Developing Clinical Guidelines: An Introductory Exercise John Voss, MD Andrew Wolf, MD Division of General Medicine University of Virginia School of Medicine Charlottesville, VA Some rights reserved under the creative commons license. For information please contact firstname.lastname@example.org
1. Describe the components of an effective guideline
2. Gain familiarity with the tasks involved developing clinical guidelines
You are a general internist working in a multispeciality practice group. The senior administrator for your group knows of your interest in quality and has asked you to develop a guideline about using PSA testing for prostate cancer screening because there seems to be uncertainty among physicians and patients about the best use of this test.
Draft a Guideline
To help you in this task we provide the following information:
A summary of the requirements for an effective screening program.
Key literature abstracts that you can use to assess the pros and cons of PSA screening.
A synopsis of the key elements of an effective guideline
You have one hour as a group to review this information and draft a guideline. Be prepared to discuss your guideline and rationale.
2009 Prostate Cancer Incidence & Mortality Insert text box about lifetime and yearly probability of diagnosis and death from prostate cancer Slide data drawn from Cancer Statistics 2009. CA Cancer J Clin 2009;59:225-49.
As you get started, recall that screening means that we are looking for disease in asymptomatic individuals. Using PSA testing to evaluate an 66 year old man complaining of low back pain that you suspect could be due to metastatic prostate cancer is not screening.
Effective Screening Program Criteria
The condition is an important health problem.
The natural history of the condition from latent to final stage illness should be well understood.
The condition should be be detectable in a latent or early symptomatic stage.
Effective treatment of early stage illness should exist.
The screening test should have acceptable sensitivity, specificity and reliability.
Patients should be willing to undergo the screening test.
Faculties for diagnosing and treating the screened population should exist.
The costs of finding and treating the illness should be commensurate with the benefits of treatment.
PSA Test Characteristics Using 4ng/ml cutpoint
Prostate biopsy $300-$1200
(1) Regional Variation in Total Cost per Radical Prostatectomy in the Healthcare Cost and Utilization Project Nationwide Inpatient Sample Database Danil V. Makarov abg, Stacy Loeb h, Adam B. Landman acg, Matthew E. Nielsen i, Cary P. Gross ad, Douglas L. Leslie j, David F. Penson k, Rani A. Desai aefg
Prostate Cancer Treatment Complications
GU incontinence 15-50%
erectile dysfunction 20-70%
External Beam XRT
GU incontinence 2-16%
erectile dysfunction 20-45%
GI diarrhea, bleeding, incontinence 6-25%
The PLCO Study
73,000 men aged 55 to 74 randomized to screening annually vs routine follow-up
Began in 1993, ten U.S. Centers
Median follow-up about ten years
Men in the screening arm were more commonly diagnosed with prostate cancer. PLCO: Diagnosing Prostate Cancers
Greater detection of prostate cancer did not produce lower prostate cancer mortality. PLCO: Diagnosing Prostate Cancers
Bottom line – no difference in death rates at 10 years between intensively screened and less-intensively screened men.
Major problems with study
52% contamination rate: more than half of controls screened
Many screened prior to study entry & had significantly reduced risk of prostate cancer death
Fewer than 50% of those with positive screen had prostate biopsy.
The ERSPC Study
162,000 men aged 55 to 69 randomized to screening vs routine follow-up (there was no standardized protocol)
Began in 1991, seven countries
Median follow-up about nine years
ERSPC Prostate-specific Mortality Results
Issues with ERSPC
Positive finding – 20% fewer prostate deaths in screened group.
Negative findings – to prevent one prostate cancer death, one needs to:
- Screen 1068 men
- Treat 48 men (over-treatment)
Questions to Consider While Formulating your Guideline
Who’s interest will you represent? That of your medical group, you as an individual MD, the perspective of your patients, or that of society at large?
Who should you screen? All men? Just high risk men (AA, family history of prostate ca)? No men at all?
If you choose screening, at what age should you start? Should it differ for normal vs high risk men? Should you ever stop screening?
Are there important facts about PSA screening that patients should know? Does PSA testing require informed consent?
Mortality results from a randomized prostate-cancer screening trial. 1
BACKGROUND: The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality.
METHODS: From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained. RESULTS: In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings.
CONCLUSIONS: After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.)
1 Mortality results from a randomized prostate-cancer screening trial 1 . Andriole GL; Grubb RL 3rd; Buys SS; Chia D; Church TR; Fouad MN; et al. N Engl J Med. 2009 Mar 26;360(13):1310-9. Epub 2009 Mar 18.
Screening and prostate-cancer mortality in a randomized European study 1
BACKGROUND: The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer.
METHODS: We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006. RESULTS: In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90).
CONCLUSIONS: PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. (Current Controlled Trials number, ISRCTN49127736.)
Screening and prostate-cancer mortality in a randomized European study 1. Schroder FH; Hugosson J; Roobol MJ; Tammela TL; Ciatto S; Nelen V; et al. N Engl J Med. 2009 Mar 26;360(13):1320-8. Epub 2009 Mar 18.
Lead time and overdiagnosis in prostate-specific antigen screening. 1
1 Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context.
Draisma G; Etzioni R; Tsodikov A; Mariotto A; Wever E; Gulati R; Feuer E; de Koning H, J Natl Cancer Inst. 2009 Mar 18;101(6):374-83. Epub 2009 Mar 10.
B ACKGROUND: The time by which prostate-specific antigen (PSA) screening advances prostate cancer diagnosis, called the lead time, has been reported by several studies, but results have varied widely, with mean lead times ranging from 3 to 12 years. A quantity that is closely linked with the lead time is the overdiagnosis frequency, which is the fraction of screen-detected cancers that would not have been diagnosed in the absence of screening. Reported overdiagnosis estimates have also been variable, ranging from 25% to greater than 80% of screen-detected cancers. METHODS: We used three independently developed mathematical models of prostate cancer progression and detection that were calibrated to incidence data from the Surveillance, Epidemiology, and End Results program to estimate lead times and the fraction of overdiagnosed cancers due to PSA screening among US men aged 54-80 years in 1985-2000. Lead times were estimated by use of three definitions. We also compared US and earlier estimates from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) that were calculated by use of a microsimulation screening analysis (MISCAN) model. RESULTS: The models yielded similar estimates for each definition of lead time, but estimates differed across definitions. Among screen-detected cancers that would have been diagnosed in the patients' lifetimes, the estimated mean lead time ranged from 5.4 to 6.9 years across models, and overdiagnosis ranged from 23% to 42% of all screen-detected cancers. The original MISCAN model fitted to ERSPC Rotterdam data predicted a mean lead time of 7.9 years and an overdiagnosis estimate of 66%; in the model that was calibrated to the US data, these were 6.9 years and 42%, respectively. CONCLUSION: The precise definition and the population used to estimate lead time and overdiagnosis can be important drivers of study results and should be clearly specified.