Introduction

Roger Chou; Tracy Dana; Christina Bougatsos; Rongwei Fu; Ian Blazina; Ken Gleitsmann; J Bruin Rugge

1Introduction

Purpose of Review and Prior USPSTF Recommendation

Screening with prostate-specific antigen (PSA) testing can detect prostate cancer in earlier, asymptomatic stages, when treatments might be more effective. In 2008, based on an earlier systematic review that focused on studies of PSA-based screening versus no screening,¹ the U.S. Preventive Services Task Force (USPSTF) found insufficient evidence to determine the balance of benefits and harms associated with prostate cancer screening in men younger than age 75 years (I statement), and recommended against screening in men ages 75 years or older (grade D recommendation).² See Appendix A for a list of all abbreviations included in this report.

Once prostate cancer has been detected by screening, treatments are frequently initiated. Understanding the benefits and harms associated with such treatments is therefore critical for informing screening decisions. Evidence on benefits and harms of treatments for localized prostate cancer was last reviewed by the USPSTF in 2002.³ This report summarizes the evidence on benefits and harms of treatment for screen-detected or early-stage prostate cancer, with an emphasis on studies published since 2002.

Condition Definition

Prostate cancer is the most commonly diagnosed cancer in American men.^4–6 Adenocarcinoma accounts for over 95% of all prostate cancer cases. Prostate cancer is typically staged according to the American Joint Committee on Cancer’s tumor, node, metastasis (TNM) system, in which the tumor stage (T) is based on the extent of penetration or invasion beyond the prostatic capsule into adjacent structures (Table 1). Localized prostate cancer is classified as stages T1 (non-palpable) and T2 (palpable) and is confined within the prostatic capsule. The likelihood of progression to invasive cancer is associated with the presence of more poorly differentiated cells and other histopathologic features.

Table 1

Prostate Cancer Tumor Staging.

This review focuses on the benefits and harms of treatments for screen-detected prostate cancer. However, many studies do not report how prostate cancer was initially detected. Therefore, we also included studies of treatments for localized (stages T1 and T2) prostate cancer, which is far more frequently detected by screening than more advanced cancer. Among newly diagnosed patients in 2004–2005, 94% had clinically localized prostate cancer.⁷

Prevalence and Burden of Disease

Within the era of PSA testing, an estimated 16% of men will receive a diagnosis of prostate cancer sometime during their lifetime,⁵ and about 2.2 million American men are estimated to be living with prostate cancer.⁸ In 2010, approximately 217,000 prostate cancer diagnoses and 32,000 prostate cancer deaths were expected in U.S. men.⁴ The likelihood of prostate cancer increases with age, particularly starting at around age 45 years.

Prostate cancer is the second leading cause of cancer-related death in American men.⁶ Despite an increase in prostate cancer diagnoses since the start of the prostate cancer screening era, the risk of dying from prostate cancer has remained relatively stable at around 3%.⁹ Since the adoption of PSA-based screening in the early 1990s, prostate cancer is being detected and treated earlier. Approximately 80% to 90% of men with prostate cancer have clinically localized disease.¹⁰ Survival following a diagnosis of localized prostate cancer has improved in the prostate cancer screening era.⁹ This may be due to advances in medical care or earlier detection, but could also be spurious due to additional lead time, overdiagnosis related to PSA testing, grade migration, or other factors.¹¹

Etiology and Natural History

The natural history of clinically localized disease varies. The tumor grade, often assessed using the Gleason score, is an important marker of tumor aggressiveness. Tumors that remain localized to the prostate are often asymptomatic, but may cause symptoms of bladder outlet obstruction. Such types of cancer generally do not affect survival. On the other hand, tumors that spread beyond the prostate to invade local structures or metastasize can have severe negative impacts on quality of life and mortality.¹²

The etiology of prostate cancer is not completely understood. Men with 5-alpha-reductase deficiency do not develop prostate cancer, suggesting that androgenic hormones play some role in pathogenesis.¹³

Risk Factors

Age, race, and family history are well-established risk factors for prostate cancer. Age is the strongest risk factor, with over 80% of prostate cancer diagnoses occurring in men older than age 65 years.¹⁴ The degree to which the incidence of prostate cancer increases exponentially with age is greater than with any other cancer.¹⁴ Autopsy studies found that as many as 75% of men older than age 85 years have prostate cancer at the time of death.¹⁵

Among U.S. men, black men have the highest incidence rates of prostate cancer, at 226 cases per 100,000 person-years.⁶ White men have an incidence of 145 per 100,000, Hispanic men have an incidence of 122 per 100,000, and Asian/Pacific Islander and Native American men have incidence rates of 78 and 72 per 100,000, respectively.

Family history is another risk factor for prostate cancer. Having a first-degree relative with a history of prostate cancer increases the risk two- to three-fold.¹⁴^,¹⁵ Data from studies of twins suggest that 42% of the risk of prostate cancer may be accounted for by genetic factors.¹⁴ However, the exact genes responsible for the development of prostate cancer are not known.¹⁴

Other potential risk factors such as endogenous levels of androgens and other hormones (vitamin D levels, insulin-like growth factors), differences in diet and use of vitamin supplements, obesity, inflammation, and vasectomy status may also be associated with prostate cancer risk, but evidence is less consistent, or associations are less strong.¹⁴

Rationale for Screening

The primary rationale for screening with PSA testing is to identify high-grade, localized prostate cancer at earlier, asymptomatic stages, in order to enhance the chances of a cure. Screening also identifies lower-grade, localized prostate cancer, for which benefits of earlier treatment are less clear.

Interventions/Treatment

This systematic evidence review evaluates common treatment options for men with localized prostate cancer, including radical prostatectomy (retropubic, perineal, and laparoscopic [with or without robotic assistance]), radiation therapy (external beam radiation therapy [EBRT] and brachytherapy), and, less commonly, androgen deprivation therapy (ADT), cryoablation, and high-intensity focused ultrasonography (HIFU) (Table 2). Other treatments for localized prostate cancer are watchful waiting and active surveillance. Although these terms are not well defined in the published literature and have sometimes been used interchangeably, active surveillance implies a higher degree of monitoring (including PSA levels and prostatic biopsies) in order to guide the decision of when to intervene, whereas watchful waiting implies a more passive approach focused on treatment of symptoms associated with disease progression.¹⁶ The choice of therapy depends on a number of factors, including cancer stage, histologic grade, presence of comorbidities, and patient preferences.

Table 2

Treatments for Localized Prostate Cancer.

Recommendations of Other Groups

Prostate cancer screening recommendations from other groups are summarized in Table 3. The American Urological Association,¹⁷ National Comprehensive Cancer Network,¹⁸ and Prostate Cancer Canada¹⁹ recommend that clinicians consider screening (or offering screening) for prostate cancer with PSA testing beginning at age 40 years. Other groups, such as the American Cancer Society,²⁰ European Association of Urologists,²¹ American Academy of Preventive Medicine,²² American Academy of Family Physicians,²³ United Kingdom National Health Service,²⁴ National Health Committee of New Zealand,²⁵ and Cancer Council of Australia²⁶ do not recommend prostate cancer screening, though many suggest that clinicians provide information about the potential benefits and harms of screening in order to help patients make an informed screening decision.

Table 3

Recommendations of Other Groups.

Publication Details

Copyright

Publisher

Agency for Healthcare Research and Quality (US), Rockville (MD)

NLM Citation

Chou R, Dana T, Bougatsos C, et al. Treatments for Localized Prostate Cancer: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Oct. (Evidence Syntheses, No. 91.) 1, Introduction.

Table 1Prostate Cancer Tumor Staging^*

Tumor Stage	Description
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Clinically unapparent tumor not palpable or visible by imaging T1a: Tumor incidental histologic finding in ≤ 5% of tissue resected T1b: Tumor incidental histologic finding in >5% of tissue resected T1c: Tumor identified by needle biopsy (e.g., because of elevated PSA levels)
T2	Tumor confined within prostate T2a: Tumor involves 50% of one lobe or less T2b: Tumor involves >50% of one lobe but not both lobes T2c: Tumor involves both lobes
T3	Tumor extends through the prostate capsule T3a: Extracapsular extension (unilateral or bilateral) T3b: Tumor invades seminal vesicle(s)
T4	Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, and/or pelvic wall

*: From the American Joint Committee on Cancer.⁹⁴

Table 2Treatments for Localized Prostate Cancer

Treatment Option	Treatment Description
Active surveillance^*	Active plan to postpone intervention. Decision to proceed with radical treatment based on rate of rise of prostate-specific antigen level and results of repeat biopsies.
Androgen deprivation therapy	Oral or injection medications or surgical removal of testicles to lower or block circulating androgens.
Brachytherapy	Radioactive implants placed under anesthesia using radiologic guidance. Lower dose/permanent implants typically used. External beam “boost” radiotherapy and/or androgen deprivation sometimes recommended.
Cryoablation	Destruction of cells through rapid freezing and thawing using transrectal guided placement of probes and injection of freezing/thawing gases.
External beam radiotherapy	Multiple doses of radiation from an external source applied over several weeks. Dose and physical characteristics of beam may vary. Conformal radiotherapy uses three-dimensional planning systems to maximize dose to prostate cancer and attempt to spare normal tissue. Intensity modulated radiation therapy provides the precise adjusted dose of radiation to target organs, with less irradiation of healthy tissues than conformal radiation therapy. Proton radiation therapy is a form of EBRT in which protons rather than photons are directed in a conformal fashion to a tumor site. The use of the heavier single proton beam (vs. photon therapy) allows for a low entrance dose and maximal dose at the desired tumor location with no exit dose. This theoretically permits improved dose distribution (delivering higher dose to the tumor with lower dose to normal tissue) than other EBRT techniques. May be used alone or in combination with proton and photon-beam radiation therapy.
High-intensity focused ultrasonography therapy	High-intensity focused ultrasonography therapy has been used as a primary therapy in patients with localized prostate cancer not suitable for radical prostatectomy. Tissue ablation of the prostate is achieved by intense heat focused on the identified cancerous area.
Laparoscopic radical prostatectomy and robotic assisted radical prostatectomy	Video-assisted, minimally invasive surgical method to remove the prostate.
Radical retropubic or perineal prostatectomy	Complete surgical removal of prostate gland with seminal vesicles, ampulla of vas, and sometimes pelvic lymph nodes. Sometimes done laparoscopically or with robotic assistance and attempt to preserve nerves for erectile function.
Watchful waiting^*	Active plan to postpone intervention. Palliative treatment given to patients exhibiting symptoms of disease progression.

: Adapted with permission from Wilt et al, 2008.⁹

*: From van As, 2007.⁹⁵

Table 3Recommendations of Other Groups

Organization, year	Population	Recommendation
American Academy of Family Physicians, 2008²³^,⁹⁶	Asymptomatic men	Adopts the U.S. Preventive Services Task Force 2008 recommendation, which found current evidence insufficient to assess the balance of benefits and harms of prostate cancer screening in men younger than age 75 years.
American Cancer Society, 2006²⁰	Asymptomatic men	Recommends that men make an informed decision with their doctor about whether to be tested for prostate cancer. Research has not yet proven that the potential benefits of testing outweigh the harms of testing and treatment. Recommends that men should not be tested without learning about what is known and not known about the risks and possible benefits of testing and treatment. Starting at age 50 years, men should talk to their doctor about the pros and cons of testing so they can decide if testing is the right choice for them. African American men or men with a father or brother who had prostate cancer before age 65 years should have this talk with their doctor starting at age 45 years.
American College of Preventive Medicine, 2008²²	Asymptomatic men	Insufficient evidence to recommend routine population screening with DRE or PSA. Clinicians caring for men, especially African American men and those with positive family histories, should provide information about potential benefits and risks of prostate cancer screening, and the limitations of current evidence for screening, in order to maximize informed decisionmaking.
American Urologist Association, 2009¹⁷	Asymptomatic men	Early detection and risk assessment of prostate cancer should be offered to asymptomatic men ages 40 years or older who wish to be screened and have an estimated life expectancy of more than 10 years.
Cancer Council Australia, 2010²⁶	Asymptomatic men	The benefits of population screening for prostate cancer are, at this time, unproven. The central concern is that many prostate cancer cases will not progress sufficiently to cause harm in a man’s lifetime, while others will progress and be lethal. No current test (including the PSA test) adequately differentiates between these types of cancer. Evidence does not support population-based screening of asymptomatic men for prostate cancer. Recent research confirms that the harms of screening with the PSA test outweigh the benefits.
European Association of Urologists, 2009²¹	Asymptomatic men	Current published data are insufficient to recommend the adoption of population screening for prostate cancer as a public health policy due to the large overtreatment effect.
Japanese Urological Association, 2008⁹⁷	Asymptomatic men	Men ages 50 years or older in general and men ages 40 or 45 years or older with a family history should be screened with the PSA test concomitant with the basic health checkup system in Japan and PSA with or without DRE in human dry-dock (Ningen dock). Fact sheets including the merits and demerits of PSA screening should be provided to candidates before carrying out the screening test. The recommended cut-off point of PSA tests for biopsy indication is 4.0 ng/mL. Alternative cut-off points for biopsy indication are age- specific reference ranges of PSA, which are set at 3.0, 3.5, and 4.0 ng/mL in the age ranges of younger than 65, 65 to 69, and 70 years or older, respectively.
National Comprehensive Cancer Network, 2009¹⁸	Asymptomatic men	Baseline DRE and PSA testing at age 40 years is recommended for men interested in early screening, as well as annual followup for men who have a PSA value ≥1.0 ng/mL. Men with PSA <1.0 ng/mL should be screened again at age 45 years. Regular screening should be offered to all participants starting at age 50 years.
National Health Committee of New Zealand, 2004²⁵	Asymptomatic men	Population-based screening for prostate cancer by PSA and/or DRE is not recommended for asymptomatic men in New Zealand.
Prostate Cancer Canada, 2010¹⁹	Asymptomatic men	Recommends that men older than age 40 years establish a baseline PSA value and men older than age 50 years have annual or semiannual PSA readings.
United Kingdom National Health Service, 2006²⁴	Asymptomatic men	Systematic population screening program is not recommended.

: Abbreviations: DRE = digital rectal examination; PSA = prostate-specific antigen.