Men’s health 2018: BPH, prostate cancer, erectile dysfunction, supplements

PROSTATE CANCER SCREENING AND TREATMENT

A 60-year-old patient calls you after receiving his laboratory testing report from his insurance physical. His prostate-specific antigen (PSA) level is 5.1 ng/mL, and he has several questions:

• Should he have agreed to the screening?
• How effective is the screening?
• What are the next steps?

Is PSA screening useful?

Over the last few years, there has been great debate as to the utility of screening for prostate cancer.

The US Centers for Disease Control and Prevention¹⁰ reported that in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it. These statistics support the notion that screening programs may be detecting what might otherwise be a silent disease.

The US Preventive Services Task Force (USPSTF)¹¹ recommends against blanket PSA screening, in view of the low probability that it reduces the risk of death from prostate cancer. For men ages 55 through 69, current guidelines give a grade C recommendation to PSA screening, meaning there is moderate agreement that the benefit is likely small, and screening should be selectively offered based on professional judgment and patient preference. In men ages 70 and older who are not at high risk, the guideline gives screening a grade D recommendation, meaning there is moderate evidence that there is no benefit from the practice. This is a change from the 2012 USPSTF guidelines,¹² which gave a grade D recommendation to PSA screening for all ages.

The American Urological Association¹³ recommends against PSA screening in men under age 40 or ages 70 and older. It does not recommend routine screening in those ages 40 to 54 at average risk, but it says the decision should be individualized in this age group in those at higher risk (eg, with a positive family history, African American). At ages 55 through 69, it recommends shared decision-making, taking into account cancer risk and life expectancy. In those who opt for screening, an interval of 2 years or more may be preferred over annual screening to reduce the risk of overdiagnosis.

The USPSTF recommendations rely heavily on data from 2 trials: the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹⁴ and the Prostate, Lung, Colorectal, and Ovarian Screening (PLCO) trial.¹⁵

The ERSPC¹⁴ demonstrated that screening for prostate cancer reduced deaths from prostate cancer by 20%, with an absolute risk difference of 0.71 deaths per 1,000 men; 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent 1 death from prostate cancer. Screening also decreased the risk of developing metastatic disease by 30%.¹⁶ On the negative side, screening increased the risk of overdiagnosis and other harms such as bleeding, sepsis, and incontinence.

The PLCO trial,¹⁵ in contrast, found no difference in death rates between men randomly assigned to annual screening and those assigned to usual care. Differences between the trial results were thought to be due to different practice settings as well as study implementation and compliance.

Tsodikov et al¹⁷ reanalyzed data from the ERSPC and the PLCO trial using 3 different mathematical models to estimate the effects of screening in both trials compared with no screening. The analysis found no evidence that the effects of screening vs not screening differed between the 2 trials, ultimately concluding that PSA screening reduced prostate cancer deaths by 25% to 32%, which the authors inferred was primarily a result of earlier detection of cancer.

The Cluster Randomized Trial of PSA Testing for Prostate Cancer,¹⁸ published in March 2018, explored the effect of single PSA screening vs no screening on prostate cancer mortality rates in 419,582 men ages 50 through 69. Although screening detected more cases of low-risk prostate cancer, there was no significant difference in prostate cancer mortality rates after a median follow-up of 10 years. However, 10% to 15% of the control group was estimated to have also been screened, and these results do not directly speak to the efficacy of serial PSA screening.

Extended follow-up of this trial is planned to report on long-term survival benefits and whether screening lowers the risk of metastasis.

Imaging-guided prostate biopsy

Once a patient is found to have an elevated PSA level, standard practice has been to perform transrectal ultrasonography to obtain 12 core biopsy samples. The results indicate whether the prostate contains cancer, how aggressive the cancer is (Gleason score), and whether there is extracapsular extension.

In the past, magnetic resonance imaging (MRI) of the prostate before biopsy was thought to be too costly, and many insurance plans do not currently cover it.

Pahwa et al,¹⁹ however, in a cost-effectiveness study using a decision-analysis model, found that using MRI to detect lesions and then guide biopsy by triaging patients into proper treatment pathways added health benefits in a cost-effective manner in 94.05% of simulations. These benefits were found across all age groups.

This study demonstrated that doctors could use MRI to better evaluate patients for potentially harmful lesions. If a focus of cancer is found, it can be biopsied; if no cancer is seen on MRI, the patient can avoid biopsy completely. Additionally, though MRI tended to miss low-risk cancers, these cancers are thought to disproportionately lead to higher healthcare costs through unnecessary treatment. Therefore, a negative MRI study was believed to be an excellent sign that the patient does not have aggressive prostate cancer. This approach led to a net gain of 0.251 additional quality-adjusted life years compared with the standard biopsy strategy.

The Prostate MRI Imaging Study²⁰ also found MRI to be effective in the prostate cancer workup. In this trial, 576 men who had never undergone biopsy underwent multiparametric MRI, transrectal ultrasonography-guided biopsy, and the reference standard, ie, transperineal template prostate mapping biopsy. Of those who underwent biopsy, 71% received a diagnosis of prostate cancer, and 40% had clinically significant disease. In patients with clinically significant disease, MRI was more sensitive than ultrasonography-guided biopsy (93% vs 48%, P < .0001) but less specific (41% vs 96%, P < .0001).

Based on these findings, if biopsy were performed only in those who had suspicious lesions on MRI, 27% of men with elevated PSA could avoid biopsy and its potential complications such as bleeding and sepsis, which occurred in 5.9% of the biopsy group.

The Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or Not? trial²¹ more recently studied MRI with or without targeted biopsy vs standard transrectal ultrasonography-guided biopsy in 500 men who had not undergone biopsy before, and reported similar results. MRI with or without biopsy led to fewer biopsies and less overdetection of clinically insignificant prostate cancers compared with the standard approach. Furthermore, those in the MRI-targeted biopsy group were 13% less likely to receive a diagnosis of clinically insignificant cancer than those who received the standard biopsy (adjusted difference −13 percentage points, 95% confidence interval [CI] −19 to −7, P < .001).

Together, these data provide another argument for adding multiparametric MRI to the workup of men with an elevated PSA level.

Surveillance vs treatment for prostate cancer

Once prostate cancer is diagnosed, surveillance is becoming an increasingly common management strategy.

The Prostate Cancer Intervention Versus Observation Trial (PIVOT),²² one of the largest and longest trials involving cancer patients, offered further evidence that active surveillance and less intervention for men with prostate cancer is a better approach in many cases. This trial compared prostatectomy and observation alone in a randomized fashion. Inclusion for the study required men to be medically fit for radical prostatectomy, along with having histologically confirmed localized prostate cancer (stage T1-T2NxM0 in the tumor-node-metastasis classification system) of any grade diagnosed within the last 12 months.

During 19.5 years of follow-up, 223 (61.3%) of the 364 men randomly assigned to radical prostatectomy died, compared with 245 (66.8%) of 367 men in the observation group; the difference was not statistically different (P = .06). Only 9.4% of the deaths were due to prostate cancer, 7.4% in the surgery group and 11.4% in the observation group (P = .06).

Surgery was associated with a lower all-cause mortality rate than observation in the subgroup of patients with intermediate-risk prostate cancer (defined as PSA 10–20 ng/mL and a Gleason score of 7). Surgery was also associated with less disease progression.²²

This finding is in line with previous data from the Scandinavian Prostate Cancer Group Study Number 4,²³ as well as the much larger Prostate Testing for Cancer and Treatment (ProtecT) trial,²⁴ both of which reported that metastasis was 1.5 and 2.6 times as common, respectively, in participants in the active surveillance groups. However, in the PIVOT trial, those in the surgery group were significantly more likely than those in the observation group to have erectile dysfunction and urinary incontinence at 10 years.

Therefore, in men with localized disease and in those with low-risk PSA levels, both the PIVOT and ProtecT trials suggest that death from prostate cancer is uncommon and that observation may be more appropriate.

Prostate cancer: Take-home points

• A new look at 2 large trials of PSA screening strengthened evidence that testing in the right patient population can reduce deaths from prostate cancer, but a third recently published trial that found no benefit from 1-time screening may reopen debate on the topic.
• MRI offers a better method than ultrasonography-guided biopsy to triage patients thought to be at high risk of prostate cancer and tends to limit costly overtreatment of disease that likely would not cause death.
• Surgery for prostate cancer may not prolong life but could reduce disease progression, at the risk of more adverse effects.
• Shared decision-making should be practiced when deciding whether to use active surveillance or active treatment of diagnosed prostate cancer.