Steven Fox

Radical Prostatectomy versus Observation for Localized Prostate Cancer

BACKGROUND The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. RESULTS During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.).

The Prostate cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): Design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer ☆

BACKGROUND Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. Ninety percent of men with prostate cancer are over aged 60 years, diagnosed by early detection with the prostate specific antigen (PSA) blood test and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting surgery to remove the prostate gland (radical prostatectomy), external beam radiation therapy and interstitial radiation therapy (brachytherapy) and androgen deprivation. Little is known about the relative effectiveness and harms of treatments due to the paucity of randomized controlled trials. The VA/NCI/AHRQ Cooperative Studies Program Study #407: Prostate cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy to watchful waiting in men with clinically localized prostate cancer. METHODS We describe the study rationale, design, recruitment methods and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy versus watchful waiting conducted in Scandinavia. RESULTS We screened 13,022 men with prostate cancer at 52 United States medical centers for potential enrollment. From these, 5023 met initial age, comorbidity and disease eligibility criteria and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African-American. Approximately 85% reported they were fully active. The median prostate specific antigen (PSA) was 7.8 ng/mL (mean 10.2 ng/mL). In three-fourths of men the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade and tumor stage, approximately 43% had low risk, 36% had medium risk and 20% had high-risk prostate cancer. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the U.S. and quite different from men in the Scandinavian trial. CONCLUSIONS PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared to watchful waiting for men with predominately PSA detected clinically localized prostate cancer.

Costing medical care: Using medicare administrative data

This paper describes how the PORTS are using data from the Medicare administrative records systems to study the medical care costs of specific conditions. The general strengths and weaknesses of the Medicare databases for studying cost related issues are discussed, and the relevant data elements are examined in detail. Changes in the nature of the data collected over time are noted. Information is provided on how the PORTS are using these data to estimate the cost to Medicare of treating Medicare beneficiaries with specific conditions and the social (opportunity) cost of treating these patients. Furthermore, information is provided on how data from the Medicare administrative records system can be used to determine the cost of services for patients who have been identified through other large databases (i.e., state hospital discharge tapes) or who have been enrolled in prospective cohort studies.

Interventions for Preschool Children at High Risk for ADHD: A Comparative Effectiveness Review

OBJECTIVES: The US Agency for Healthcare Research and Quality sponsored a comparative effectiveness review of interventions for preschoolers at risk for attention-deficit/hyperactivity disorder (ADHD). METHODS: Medline, Cochrane CENTRAL, Embase, PsycInfo, and Education Resources Information Center were searched from 1980 to November 24, 2011. Selected studies were comparative, and enrolled children <6 years with clinically significant disruptive behavior, including ADHD. The interventions evaluated were parent behavior training (PBT), combined home and school/day care interventions, and methylphenidate use. Data were extracted by using customized software. Two independent raters evaluated studies as good, fair, or poor by using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies Risk of Bias. Overall strength of evidence (SOE) was rated for each intervention’s effectiveness, accounting for study design, systematic error, consistency of results, directness of evidence, and certainty regarding outcome. RESULTS: Fifty-five studies were examined. Only studies examining PBT interventions could be pooled statistically using meta-analysis. Eight “good” studies examined PBT, total n = 424; SOE was high for improved child behavior, standardized mean difference = –0.68 (95% confidence interval: –0.88 to –0.47), with minimal heterogeneity among studies. Only 1 good study evaluated methylphenidate, total n = 114; therefore, SOE for methylphenidate was low. Combined home and school/day care interventions showed inconsistent results. The literature reported adverse effects for methylphenidate but not for PBT. CONCLUSIONS: With more studies consistently documenting effectiveness, PBT interventions have greater evidence of effectiveness than methylphenidate for treatment of preschoolers at risk for ADHD.

Observational studies in systemic reviews of comparative effectiveness: AHRQ and the Effective Health Care Program

OBJECTIVE Systematic reviewers disagree about the ability of observational studies to answer questions about the benefits or intended effects of pharmacotherapeutic, device, or procedural interventions. This study provides a framework for decision making on the inclusion of observational studies to assess benefits and intended effects in comparative effectiveness reviews (CERs). STUDY DESIGN AND SETTING The conceptual model and recommendations were developed using a consensus process by members of the methods workgroup of the Effective Health Care Program of the Agency for Healthcare Research and Quality. RESULTS In considering whether to use observational studies in CERs for addressing beneficial effects, reviewers should answer two questions: (1) Are there gaps in the evidence from randomized controlled trials (RCTs)? (2) Will observational studies provide valid and useful information? The latter question involves the following: (a) refocusing the study questions on gaps in the evidence from RCTs, (b) assessing the risk of bias of the body of evidence of observational studies, and (c) assessing whether available observational studies address the gap review questions. CONCLUSIONS Because it is unusual to find sufficient evidence from RCTs to answer all key questions concerning benefit or the balance of benefits and harms, comparative effectiveness reviewers should routinely assess the appropriateness of inclusion of observational studies for questions of benefit. Furthermore, reviewers should explicitly state the rationale for inclusion or exclusion of observational studies when conducting CERs.

The Use of Expensive Health Technologies in the Era of Managed Care: The Remarkable Case of Neonatal Intensive Care

The use of neonatal intensive care (NIC) continued to rise rapidly in the 1990s despite the concerns of observers about its cost effectiveness and its successes being mostly in facilities with high volume and capabilities. The objective of this study is to test the effects of insurance type, competition among hospitals, and market pressure from managed care plans on the supply and cost of NIC. The analysis uses logistic and linear models with techniques to avoid bias from (a) market area definitions based on actual patient flows and (b) self-selection of hospitals by patients with unmeasured risk of needing NIC. The data source contains all births in short-term hospitals in New Jersey during 1990 and 1994. Both the number of days and charges for NIC are reported. Key findings are that the decision of a hospital to offer NIC was associated with teaching status, the proportion of infants in the market area with documented high risk, and the market concentration of major competitors. The market share of managed care plans and the concentration of enrollment were not associated with either NIC being offered or with the standardized charges. Whether a particular patient was given to a NIC depended on patient risk factors and whether a NIC unit was present, but not on payer group. The results are consistent with the hypothesis that young insured parents (with the advice of their obstetricians) prefer hospitals with NIC and also are relatively profitable enrollees for health plans. In conclusion: using the results here and in other research, public and private policy makers may consider several ways to strengthen the incentives for health plans to contract for cost-effective birth-related services. The results also raise questions for a number of regulatory and payment policies and call for better public data on costs and outcomes for NIC.

Ascertaining cause of death among men in the Prostate Cancer Intervention Versus Observation Trial

Background The Prostate Cancer Intervention Versus Observation Trial (PIVOT) randomized 731 men with localized prostate cancer to radical prostatectomy or observation. Purpose We describe the methods and results for cause-of-death assignments in PIVOT, and compare them to alternative strategies for ascertaining prostate cancer–specific mortality, as well as to the methods and results in the similar Scandinavian Prostate Cancer Group Study 4 (SPCG-4) trial. Methods Three PIVOT Endpoints Committee members, blinded to randomized treatment assignments, reviewed medical records and death certificates when available to assign a cause of death using a primary and a secondary adjudication question. Initial disagreements were resolved through discussion. The level of initial agreement among committee members was examined, as well as guesses at randomized treatment assignments for a convenience sample of cases. Final cause of death determinations were compared to death certificates. Results Complete agreement on cause of death by all three committee members before any discussion was achieved in 200/354 (56%) cases on the primary and 209/354 (59%) cases on the secondary. However, complete agreement on the primary rose to 306/354 (86%) when ‘definite’ and ‘probably’ categories were collapsed, as planned a priori. The three committee members’ proportions of correct guesses of randomized treatment assignment were 82/121 (68%), 113/148 (76%), and 99/134 (74%). Using the committee’s final adjudications as a gold standard, death certificates had suboptimal sensitivities, specificities, or predictive values depending on how they were used to determine cause of death. Limitations There was no separate ‘gold standard’ by which to judge the accuracy of the final endpoints committee adjudications, and useful death certificates could not be obtained on about a third of PIVOT participants who died. Conclusions The low level of initial agreement on cause of death among endpoint committee members and the potential for biased determinations due to partial unblinding to treatment assignment raise methodologic concerns about using prostate cancer mortality as an endpoint in clinical trials like PIVOT.