Developing Clinical Guidelines:

An Introductory Exercise

John Voss, MD

Andrew Wolf, MD

Division of General Medicine

University of Virginia School of MedicineCharlottesville, VA

Some rights reserved under the creative commons license. For information please contact jv4w@virginia.edu

Learning Objectives

1. Describe the components of an effective guideline

2. Gain familiarity with the tasks involved developing clinical guidelines

Assignment

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:

1. A summary of the requirements for an effective screening program.

2. Key literature abstracts that you can use to assess the pros and cons of PSA screening.

3. 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.

219,440

192,280

146,970

192,370

11,270

159,390

40,17027,360

49,920

4,0700

50,000

100,000

150,000

200,000

250,000

Breast Colon Cervical Prostate Lung

IncidenceMortality

Number of Cases per Year

2009 Prostate Cancer Incidence & Mortality

Insert text box about lifetime and yearly probability of diagnosis and death from prostate

cancerSlide data drawn from Cancer Statistics 2009. CA Cancer J Clin

2009;59:225-49.

Copyright ©2010 American Cancer Society

From Wolf, A. M. D. et al. CA Cancer J Clin 2010;60:70-98.

Trends in prostate cancer incidence and mortality rates, US, 1975-2006

Requirements for Effective Screening

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

1. The condition is an important health problem.2. The natural history of the condition from latent

to final stage illness should be well understood.3. The condition should be be detectable in a

latent or early symptomatic stage.4. Effective treatment of early stage illness should

exist.5. The screening test should have acceptable

sensitivity, specificity and reliability.6. Patients should be willing to undergo the

screening test.7. Faculties for diagnosing and treating the

screened population should exist.8. The costs of finding and treating the illness

should be commensurate with the benefits of treatment.

PSA Test CharacteristicsUsing 4ng/ml cutpoint

Test characteristics

•Sensitivity 20-80%

•Specificity 60-94%

•PPV ~30%

Costs

• PSA $50-$75

•Prostate biopsy $300-$1200

•Prostatectomy $9100(1)

•Radioactive implants

(1) Regional Variation in Total Cost per Radical Prostatectomy in the Healthcare Cost and Utilization Project Nationwide Inpatient Sample DatabaseDanil V. Makarovabg, Stacy Loebh, Adam B. Landmanacg, Matthew E. Nielseni, Cary P. Grossad, Douglas L. Lesliej, David F. Pensonk, Rani

A. Desaiaefg

Prostate Cancer Treatment Complications

Prostatectomy

•mortality 0.5-1%

•GU incontinence 15-50%

•erectile dysfunction 20-70%

External Beam XRT

•mortality 0%

•GU incontinence 2-16%

•erectile dysfunction 20-45%

•GI diarrhea, bleeding, incontinence 6-25%

The PLCO StudyThe PLCO Study

• 73,000 men aged 55 to 74 randomized to 73,000 men aged 55 to 74 randomized to screening annually vs routine follow-upscreening annually vs routine follow-up

• Began in 1993, ten U.S. CentersBegan in 1993, ten U.S. Centers

• Median follow-up about ten yearsMedian 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

PLCO ResultsPLCO Results

• Bottom line – no difference in death rates at 10 Bottom line – no difference in death rates at 10 years between intensively screened and less-years between intensively screened and less-intensively screened men.intensively screened men.

• Major problems with studyMajor problems with study

• 52% contamination rate: more than half of controls 52% contamination rate: more than half of controls screenedscreened

• Many screened prior to study entry & had Many screened prior to study entry & had significantly reduced risk of prostate cancer deathsignificantly reduced risk of prostate cancer death

• Fewer than 50% of those with positive screen had Fewer than 50% of those with positive screen had prostate biopsy.prostate biopsy.

The ERSPC StudyThe ERSPC Study

• 162,000 men aged 55 to 69 randomized to 162,000 men aged 55 to 69 randomized to screening vs routine follow-up (there was no screening vs routine follow-up (there was no standardized protocol)standardized protocol)

• Began in 1991, seven countriesBegan in 1991, seven countries

• Median follow-up about nine yearsMedian follow-up about nine years

ERSPC Prostate-specific Mortality Results

Issues with ERSPCIssues with ERSPC

• Positive finding – 20% fewer prostate deaths Positive finding – 20% fewer prostate deaths in screened group.in screened group.

• Negative findings – to prevent one prostate Negative findings – to prevent one prostate cancer death, one needs to:cancer death, one needs to:

- Screen 1068 men- Screen 1068 men

- Treat 48 men (over-treatment)- Treat 48 men (over-treatment)

Questions to ConsiderWhile 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.)

1Mortality results from a randomized prostate-cancer screening trial1. 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

study1

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 study1. 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

1Lead 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.

BACKGROUND: 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.