The final Research Plan is used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Review will form the basis of the USPSTF Recommendation Statement on this topic.

This draft Research Plan was available for comment from October 29 until November 25, 2015 at 8:00 p.m., ET.

Abbreviation: PSA = prostate cancer-specific antigen.

1. Is there direct evidence that prostate cancer-specific antigen (PSA)-based screening for prostate cancer reduces short- or long-term prostate cancer morbidity* and mortality and all-cause mortality?
   1. Does the effectiveness of PSA-based screening vary by subpopulation/risk factor (e.g., age, race/ethnicity, family history, and clinical risk assessment)?
2. What are the harms of PSA-based screening for prostate cancer and diagnostic followup?
   1. Do the harms of PSA-based screening for prostate cancer and diagnostic followup vary by subpopulation/risk factor (e.g., age, race/ethnicity, family history, and clinical risk assessment)?
3. Is there evidence that various treatment approaches for early-stage or screen-detected prostate cancer reduce morbidity* and mortality?
   1. Does the effectiveness of these treatment approaches vary by subpopulation/risk factor (e.g., age, race/ethnicity, baseline PSA level, family history, comorbid conditions, and clinical risk assessment)?
4. What are the harms of the various treatment approaches for early-stage or screen-detected prostate cancer?
   1. Do the harms of these treatment approaches vary by risk factor (e.g., age, race/ethnicity, baseline PSA level, family history, comorbid conditions, and clinical risk assessment)?
   2. Do the harms differ by treatment approach?
5. Is there evidence that use of a prebiopsy prostate cancer risk calculator, in combination with PSA-based screening, accurately identifies men with clinically significant prostate cancer (i.e., cancer that is more likely to cause symptoms or lead to advanced disease) compared to PSA-based screening alone?

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

1. How often are the various treatment approaches currently performed in U.S. men with prostate cancer detected by PSA-based screening (i.e., what percentage of men initially choose active surveillance or watchful waiting vs. invasive treatment, such as surgery, radiation, or cryotherapy)?
   1. Do the use of various treatment approaches vary by risk factor (e.g., age, race/ethnicity, and stage at diagnosis)?
2. Can patient- or physician-level interventions (e.g., decision aids) successfully align prostate cancer screening and treatment decisions with patients’ informed personal preferences?
3. Can adjunctive screening strategies (e.g., urine or genomic testing, advanced imaging studies) performed in conjunction with PSA-based screening in the peribiopsy period improve the identification of men who are likely to develop aggressive or advanced-stage prostate cancer?
4. What do model estimates suggest about:
   1. The possible mitigation of harms of PSA-based screening for prostate cancer by using different screening strategies (i.e., varying the age at which to start/stop screening, the screening interval, the threshold for biopsy, and treatments)?
   2. The net benefit for subpopulations at higher risk for prostate cancer, prostate cancer mortality, or both (e.g., African Americans, men with a family history of prostate cancer)?
   3. The magnitude of overdiagnosis of prostate cancer with PSA-based screening?
5. Do model estimates of net benefit depend on patients’ values and/or preferences for various health states?

The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the key questions (KQs).

* We will consider asymptomatic men as those without symptoms that are highly suspicious for prostate cancer. Many older men have chronic, stable lower urinary track symptoms (e.g., due to benign prostate hyperplasia) that are not generally associated with an increased risk for prostate cancer.¹
† Treatments for men with later-stage prostate cancer (stages III or IV) differ from those for men with early-stage prostate cancer (stages I or II); large, population-based PSA-based screening studies have primarily detected early-stage cancer (90% to 96% of cancers detected).^{2, 3}
‡ Sample size of at least 1,000 men; smaller samples sizes will be included only if randomized, controlled trials; cohort studies; and larger uncontrolled studies are not available.
§  Although the review's search dates for trials of prostate cancer screening effectiveness will cover 2011 through the present, the USPSTF will consider evidence from older trials included in prior systematic reviews. That is, the evidence review will primarily search for new studies or updates of previous trials but the USPSTF, in making its recommendation, will consider the totality of evidence available, not just studies published since 2011.

The draft Research Plan was posted for public comment on the U.S. Preventive Services Task Force (USPSTF) Web site from October 29 to November 25, 2015. In response, the USPSTF clarified (through the addition of sub-KQs [e.g., 1a, 2a]) that the review of the effectiveness and harms of PSA-based screening and treatment of screen-detected or early-stage prostate cancer will assess for differences within patient subpopulations at higher risk of prostate cancer. The USPSTF also clarified that the harms of PSA-based screening will encompass the harms of diagnostic followup (e.g., biopsy). Contextual Question 2 (originally about treatment preferences) was replaced with a question about the use of informed and shared decisionmaking tools to guide screening and treatment decisions. To further explore the evidence presented by screening and treatment models, the USPSTF added Contextual Questions 4 and 5 to provide context for how the benefits and harms of PSA-based screening may vary under different clinical scenarios. Most of the remaining comments were addressed through minor revisions and by providing further details on the interventions, comparators, and outcomes as outlined in the Research Approach. The USPSTF made no major changes to the scope of the review or the approach to synthesizing the evidence.

1. Akaza H, Kanetake H, Tsukamoto T, Miyanaga N, Sakai H, Masumori N, et al. Efficacy and safety of dutasteride on prostate cancer risk reduction in Asian men: the results from the REDUCE study. Jpn J Clin Oncol. 2011;41(3):417-23.
2. Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360(13):1310-9.
3. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320-8.