US Pharm
. 2013;38(7)(Oncology suppl):3-7.

ABSTRACT: Prostate-specific antigen (PSA) tests have been used for more than 20 years to detect early prostate cancer. Recently, however, controversies have arisen around prostate cancer diagnosis and treatment. The U.S. Preventive Services Task Force recommends against PSA-based screening tests for men of all ages because of the risks of overdiagnosis and overtreatment, which have resulted in many adverse effects, serious complications, and even death. The American Urological Association and clinicians from various cancer centers believe that PSA-based screening and early treatment for prostate cancers are still essential for men but recommend they be applied selectively. Consequently, clinical pharmacists can play an important role in consulting with and educating men about prostate cancer so that optimal choices on diagnosis and treatment can be made.

Prostate cancer is the most common cancer in men and the second leading cause of cancer death after lung cancer in the United States.1-3 Risk factors include race (i.e., African American), family history of prostate cancer, increasing age, and abnormal digital rectal examination (DRE).1-3 Prostate cancer grows slowly and rarely occurs in men before 50 years of age, and most cases do not need treatment. Most patients who die of prostate cancer are 75 years or older.3  

Normally, prostate cancer is asymptomatic, except at advanced stages when patients may experience hematuria or impotence. Advanced prostate cancer can spread to the bones, causing pain in the hips, back (spine), ribs (chest), or other areas.2 Some advanced prostate cancers may have similar symptoms to those of benign prostatic hyperplasia (BPH; slow or weakened urinary stream and urinary frequency). Patients with bone metastases have a poor prognosis, with a median survival of <6 months.4

SCREENING & DIAGNOSIS: CONTROVERSIAL ISSUES

Prostate cancer may be detected early by testing prostate-specific antigen (PSA) in the blood, DRE, and biopsy. Controversial issues concerning these methods are shown in TABLE 1.1-3,5-13


PSA Blood Testing

PSA is produced by the prostate gland and is found mostly in semen, with a small amount found in the blood. PSA testing has been widely used for early detection of prostate cancer for more than 20 years.1 PSA test results are interpreted as follows9:

  • Between 0 and 4 ng/mL: normal
  • 4 to 10 ng/mL: gray zone with 25% chance of developing cancer
  • >10 ng/mL: cancer risk is >50%.

However, some men with normal PSA levels still have prostate cancer, while some men with high PSA levels do not. Thus, no PSA cutoff can guarantee that a man does not have prostate cancer.2 In a prospective, multicenter clinical trial, biopsy revealed that men having total PSA from 4 to 10 ng/mL had 25% and 45% risk of cancer with normal DRE and DRE indication of cancer, respectively. For men with a total PSA level >10 ng/mL, the cancer rate increased to >50% (normal DRE) and >75% (DRE indication of cancer).9

Because other factors besides prostate cancer can also increase or decrease PSA levels (TABLE 2),2 PSA blood testing can have false-positive results (high PSA number for men without cancer) or false-negative results (low PSA number for men with cancer). About 80% of positive PSA test results are false-positive when the cutoff levels are set between 2.5 and 4 ng/mL.3 False-positive results may cause negative psychological effects (persistent worry about prostate cancer) and unnecessary prostate biopsy (with risk of pain, infection, bleeding, and transient urinary difficulties).3


PSA-based screening has detected many cases of asymptomatic prostate cancer, with a large number of these having a tumor that either did not progress or progressed so slowly that patients remained asymptomatic for their lifetime. As a result, the U.S. Preventive Services Task Force (USPSTF) concluded that PSA testing results in overdiagnosis, with an estimated rate from 17% to 50%.3,5

An analysis of community data from Albuquerque, New Mexico (1995-1998), revealed that in PSA testing and biopsy of 2,620 men 40 years and older, only 35% with positive PSA testing had prostate cancer after biopsy.8 In addition, since research has not yet proven that the benefits of testing and treatment outweigh the harm of the testing, the American Cancer Society (ACS) proposes that men should not be tested until they are aware of the risks and benefits of testing and treatments.2,3

Due to the PSA test’s low accuracy in predicting prostate cancer, percent-free PSA testing, which measures the percent of PSA that is free in the blood compared to the PSA that is bound to other proteins, has been used for men having total PSA levels from 4 to 10 ng/mL to prevent unnecessary biopsy.8-12 A cutoff of 25%-free PSA is recommended for men having a total PSA from 4 to 10 ng/mL and a palpably benign prostate gland, regardless of age or prostate size. The lower the percent-free PSA, the higher the probability of cancer.10 Based on a prospective, multicenter clinical trial, the 25%-free PSA cutoff detected 95% of cancers while avoiding 20% of unnecessary biopsies.9,10,13 In addition, for men with percent-free PSA level >25%, if cancer was detected, it was less threatening in tumor grade and volume.

Digital Rectal Examination

During a DRE, the physician inserts a lubricated, gloved finger into the rectum to feel for any irregular, nodular, or indurated areas on the prostate that are suspicious for cancer.14 Most prostate cancers start in the back part of the gland, which can be felt during the examination. Based on a randomized trial, a high percentage of men had palpable prostate cancers.14 However, DRE is less effective than PSA blood testing in detecting prostate cancer.2 DRE also has a high percentage of false-positive (89%) and false-negative (74%) prostate cancer results.14

Prostate Biopsy

A prostate biopsy is normally indicated if serum PSA is elevated (total PSA >4 ng/mL and free PSA <25%) and/or if the DRE finding is not normal (i.e., discrete nodule, focal induration, a diffusely hard prostate, or asymmetrical prostate gland).15 In this procedure, the physician uses transrectal ultrasonography to guide a core needle to take 12 to 18 samples from the peripheral zone of the prostate gland. Biopsy samples are sent to the laboratory for pathologist diagnosis. If cancer is detected, a grade (Gleason score) from 2 to 10 is assigned. The higher the Gleason score, the quicker the cancer will grow and spread to the surrounding areas.2

The accuracy of biopsy in detecting cancer depends on the number of core samples. For cancer >0.5 cc in volume, the cancer detection rate for the 11-core multisite-directed scheme is 94%, followed by the 5-region peripheral zone 18 cores (87%), then the 5-region peripheral zone 13 cores (86%). The cancer detection rate also depends on the zones where gland samples are extracted. Only about 20% of prostate cancers originate from the transition zone, while 75% are from the peripheral zone. In addition, past studies have revealed that the cancer rate detected was higher with smaller prostate glands than with larger glands.15,16

Due to the likelihood of overdiagnosis with PSA screening and of its potential harms exceeding its benefits, the USPSTF recommends against PSA-based screening for prostate cancer (grade D recommendation).3 This applies to men in the general U.S. population regardless of age, except for its use in active surveillance after diagnosis or treatment of prostate cancer. The ACS suggests that patients should consult their physicians and compare the risks and benefits before making decisions about prostate cancer screening.2

The American Urological Association (AUA) states that PSA tests, if interpreted appropriately, still provide important information about prostate cancer diagnosis, pretreatment stages or risk assessment, and monitoring.6 Recently, however, the AUA changed its position and recommends against such screening for men aged 40 to 54 years with an average risk of prostate cancer. In the new AUA Guideline for Early Detection of Prostate Cancer, released in May 2013, the following guideline statements are noted7:

  • PSA screening for men aged <40 years is not recommended.
  • Routine PSA screening is not recommended for men ages 40 to 54 years with an average risk of prostate cancer. For men >55 years with a higher risk (i.e., African American or positive family history of prostate cancer), screening decisions should be made individually.
  • For men ages 55 to 69 years who are considering PSA screening, shared decision making is recommended, and whether to proceed is based on a man’s values and preferences.
  • A routine PSA screening interval should be changed from annually to every 2 years to reduce screening harms for men who have participated in shared decision making and decided on screening. Also, screening intervals may be individualized based on a baseline PSA level.
  • Routine PSA screening is not recommended for men aged >70 years, or for any man having a less than 10- to 15-year life expectancy.

Recently, experts from different cancer centers have argued against the USPSTF recommendation.17 They maintain that the best trials in progress have demonstrated that screening can reduce prostate cancer death by 20% to 44% and that the USPSTF recommendation against screening is a combination of factual errors, interpretation, and statistics. However, these experts recommend avoiding PSA testing in men with little to gain (i.e., asymptomatic men with a short life expectancy). Therefore, men >70 years of age should only be tested when their PSA levels are higher than the median and they have excellent overall health. Men with low PSA levels (<1 ng/mL) can be tested less frequently, such as every 7 to 8 years, with screening ending at age 60 years if PSA levels remain at 1 ng/mL or less. Men with PSA levels above the age median but below biopsy thresholds are counseled about elevated risk and advised about regular screening and comprehensive risk assessment.17

TREATMENT CONTROVERSIES

Determining how to treat localized prostate cancer detected by PSA screening is controversial. While the European Randomized Study of Screening for Prostate Cancer (ERSPC) showed a 20% reduction in prostate cancer–specific mortality, the prostate arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial in the U.S. did not demonstrate a mortality reduction for men randomly screened by PSA testing.1 In addition, prostate cancer treatment has many serious and/or potentially life-threatening adverse effects. As a result, choosing an optimal treatment for localized prostate cancer is difficult and controversial.1

In general, a prostate cancer treatment choice should be based on the patient’s life expectancy, overall health status, tumor characteristics, and personal values or preferences. Common treatments for localized prostate cancers are active surveillance (watchful waiting), radiation therapy, and surgery. The adverse effects of these treatments are shown in TABLE 3.3,6,18-20


Active Surveillance: In active surveillance, PSA is checked and DRE is done; prostate biopsy may be performed regularly because some prostate cancers may never become life threatening. Advantages of this treatment are low cost and no immediate complications (with no biopsy). It is a good choice for a patient with a long life expectancy and a low-risk tumor (normally a lower Gleason score, PSA level, and clinical stage). However, the main disadvantage of this treatment is that the cancer may become worse and spread to the surrounding areas.18

Radiation Therapy: This includes interstitial prostate brachytherapy (small radioactive “seeds” are planted in the prostate) and external beam radiation (EBR) therapy (prostate and other tissues are treated with a carefully targeted beam of radiation). Both radiation therapies may be combined, or EBR may be combined with hormone therapy, also known as androgen deprivation therapy (ADT). Side effects of radiation therapy include urinary incontinence, erectile dysfunction (ED), and bowel, urinary tract, and genital tract complications.18 EBR therapy significantly reduces distant and clinical progression with no significant difference in prostate cancer survival.19

Surgery: Radical prostatectomy is a surgical procedure to remove prostate and nearby tissues. Per the USPSTF, most men with PSA-detected prostate cancer in the U.S. have early treatment with surgery, radiation, or ADT.3 However, evidence has shown that 0.5% of these patients will die within 1 month of radical prostatectomy, and 1% to 7% will have serious complications.3,20 In the PIVOT study for early detected localized prostate cancer, radical prostatectomy did not significantly reduce all-cause prostate cancer mortality, as compared with observation, through at least 12 years of follow-up, except for men with PSA levels >10 ng/mL and higher-risk cancers.21 A randomized trial showed that radical prostatectomy does not reduce prostate cancer mortality and the risk of metastasis 10 years after surgery.22 For low-risk prostate cancer in men younger than 65 years, survival rate was similar after 9 and 15 years’ follow-up.23

Another surgical method used for treating early-stage prostate cancer is cryosurgery (cryotherapy or cryoablation). This procedure uses very cold gas to freeze and then thaw the prostate. Cryosurgery has less serious side effects than prostatectomy due to a less invasive technique, but its long-term effectiveness is not known.24

Hormone Therapy (ADT): This is used to shrink the cancer before radiation therapy, combined with radiation for treating higher risk prostate cancer (e.g., high Gleason score, high PSA, or cancer spreading outside the prostate), or in cases when surgery and radiation cannot be used. Different types of ADT include orchiectomy (surgical castration to remove testicles to stop production of testosterone and dihydro-testosterone [DHT]); luteinizing hormone-releasing hormone (LHRH) analogues (drugs such as leuprolide, goserelin, triptorelin, and histrelin that are used to shrink the testicles); and anti-androgens (flutamide, bicalutamide, nilutamide). Clinicians consider anti-androgens combined with orchiectomy or LHRH analogues a first-line hormone therapy. Common adverse effects of hormone therapy include reduced sexual desire, ED, hot flashes, osteoporosis, anemia, weight gain, fatigue, loss of muscle mass, increased cholesterol, and depression.25

Because studies have not found that ADT prolonged life, hormone therapy is not recommended for early-stage prostate cancer. Whether to start hormone treatment for asymptomatic patients as soon as possible or to wait until symptoms appear is still a controversial issue for clinicians in treating prostate cancer. More than that, over time most prostate cancer patients become resistant to hormone therapy.24

Conflicting Recommendations

Based on evidence from various studies, the USPSTF concluded that the PSA-based screening for prostate cancer results in considerable overtreatment and associated harms.3,5,26,27 However, researchers from several major cancer centers do not agree with the USPSTF recommendations. To maximize the benefits of PSA testing and prostate cancer treatments and minimize the harms, they recommend17,26:

1. Avoid PSA testing in men with little to gain (men aged >70 years and/or with life expectancy <10 years due to other concurrent serious diseases).

2. Do not treat those who do not need treatment, such as men with low-risk prostate cancer having a Gleason score of 6 and clinical stage T1 or T2a at biopsy. Active surveillance is preferred for these patients, as the probability of dying of prostate cancer is low.

3. Refer men who do need treatment to high-volume centers to improve cancer control and decrease complications.

CONCLUSION

Prostate screening tests, including PSA-based testing, DRE, and biopsy, have detected more prostate cancers. However, due to their inaccuracies, unnecessary biopsies are performed, causing bleeding, pain, and infections in patients without any benefits. In addition, aggressive treatments for localized prostate cancers (radiotherapy and surgery) cause many serious complications and even death. As a result, the USPSTF recommends against the use of PSA-based screening tests for men of all ages. On the other hand, the new AUA guidelines do not agree totally with the USPSTF screening recommendations. The AUA still recommends PSA screening for a selected group of men based on age, risk factors, life expectancy, and individual values. However, the PSA-based screening tests and associated treatments of early-detected prostate cancers should be applied only to men who may benefit from early detection and related treatments. In addition, to decrease complications and improve treatment effectiveness, prostate cancer treatments should be performed at high-volume centers for better control and follow-up.

Men with potential prostate cancers have to face these two opposing recommendations and will struggle to make the right decision. As a result, clinical pharmacists may play an important role in consulting with and educating patients about the screening tests, treatments, and related benefits and harms. Pharmacists can also coordinate with physicians in helping patients make an optimal decision for prostate cancer screening and treatment based on each individual’s age, risk factors, life expectancy, and values.

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