR for death = 1.49, 95% CI = 1.28 to 1.73; P < .001), advanced-stage ovarian cancer (HR for death = 1.61, 95% CI = 1.18 to 2.18; P = .002), and advanced-stage prostate cancer (HR for death = 1.21, 95% CI = 1.08 to 1.37; P = .001). No statistically significant association between race and survival for lung cancer, colon cancer, lymphoma, leukemia, or myeloma was observed. Additional adjustments for socioeconomic status did not substantially change these observations. Ten-year (and median) overall survival rates for African American vs all other patients were 68% (not reached) vs 77% (not reached), respectively, for early-stage, premenopausal breast cancer; 52% (10.2 years) vs 62% (13.5 years) for early-stage, postmenopausal breast cancer; 13% (1.3 years) vs 17% (2.3 years) for advanced ovarian cancer; and 6% (2.2 years) vs 9% (2.7 years) for advanced prostate cancer. CONCLUSIONS: African American patients with sex-specific cancers had worse survival than white patients, despite enrollment on phase III SWOG trials with uniform stage, treatment, and follow-up.

Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

CONTEXT: Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer. OBJECTIVE: To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer. INTERVENTIONS: Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years. MAIN OUTCOME MEASURES: Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer. RESULTS: As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group. CONCLUSION: Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00006392.

The Southwest Oncology Group: progress in cancer research.

Beginning in the mid 1950s and continuing through today, the Southwest Oncology Group (SWOG) has been a leader in cancer clinical research in adults. SWOG has contributed to the field of cancer research through both the logistical development of new systems, technologies, statistical methodologies, and training, and through specific tangible contributions to science, addressing the standard of care for almost every adult malignancy. This review summarizes the highlights of SWOG contributions over the years, including contributions in medical oncology, staging, radiation oncology, surgery, and other cancer-related disciplines.

The performance of prostate specific antigen for predicting prostate cancer is maintained after a prior negative prostate biopsy.

PURPOSE: It has been suggested that prostate specific antigen has no predictive value for prostate cancer after a first negative biopsy has been performed. We compared the performance operating characteristics of prostate specific antigen for prostate cancer between a first and subsequent prostate biopsy in a group of men with complete verification of cancer status. MATERIALS AND METHODS: From the 18,882 participants in the Prostate Cancer Prevention Trial we examined men in the placebo group who had only a first biopsy or a first and second prostate biopsy with a prostate specific antigen and digital rectal examination within 1 year before each biopsy. The receiver operating characteristic curve was estimated for prostate specific antigen for detection of prostate cancer on the first biopsy compared to the second, and the C-statistics were compared. RESULTS: Of this group 5,608 men had a first biopsy and 687 of those with a negative first biopsy underwent a second biopsy. The C-statistic was 0.650 (95% CI 0.632, 0.668) for the first biopsy and 0.664 (95% CI 0.607, 0.721) for the second biopsy. The C-statistic for the second biopsy was statistically significantly greater than 0.5 (p <0.001) and overlapped with that from the first biopsy. CONCLUSIONS: Prostate specific antigen does not lose predictive value for the detection of prostate cancer even after a first biopsy shows no evidence of cancer, and its performance characteristics are only slightly decreased.

Does the level of prostate cancer risk affect cancer prevention with finasteride?

OBJECTIVES: Finasteride reduced the risk of prostate cancer by 24.8% in the Prostate Cancer Prevention Trial (PCPT). Whether this represents treatment or prevention and who is most likely to benefit are unknown. We sought to clarify these issues by this investigation. METHODS: We fit a logistic regression model to men in the placebo group of the PCPT using risk factors for prostate cancer at entry to predict prostate cancer during the subsequent 7 years of study. Men in the two treatment groups were categorized into quintiles of risk of prostate cancer based on the predictive logistic model. A second model was fit evaluating finasteride's effect on prostate cancer for each subgroup defined by quartiles of baseline prostate-specific antigen (PSA) . The magnitude of the prevention effect of finasteride on prostate cancer was then evaluated across risk and PSA strata. RESULTS: Finasteride significantly reduced prostate cancer risk for all risk quintiles. For quintiles 1 through 5, odds ratios were 0.72, 0.52, 0.64, 0.66, and 0.71, respectively (all P < or = 0.05). For quartiles of risk of entry PSA (less than 0.7 ng/mL, 0.7 to 1.1 ng/mL, 1.1 to 1.7 ng/mL, and 1.8 to 3.0 ng/mL), odds ratios increased (smaller treatment effect) as PSA increased: 0.60, 0.62, 0.66, and 0.69, respectively, but remained significant for all strata (each P < 0.001). CONCLUSIONS: Finasteride significantly reduced prostate cancer risk regardless of the level of this risk, estimated either by multivariable risk or by PSA stratum; this suggests that finasteride exerts both treatment and preventive effects. All men undergoing PSA screening should be informed of the potential for finasteride to reduce their risk of prostate cancer.

Pathologic characteristics of cancers detected in The Prostate Cancer Prevention Trial: implications for prostate cancer detection and chemoprevention.

The Prostate Cancer Prevention Trial (PCPT) showed a risk of prostate cancer at prostate-specific antigen (PSA) <4.0 ng/mL and that prostate cancer risk is reduced by finasteride. A major concern about early detection by PSA and prevention by finasteride is that they may involve biologically inconsequential tumors. We reviewed the pathologic characteristics of prostate biopsies from men in the placebo and finasteride groups of the PCPT. We examined tumor pathology characteristics stratified by level of PSA for men in the placebo group who underwent radical prostatectomy. Seventy-five percent of all cancers and 62% of Gleason score or=7) tumors for the same PSA strata were 15.6%, 37.9%, 49.1%, and 52.4%, respectively. These data highlight the dilemma of PSA when used for screening: Lower cutoff levels increase detection of insignificant disease, but cure is more likely, whereas higher cutoff levels make detection of significant cancer more likely, but cure is less likely. Therefore, the effectiveness of finasteride in preventing prostate cancer, including Gleason score

Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach.

Finasteride taken for 7 years in the Prostate Cancer Prevention Trial (PCPT) reduced the risk of prostate cancer by 25%, but with an apparent increased risk of high-grade disease. Subsequent analyses found that finasteride biases toward improved prostate cancer detection and accuracy in prostate cancer grading at biopsy. In our first analysis of the present study, we accounted for these biases in estimating the effect of finasteride on the risk of overall and high-grade prostate cancer. This analysis used PCPT data that included 3-month longer collection of endpoints than in the original report with observed prostate cancer rates of 22.9% (4.8% with high grade; placebo) versus 16.6% (5.8% with high grade; finasteride). Based on these updated results, the bias-adjusted prostate cancer rates are estimated to be 21.1% (4.2% high grade; placebo) and 14.7% (4.8% high grade; finasteride), a 30% risk reduction in prostate cancer [relative risk (RR), 0.70; 95% confidence interval (95% CI), 0.64-0.76; P < 0.0001] and a nonsignificant 14% increase in high-grade cancer (RR, 1.14; 95% CI, 0.96-1.35; P = 0.12) with finasteride. We then estimated rates of high-grade prostate cancer based on an analysis that incorporated grading information from radical prostatectomies in 500 subjects diagnosed with cancer. The resulting estimates were high-grade cancer rates of 8.2% (placebo) versus 6.0% (finasteride), a 27% risk reduction (RR, 0.73; 95% CI, 0.56-0.96; P = 0.02) with finasteride. Our third analysis examined the impact of biopsy sensitivity on the relative risk of high-grade prostate cancer and found that differential sensitivity of biopsy between the treatment arms can have a significant impact on risk ratio estimates. These collective results suggest that the observed, unadjusted higher risk of high-grade disease with finasteride seems to have been due to facilitated diagnosis resulting primarily from increased biopsy sensitivity with finasteride. Therefore, men undergoing regular prostate cancer screening or who express an interest in cancer prevention should be informed of the opportunity to take finasteride for preventing prostate cancer.

Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial.

BACKGROUND: The Prostate Cancer Prevention Trial (PCPT) reported a decreased incidence of prostate cancer overall but an increase in the incidence of high-grade prostate cancer with finasteride compared with placebo. We assessed whether the increased high-grade prostate cancer associated with finasteride in the PCPT was due to finasteride's potential effects on tumor morphology or prostate size. METHODS: Prostate biopsies with Gleason score 8-10 (n = 90, finasteride; n = 52, placebo) were examined histologically for hormonal effects, and those with Gleason score 7-10 (n = 282, finasteride; n = 244, placebo) were examined for pathologic surrogates of disease extent. Prostate volumes were measured at biopsy. Samples from radical prostatectomies (n = 222, finasteride; n = 306, placebo) were examined for tumor grade and extent, and, where possible, grades at biopsy and prostatectomy were compared between the groups. Logistic regression was used to analyze differences between treatment groups with respect to pathologic criteria. All statistical tests were two-sided. RESULTS: Degenerative hormonal changes in high-grade biopsies were equivalent between the finasteride and placebo groups, but prostate volumes were lower in the finasteride group (median = 25.1 versus 34.4 cm3, P<.001). Pathologic surrogates for tumor extent were lower with finasteride than with placebo, including mean percentage of positive cores (34% versus 38%, P = .016), mean tumor linear extent (greatest [4.4 versus 4.8 mm, P = .19] and aggregate [7.6 versus 9.2 mm, P = .13]), bilaterality (22.8% versus 30.6%, P = .046), and perineural invasion (14.2% versus 20.3%, P = .07). Among patients who had prostatectomy, the finasteride-associated increase in high-grade disease (Gleason score > or = 7) at biopsy (42.7% finasteride versus 25.4% placebo, P<.001) was diminished at prostatectomy (46.4% finasteride versus 38.6% placebo, P = .10). Biopsy identified a greater proportion of patients with high-grade disease present at prostatectomy in the finasteride group than in the placebo group (69.7% versus 50.5%, P = .01). The rate of upgrading (from low-grade cancer at biopsy to high-grade cancer at prostatectomy) and pathologic stage at prostatectomy were similar in both groups. CONCLUSIONS: Effects of finasteride on prostate volume and selective inhibition of low-grade cancer, rather than effects on tumor morphology, may have contributed to the increase in high-grade cancers with finasteride in the PCPT. Although induction of high-grade cancer cannot be excluded, the results suggest that high-grade cancer was detected earlier and was less extensive in the finasteride group than in the placebo group.

Prediction of prostate cancer for patients receiving finasteride: results from the Prostate Cancer Prevention Trial.

PURPOSE: Using data from men in the finasteride group of the Prostate Cancer Prevention Trial (PCPT), we evaluated the impact of prostate-specific antigen (PSA) and other risk factors on the risk of prostate cancer. METHODS: Four thousand four hundred forty men in the finasteride group of the PCPT underwent prostate biopsy, had at least one PSA and a digital rectal exam (DRE) during the year before biopsy, had at least two PSA values from the 3 years before biopsy, and were on finasteride at the time of PSA evaluation. Logistic regression was conducted using the variables age, race, family history of prostate cancer, PSA, PSA velocity, and DRE adjusting for history of prior prostate biopsy. RESULTS: Six hundred forty-nine (14.6%) of 4,440 men were diagnosed with prostate cancer; 250 had Gleason 7 or higher cancer. Factors associated with an increased risk of prostate cancer included high PSA value and a rising PSA (24.9% risk for PSA value of 1.0 ng/mL and 24.8% risk for a rising PSA), family history of prostate cancer, abnormal DRE result, African American race, and older age. Factors associated with an increased risk of Gleason 7 or higher grade prostate cancer included PSA, abnormal DRE, and older age. A prior negative biopsy was associated with decreased risk of prostate cancer and high-grade prostate cancer. CONCLUSION: Risk factors for prostate cancer on biopsy for men receiving finasteride include PSA, DRE, age, race, family history, and history of a prior negative biopsy. With the exception of the approximate reduction of PSA by half with finasteride, the impact of these risk factors is similar to men who do not receive finasteride.

Longitudinal analysis of sexual function reported by men in the Prostate Cancer Prevention Trial.

BACKGROUND: The Prostate Cancer Prevention Trial (PCPT) was a randomized, double-blind, placebo-controlled study of the efficacy of finasteride in preventing prostate cancer in 18,882 men aged 55 years or older. The PCPT offered an opportunity to prospectively study the effects of finasteride and other covariates on sexual dysfunction. METHODS: We assessed sexual dysfunction in 17,313 PCPT participants during a 7-year period. A battery of questionnaires assessed sexual dysfunction (Sexual Activity Scale score); age; race; SF-36 Mental Health Inventory-5, Physical Function, and Vitality scores; body mass index; smoking status; and the presence of diabetes and hypertension. Assessments began at month 6 after random assignment and included the Sexual Activity Scale score at randomization as a covariate. Two-sided general t tests, with a cutoff of P value less than .05, were used to determine the statistical significance for mixed model effects with correlated random time slopes and intercepts. The changing impact of covariates on sexual dysfunction was also assessed at 6 months, 3.5 years, and 6.5 years after randomization. RESULTS: Finasteride increased sexual dysfunction only slightly and its impact diminished over time; the increase in the Sexual Activity Scale score relative to placebo of 3.21 points (95% confidence interval [CI] = 2.83 to 3.59 points; P<.001) at the first assessment decreased to 2.11 points (95% CI = 1.44 to 2.81 points; P<.001) at the end of study. These Sexual Activity score values were small on a scale of 0-100, the range observed in the study, and in comparison with individual variation. After adjustment for all covariates, mean sexual dysfunction increased in both arms from baseline (6 months after randomization) by 1.26 Sexual Activity points (95% CI = 1.16 to 1.36 points; P<.001) per year, corresponding to a cumulative increase of 8.22 points (95% CI = 7.52 to 8.92 points; P<.001) over the study period. CONCLUSIONS: The effect of finasteride on sexual functioning is minimal for most men and should not impact the decision to prescribe or take finasteride.

Finasteride decreases the risk of prostatic intraepithelial neoplasia.

PURPOSE: High grade prostatic intraepithelial neoplasia is likely a premalignant lesion of the prostate. Decreasing the frequency of high grade PIN may decrease the risk of prostate cancer. In the Prostate Cancer Prevention Trial we evaluated the impact of finasteride on the risk of a needle biopsy diagnosis of high grade prostatic intraepithelial neoplasia. MATERIALS AND METHODS: The Prostate Cancer Prevention Trial was a randomized, placebo controlled clinical trial that enrolled 18,882 men without evidence of prostate cancer, prostate specific antigen less than 3.0 ng/ml and normal digital rectal examination, and randomized them to 5 mg finasteride daily or placebo. Subjects were followed for 7 years with biopsy recommended for prostate specific antigen greater than 4.0 ng/ml, adjusted in the finasteride group to achieve an equal number of biopsy recommendations or for abnormal digital rectal examination. All cancer-free subjects were recommended to undergo biopsy after 7 years on study. We evaluated the diagnosis of high grade prostatic intraepithelial neoplasia with or without concomitant prostate cancer in these 2 study groups. RESULTS: The number of men evaluable for high grade prostatic intraepithelial neoplasia was 4,568 in the finasteride group and 4,886 in the placebo group. High grade prostatic intraepithelial neoplasia alone was diagnosed in 276 men (6.0%) in the finasteride group vs 347 (7.1%) in the placebo group (RR 0.85, 95% CI 0.73-0.99, p=0.04). High grade prostatic intraepithelial neoplasia accompanied by prostate cancer was diagnosed in 144 men (3.2%) in the finasteride group vs 223 (4.6%) in the placebo group (RR 0.69, 95% CI 0.56-0.85, p=0.0004). Finasteride significantly decreased the overall risk of high grade prostatic intraepithelial neoplasia (alone and with cancer) from 570 cases (11.7%) in the placebo group to 420 (9.2%) in the finasteride group (HR 0.79, 95% CI 0.70-0.89, p<0.001). CONCLUSIONS: Finasteride significantly decreased the risk of high grade PIN. This observation may explain how finasteride decreased prostate cancer in the Prostate Cancer Prevention Trial, supporting the notion that high grade prostatic intraepithelial neoplasia is a premalignant lesion of the prostate, and it provides new information relevant to the consideration of finasteride for prostate cancer prevention.

Finasteride improves the sensitivity of digital rectal examination for prostate cancer detection.

PURPOSE: Men undergoing screening for prostate cancer are recommended to undergo digital rectal examination and prostate specific antigen measurement. We previously presented data from the Prostate Cancer Prevention Trial indicating that finasteride improves the performance characteristics of prostate specific antigen for cancer detection. In the current study we report the impact of finasteride on digital rectal examination sensitivity and specificity. MATERIALS AND METHODS: We examined the sensitivity and specificity of digital rectal examination in Prostate Cancer Prevention Trial subjects receiving finasteride or placebo who underwent prostate biopsy, had prostate specific antigen measurement and digital rectal examination within 1 year before biopsy and were on treatment at biopsy. RESULTS: Of 9,423 men in the finasteride group 4,579 and 5,112 of 9,459 in the placebo group met study evaluation requirements. Of 4,579 men in the finasteride group 695, including 264 with Gleason 7 or greater and 81 with Gleason 8 or greater, and 1,111 of 5,112 in the placebo group, including 240 with Gleason 7 or greater and 55 with Gleason 8 or greater, were diagnosed with prostate cancer. In men in the placebo and finasteride groups digital rectal examination sensitivity was greater for detecting higher grade tumors. The sensitivity of digital rectal examination was significantly greater for cancer detection in men receiving finasteride than placebo (21.3% vs 16.7%, p=0.015). Digital rectal examination sensitivity was also greater for detecting high grade (Gleason 7 or greater and 8 or greater) cancers in men receiving finasteride but this did not attain statistical significance. Digital rectal examination specificity was similar in men receiving finasteride or placebo. CONCLUSIONS: Finasteride significantly improves prostate cancer detection with digital rectal examination.

Effect of finasteride on the sensitivity of PSA for detecting prostate cancer.

BACKGROUND: In the Prostate Cancer Prevention Trial (PCPT), men receiving finasteride had a 24.8% lower risk of prostate cancer than men receiving placebo but a higher risk of high-grade cancer. We examined the impact of finasteride on the sensitivity and area under the receiver operating characteristic curve (AUC) of prostate-specific antigen (PSA) for detecting prostate cancer. METHODS: We studied men in the placebo and finasteride groups of the PCPT who had a prostate biopsy and concurrent PSA tests during the 7-year study. We compared the placebo and finasteride groups for sensitivity and AUC of PSA for the detection of all prostate cancer, of Gleason grade 7 or higher prostate cancer, and of Gleason grade 8 or higher prostate cancer. All statistical tests were two-sided. RESULTS: Of 5112 men in the placebo group, prostate cancer was detected in 1111. Gleason tumor grade was available for 1100 men, of whom 240 had grade 7 or higher and 55 had grade 8 or higher. Of 4579 men in the finasteride group, 695 had prostate cancer. Gleason grade was available for 686 men, of whom 264 had grade 7 or higher and 81 had grade 8 or higher. The AUC of PSA for all outcomes was greater for the finasteride group than the placebo group. For detecting prostate cancer versus no cancer, the AUCs were 0.757 and 0.681, respectively (P < .001); for detecting Gleason grade > or = 7 versus < or = 6 or no cancer, the AUCs were 0.838 and 0.781, respectively (P = .003); and for detecting Gleason grade > or = 8 versus < or = 7 or no cancer, the AUCs were 0.886 and 0.824, respectively (P = .071). The sensitivity of PSA was higher for men in the finasteride group than in the placebo group at all PSA cutoffs matched by specificity. CONCLUSIONS: PSA had statistically significantly better sensitivity and AUC for detecting prostate cancer in the finasteride arm of the PCPT than in the placebo arm. This bias would be expected to contribute to greater detection of all grades of prostate cancer with finasteride.

The prostate cancer prevention trial: design, biases and interpretation of study results.

PURPOSE: We describe the complexities of the study design of the PCPT and how they influenced the end point chosen, trial implementation, analysis and interpretation of the results. MATERIALS AND METHODS: Data from the PCPT are provided to evaluate and quantify the potential biases of this trial design. RESULTS: Six potential sources of bias, including prostate specific antigen, digital rectal examination, prostate biopsy technique, study medication nonadherence and contamination, and transurethral prostate resection are presented. These biases resulted in the need for the end of study biopsy to evaluate the trial objectives. CONCLUSIONS: There were a large number of known and potential biases that worked for and against finasteride. Because of the trial design and inherent biases, it is imperative that interim biopsy results should be interpreted with caution. While the period prevalence end point that relied on an end of study biopsy was perhaps not the most clinically relevant, it was the only way to remove as much bias as possible and meet the study objective of determining if finasteride could decrease the risk of prostate cancer. The success of the PCPT depended on constant scrutiny by the Data and Safety Monitoring Committee to monitor these biases. The design and biopsy assumptions outlined at the inception of the trial were met, including adherence and contamination rates, the for-cause biopsy rate and the final percent of men with study end points.

Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial.

BACKGROUND: Prostate-specific antigen (PSA) testing is the primary method used to diagnose prostate cancer in the United States. Methods to integrate other risk factors associated with prostate cancer into individualized risk prediction are needed. We used prostate biopsy data from men who participated in the Prostate Cancer Prevention Trial (PCPT) to develop a predictive model of prostate cancer. METHODS: We included 5519 men from the placebo group of the PCPT who underwent prostate biopsy, had at least one PSA measurement and a digital rectal examination (DRE) performed during the year before the biopsy, and had at least two PSA measurements performed during the 3 years before the prostate biopsy. Logistic regression was used to model the risk of prostate cancer and high-grade disease associated with age at biopsy, race, family history of prostate cancer, PSA level, PSA velocity, DRE result, and previous prostate biopsy. Risk equations were created from the estimated logistic regression models. All statistical tests were two-sided. RESULTS: A total of 1211 (21.9%) men were diagnosed with prostate cancer by prostate biopsy. Variables that predicted prostate cancer included higher PSA level, positive family history of prostate cancer, and abnormal DRE result, whereas a previous negative prostate biopsy was associated with reduced risk. Neither age at biopsy nor PSA velocity contributed independent prognostic information. Higher PSA level, abnormal DRE result, older age at biopsy, and African American race were predictive for high-grade disease (Gleason score > or =7) whereas a previous negative prostate biopsy reduced this risk. CONCLUSIONS: This predictive model allows an individualized assessment of prostate cancer risk and risk of high-grade disease for men who undergo a prostate biopsy.

Impact of the year 2000 Medicare policy change on older patient enrollment to cancer clinical trials.

PURPOSE: A prior analysis by the Southwest Oncology Group (SWOG) showed that women and African American patients were adequately represented on cancer clinical treatment trials but that older patients were substantially underrepresented. Twenty-five percent of patients > or = 65 years old were enrolled onto SWOG trials from 1993 to 1996, whereas 63% of all patients with cancer were > or = 65 years old. Recognition of this under-representation led to a change in Medicare policy in 2000 to include coverage of routine patient care costs of clinical trials. We conducted an updated analysis of accrual trends. METHODS: The proportions of enrollment onto SWOG treatment trials by sex, race/ethnicity, and age (> or = 65 years) were computed for the years 1997 to 2000; corresponding rates in the United States were derived from US Census and National Cancer Institute Surveillance, Epidemiology, and End results data. Additionally, method of payment data were analyzed over time (1993 to 2003) to assess whether patterns in method of payment changed with the new Year 2000 Medicare policy on clinical trials coverage. RESULTS: The results showed continued adequate representation by sex and race/ethnicity. Older patient accrual on SWOG trials increased significantly since 2000, with 31% of patients > or = 65 years old enrolled from 1997 to 2000 and 38% enrolled from 2001 to 2003 (v 25% from 1993 to 1996). The percentage of patients using Medicare plus supplemental insurance also increased beginning in 2000, whereas the percentage of patients using Medicare alone remained the same. CONCLUSION: Method of payment analyses provided evidence that the Year 2000 Medicare policy change had a positive impact, but only for those patients with supplemental private coverage of coinsurance costs. Improvements in the Medicare payment structure could further increase older patient participation in clinical trials.

Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower.

CONTEXT: Three fourths of US men older than 50 years have been screened with prostate-specific antigen (PSA) for prostate cancer. OBJECTIVE: To estimate the receiver operating characteristic (ROC) curve for PSA. DESIGN, SETTING, AND PARTICIPANTS: Calculation of PSA ROC curves in the placebo group of the Prostate Cancer Prevention Trial, a randomized, prospective study conducted from 1993 to 2003 at 221 US centers. Participants were 18 882 healthy men aged 55 years or older without prostate cancer and with PSA levels less than or equal to 3.0 ng/mL and normal digital rectal examination results, followed up for 7 years with annual PSA measurement and digital rectal examination. If PSA level exceeded 4.0 ng/mL or rectal examination result was abnormal, a prostate biopsy was recommended. After 7 years of study participation, an end-of-study prostate biopsy was recommended in all cancer-free men. MAIN OUTCOME MEASURES: Operating characteristics of PSA for prostate cancer detection, including sensitivity, specificity, and ROC curve. RESULTS: Of 8575 men in the placebo group with at least 1 PSA measurement and digital rectal examination in the same year, 5587 (65.2%) had had at least 1 biopsy; of these, 1225 (21.9%) were diagnosed with prostate cancer. Of 1213 cancers with Gleason grade recorded, 250 (20.6%) were Gleason grade 7 or greater and 57 (4.7%) were Gleason grade 8 or greater. The areas under the ROC curve (AUC) for PSA to discriminate any prostate cancer vs no cancer, Gleason grade 7 or greater cancer vs no or lower-grade cancer, and Gleason grade 8 or greater cancer vs no or lower-grade cancer were 0.678 (95% confidence interval [CI], 0.666-0.689), 0.782 (95% CI, 0.748-0.816), and 0.827 (95% CI, 0.761-0.893), respectively (all P values <.001 for AUC vs 50%). For detecting any prostate cancer, PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4%, 52.6%, 32.2%, and 20.5%, and specificities of 38.9%, 72.5%, 86.7%, and 93.8%, respectively. Age-stratified analyses showed slightly better performance of PSA in men younger than 70 years vs those 70 years or older with AUC values of 0.699 (SD, 0.013) vs 0.663 (SD, 0.013) (P = .03). CONCLUSION: There is no cutpoint of PSA with simultaneous high sensitivity and high specificity for monitoring healthy men for prostate cancer, but rather a continuum of prostate cancer risk at all values of PSA.

Estimated impact of the Prostate Cancer Prevention Trial on population mortality.

BACKGROUND: The potential public health impact of the recently completed Prostate Cancer Prevention Trial (PCPT) is debated. The results indicated that the period prevalence of prostate cancer was reduced by 24.8% due to finasteride, whereas an increase in the rate of high-grade tumors (Gleason score 8-10) among men who were diagnosed with cancer also was found (5.0% in the PCPT placebo arm vs. 11.9% in the PCPT finasteride arm). Whether the increased Gleason score was valid or was a histologic artifact is under investigation. METHODS: The authors estimated the number of person-years saved assuming a 24.8% reduction in the incidence of prostate cancer for 5 years among United States males age > or = 55 years. Scenarios for different proportions of patients with high-grade Gleason scores also were considered. RESULTS: With a 24.8% reduction in the number of men with newly diagnosed prostate cancer, the authors estimated that 316,760 person-years would be saved due to finasteride in the United States. An absolute increase of 6.9% in the proportion of men with high-grade tumors in the United States cancer population (corresponding to the difference between the rates on the placebo and finasteride arms of the PCPT) would reduce the number of person-years saved to 262,567. For each absolute increase of 5% in the proportion of patients with high-grade tumors, the number of person-years saved would be reduced by approximately 39,000. CONCLUSIONS: The results of the PCPT may have a major impact on population mortality from prostate cancer if they are applied clinically. The potential detrimental effects of an increased rate of patients who have prostate cancer with high-grade Gleason scores would be outweighed by a reduction in incidence.

Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

Prostate cancer continues to be a major health threat, especially among African American men. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), which opened on July 25, 2001, was planned to study possible agents for the prevention of prostate cancer in a population of 32,400 men in the United States, including Puerto Rico, and Canada. SELECT is a phase III randomized, placebo-controlled trial of selenium (200 microg/day from L-selenomethionine) and/or vitamin E (400 IU/day of all rac alpha-tocopheryl acetate) supplementation for a minimum of 7 years (maximum of 12 years) in non-African American men at least 55 years of age and African American men at least 50 years of age. SELECT is a large, simple trial that conforms as closely as possible with community standards of care. This commentary discusses the design problems the SELECT investigators had to resolve in developing the trial, including the role of prostate cancer screening, the best forms and doses of the study agents, and estimation of the event (prostate cancer) rate of men on the placebo arm.