Almost 3000 men who received a placebo in the Prostate Cancer Prevention Trial and who never had a prostate-specific antigen (PSA) level of more than 4.0 ng per milliliter during the seven years of ...the trial underwent a prostate biopsy at the end of the study. Biopsy revealed prostate cancer in 449 men (15 percent), 67 of whom had high-grade tumors.
A PSA level of 4.0 ng per milliliter or less does not rule out the presence of prostate cancer, including high-grade tumors.
When first described in 1979, prostate-specific antigen (PSA) was considered a useful marker for assessing treatment responses and follow-up among patients with prostate cancer.
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After the publication of reports on several series in which the need for a biopsy of the prostate was based on the results of PSA tests, the potential of the PSA level as a screening tool was recognized.
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Further experience led to the consensus that a PSA level of more than 4.0 ng per milliliter had predictive value for the diagnosis of prostate cancer.
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Disease detection subsequently increased dramatically.
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More recent data suggest that a . . .
A report in this issue of Cancer reviews the concept of bilateral salpingectomy as a preventive approach for high‐grade serous carcinomas and describes the potential for risk reduction while limiting ...adverse effects of premature menopause that occur after salpingo‐oophorectomy. The findings indicate that salpingectomy for risk‐reduction in high‐risk women remains a source of debate and requires additional research, particularly with respect to the role of the ovary in ovarian cancer progression.
See also pages 1714‐20.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Premature menopause is a serious long-term side effect of chemotherapy. We evaluated long-term pregnancy and disease-related outcomes for patients in S0230/POEMS, a study in premenopausal women with ...stage I-IIIA estrogen receptor-negative, progesterone receptor-negative breast cancer to be treated with cyclophosphamide-containing chemotherapy. Women were randomly assigned to standard chemotherapy with or without goserelin, a gonadotropin-releasing hormone agonist, and were stratified by age and chemotherapy regimen. All statistical tests were two-sided. Of 257 patients, 218 were eligible and evaluable (105 in the chemotherapy + goserelin arm and 113 in the chemotherapy arm). More patients in the chemotherapy + goserelin arm reported at least one pregnancy vs the chemotherapy arm (5-year cumulative incidence = 23.1%, 95% confidence interval CI = 15.3% to 31.9%; and 12.2%, 95% CI = 6.8% to 19.2%, respectively; odds ratio = 2.34; 95% CI = 1.07 to 5.11; P = .03). Randomization to goserelin + chemotherapy was associated with a nonstatistically significant improvement in disease-free survival (hazard ratio HR = 0.55; 95% CI = 0.27 to 1.10; P = .09) and overall survival (HR = 0.45; 95% CI = 0.19 to 1.04; P = .06). In this long-term analysis of POEMS/S0230, we found continued evidence that patients randomly assigned to receive goserelin + chemotherapy were not only more likely to avoid premature menopause, but were also more likely to become pregnant without adverse effect on disease-related outcomes.
Abstract
Blood-based assays using various technologies and biomarkers are in commercial development for the purpose of detecting multiple cancer types concurrently at an early stage of disease. These ...multicancer early detection (MCED) assays have the potential to improve the detection of cancers, particularly those for which no current screening modality exists. However, the unknown clinical benefits and harms of using MCED assays for cancer screening necessitate the development and implementation of a randomized controlled trial (RCT) to ascertain their clinical effectiveness. This was the consensus of experts at a National Cancer Institute–hosted workshop to discuss initial design concepts for such a trial. Using these assays to screen simultaneously for multiple cancers poses novel uncertainties for patient care compared with conventional screening tests for single cancers, such as establishing the diagnostic workup to confirm the presence of cancer at any organ site; clarifying appropriate follow-up for a positive assay for which there is no definitive diagnosis; identifying potential harms such as overdiagnosis of indolent disease; determining clinically effective and efficient strategies for disseminating MCED screening in real-world practice; and understanding the ethical implications, such as potentially alleviating or exacerbating existing health disparities. These assays present new and complex challenges for designing an RCT. Issues that emerged from the meeting centered around the need for a flexibly designed, clinical utility RCT to rigorously capture the evidence required to fully understand the net benefit of this promising technology. Specific topic areas were endpoints, screening protocols, recruitment, diagnostic pathway, pilot phase, data elements, specimen collection, and ethical considerations.
Cancer screening trials have required large sample-sizes and long time-horizons to demonstrate cancer mortality reductions, the primary goal of cancer screening. We examine assumptions and potential ...power gains from exploiting information from testing control-arm specimens, which we call the "Intended Effect" (IE) analysis that we explain in detail herein. The IE analysis is particularly suited to tests that can be conducted on stored specimens in the control-arm, such as stored blood for multicancer detection (MCD) tests.
We simulated hypothetical MCD screening trials to compare power and sample-size for the standard vs IE analysis. Under two assumptions that we detail herein, we projected the IE analysis for 3 existing screening trials (National Lung Screening Trial (NLST), Minnesota Colon Cancer Control Study (MINN-FOBT-A), and Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial-colorectal component (PLCO-CRC)).
Compared to the standard analysis for the 3 existing trials, the IE design could have reduced cancer-specific mortality p-values 5-fold (NLST), 33-fold (MINN-FOBT-A), or 14,160-fold (PLCO-CRC), or alternately, reduced sample-size (90% power) by 26% (NLST), 48% (MINN-FOBT-A), or 59% (PLCO-CRC). For potential MCD trial designs requiring 100,000 subjects per-arm to achieve 90% power for multi-cancer mortality for the standard analysis, the IE analysis achieves 90% power for only 37,500-50,000 per arm, depending on assumptions concerning control-arm test-positives.
Testing stored specimens in the control arm of screening trials to conduct the IE analysis could substantially increase power to reduce sample-size or accelerate trials, and provide particularly strong power gains for MCD tests.
The initial report on finasteride for prevention of prostate cancer documented a reduction in prostate cancers but a paradoxical increase in high-grade tumors. Prolonged follow-up and surveillance ...revealed that the number of deaths from prostate cancer was not increased by finasteride.
Abstract Objectives Enrollment of a representative population to cancer clinical trials ensures scientific reliability and generalizability of results. This study evaluated the similarity of patients ...enrolled in NCI-supported group gynecologic cancer trials to the incident US population. Methods Accrual to NCI-sponsored ovarian, uterine, and cervical cancer treatment trials between 2003 and 2012 were examined. Race, ethnicity, age, and insurance status were compared to the analogous US patient population estimated using adjusted SEER incidence data. Results There were 18,913 accruals to 156 NCI-sponsored gynecologic cancer treatment trials, ovarian (56%), uterine (32%), and cervical cancers (12%). Ovarian cancer trials included the least racial, ethnic and age diversity. Black women were notably underrepresented in ovarian trials (4% versus 11%). Hispanic patients were underrepresented in ovarian and uterine trials (4% and 5% versus 18% and 19%, respectively), but not in cervical cancer trials (14 versus 11%). Elderly patients were underrepresented in each disease area, with the greatest underrepresentation seen in ovarian cancer patients over the age of 75 (7% versus 29%). Privately insured women were overrepresented among accrued ovarian cancer patients (87% versus 76%), and the uninsured were overrepresented among women with uterine or cervical cancers. These patterns did not change over time. Conclusions Several notable differences were observed between the patients accrued to NCI funded trials and the incident population. Improving representation of racial and ethnic minorities and elderly patients on cancer clinical trials continues to be a challenge and priority.
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In cancer clinical trials, symptomatic adverse events (AEs), such as nausea, are reported by investigators rather than by patients. There is increasing interest to collect symptomatic AE data via ...patient-reported outcome (PRO) questionnaires, but it is unclear whether it is feasible to implement this approach in multicenter trials.
To examine whether patients are willing and able to report their symptomatic AEs in multicenter trials.
A total of 361 consecutive patients enrolled in any 1 of 9 US multicenter cancer treatment trials were invited to self-report 13 common symptomatic AEs using a PRO adaptation of the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) via tablet computers at 5 successive clinic visits. Patient adherence was tracked with reasons for missed self-reports. Agreement with clinician AE reports was analyzed with weighted κ statistics. Patient and investigator perspectives were elicited by survey. The study was conducted from March 15, 2007, to August 11, 2011. Data analysis was performed from August 9, 2013, to March 21, 2014.
Of the 361 patients invited to participate, 285 individuals enrolled, with a median age of 57 years (range, 24-88), 202 (74.3%) female, 241 (85.5%) white, 73 (26.8%) with a high school education or less, and 176 (64.7%) who reported regular internet use (denominators varied owing to missing data). Across all patients and trials, there were 1280 visits during which patients had an opportunity to self-report (ie, patients were alive and enrolled in a treatment trial at the time of the visit). Self-reports were completed at 1202 visits (93.9% overall adherence). Adherence was highest at baseline and declined over time (visit 1, 100%; visit 2, 96%; visit 3, 95%; visit 4, 91%; and visit 5, 85%). Reasons for missing PROs included institutional errors in 27 of 48 (56.3%) of the cases (eg, staff forgetting to bring computers to patients at visits), patients feeling "too ill" in 8 (16.7%), patient refusal in 8 (16.7%), and internet connectivity problems in 5 (10.4%). Patient-investigator CTCAE agreement was moderate or worse for most symptoms (most κ < 0.05), with investigators reporting fewer AEs than patients across symptoms. Most patients believed that the system was easy to use (234 93.2%) and useful (230 93.1%), and investigators thought that the patient-reported AEs were useful (133 94.3%) and accurate (119 83.2%).
Participants in multicenter cancer trials are willing and able to report their own symptomatic AEs at most clinic visits and report more AEs than investigators. This approach may improve the precision of AE reporting in cancer trials.
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 μg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-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: NCT00006392Published online December 9, 2008 (doi:10.1001/jama.2008.864).
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