Prostate Cancer Screening and Management: Two Men in Their Mid-70s Consider Their Path to Treatment

Correct answer: D. There is essentially no long-term mortality benefit between early surgery, radiation, or surveillance for standard risk PSA-screened men with biopsy positive for prostate carcinoma.

Discussion. The case vignettes presented serve to introduce, once again, the general topic of prostate cancer. Why should this be reviewed on a regular ongoing basis? First, prostate cancer is currently the most frequently diagnosed non-skin cancer of men in the United States, with approximately 250,000 cases per year. It is also the second most common cause of cancer deaths in men (after lung), with approximately 35,000 cases per year.¹ Second, the natural history of prostate cancer is long, such that good studies take years to "ripen" regarding whether there are any mortality benefits from any intervention. Indeed, more recent initiatives and data must be periodically reviewed. Finally, the topic has a great deal of somewhat conflicting (and, at times, noisy) opinion depending on how each individual clinician interprets the data that is being evaluated.

Looking at the data, there are two dominant issues regarding prostate cancer: the role of PSA screening and the decision making for management options for prostate cancer once diagnosed. One can recall the old clinical saw that "most patients with prostate cancer die with, rather than of, prostate cancer."

As to screening, the key methodology is measuring PSA. This protein is made in the prostate tissue, and "normal" levels remain less than 3-4 ng/dL, despite decades of attempts to refine the basic assay. In that time, the finding of a value above 4.0 ng/d/L had prompted an immediate biopsy. Currently, when the finding of a value above 4.0 ng/d/L occurs, at minimum, a discussion with the patient (eg, shared decision-making) is necessary to determine whether or not to do a biopsy as well as when to do so. Regarding whether to screen, 8% positivity in a random population will have abnormal PSA; 18% of that PSA-positive group having a biopsy will demonstrate prostate cancer; those negative on PSA screening with low PSA have a minimal (less than 0.3%) lifetime risk for prostate cancer. Importantly, screening 1000 men ages 50 to 76 will prevent 1.3 deaths from prostate cancer at 13+ years and counting.¹

Turning the statistics and emphasis around, a clinician needs to PSA screen 1000 men to prevent prostate cancer mortality after 13+ years of follow-up in 1.3 patients. Meanwhile, the invasive and expensive ordnance of post-screening biopsy, followed by positive biopsy therapeutics in the remaining 999 patients, who receive no mortality benefit, seems a prodigious input of capital versus return on equity.

Regarding the overdiagnosis and overtreatment resulting from current PSA screening schemes, suggestions include, a higher threshold for biopsy to avoid low-grade clinically insignificant disease, implementing age limits, and using velocity of change in PSA over time in thresholds for biopsy could potentially improve efficiency in screening.²

Another large recent study³ added magentic resonance imaging (MRI) to help choose who receives an immediate versus targeted biopsy. This study showed that the introduction of MRI after a positive PSA screening and only performing MRI-directed biopsy was not inferior to standard 12-core prostate biopsy in all PSA-positive cases for detecting high-risk prostate cancer cases. It was, however, associated with 39% less biopsy procedures, 30% less benign biopsies, and 17% less Gleason 6 scores (low-grade cancers) for a total of 47% less clinically normal or insignificant biopsies performed.³ I suspect this maneuver will become the new standard of care.

So, what are the current guidelines? They can be summarized and listed in order of conservative-to-aggressive:²

• US Preventive Task Force (USPSTF): Discuss harms and benefits of screening, screen ages 55 to 69, and no screening for men older than 70 years of age.
• American Academy of Family Physicians (AAFP): essentially the same as the USPSTF.
• American Urological Association (AUA). No screening for ages 40 to 54, shared decision-making for ages 55 to 69, and no screening for those older than 70 years of age.
• American Cancer Society. Discuss screening. Screen for those older than 50 years of age, Black men or men with first degree relative with prostate cancer prior to age 65, and those older than 45 years of age. (Author’s Note: There is no mention of stopping screening for those older than 70 years of age like the USPSTF, AAFP, and AUA).

Regarding the management of prostate cancer once diagnosed, there are three well-studied ways of approaching "low risk" cancers (e.g. up to Gleason 3/4 on pathology reports), which comprise more than 75% of prostate cancer diagnoses: (1) radical prostatectomy, (2) radiation therapy, and (3) active observation (also referred to as "watchful waiting.")

The good news is that strong randomized studies have shown essentially no statistical differences in the key end points of prostate cancer mortality and overall mortality at 13 years after initial diagnosis, and most likely, 15 to 20 years out as well.^1,4 This is encouraging data for a condition diagnosed with greatest incidence in age group in their 70s. There are some differing side effects among the three modalities, the most important being a higher frequency of side effects with surgery (especially urinary incontinence, 17.3%, sexual dysfunction 14.5%). For radiation, side effects include an increased incidence of bowel dysfunction. With observation, can the patient tolerate the waiting?^1,4

Regarding the treatment options, currently PSA levels during follow-up are used to detect "biochemical recurrence."⁵ In fact, patients do so well that it’s worth asking whether there are more accurate ways of detecting dangerous recurrence versus PSA biochemical recurrence screening since even the addition of androgen deprivation therapies (ADT) like leuprolide have noxious effects such as bone demineralization and increased fracture incidence.⁵ Newer agents, such as next generation ADTs and enzalutamide, have been studied and seem to improve outcomes in biochemical recurrent prostate cancers without undue additional toxicity.^5,6 In a study comparing outcomes at 5+ years in more than 700 patients with recurrent prostate cancer, there was superior metastasis free survival but not overall survival.⁶  But in my view, the study understates some of the data in their result charts to favor more therapy. For example, looking at overall deaths at 60 months, the leuprolide alone group had 55 deaths, while the enzalutamide combination group had 42 (13 less, but not statistically significant). For distant metastases, there were 19 less deaths, again not statistically significant. Meanwhile, the toxicity profile showed that 53 patients in the enzalutamide combination group had cognitive and memory impairment compared with 23 patients in the leuprolide alone group. Additionally, the enzalutamide combination group had 65 fractures related to androgen lowering versus 48 with the leuprolide alone group.⁶ Unless longer term follow-up provides stronger mortality benefit, I do not find these results compelling, and were I a voting member on an FDA panel, I would not cast a vote to approve use. As the accompanying editorial states, "there is more to life than death."⁵

I have always been somewhat strict in analyzing papers. Indeed, I am wary when "improved clinical outcomes" rather than mortality and/or prostate cancer-related mortality are utilized to cover essentially any and all lesser surrogate end points along the way. The mortality-related end point should remain the gold standard of end points. And raw numbers of events speak more to me than statistical mixtures of surrogate end points too often used in new agent therapeutic studies.

In summary, both PSA screening and therapy for biopsy positive prostate cancer are double-edged swords. This is a good thing since patients are doing so well that it takes 10 to 20 years to determine what, if any, advantages accrue. And further, the differences are so relatively small that it requires 1000 PSA screenings to save one patient from prostate cancer death at 13+ years and requires 300 patients to undergo active prostate cancer therapies (raditation therapy or surgery) to prevent two such deaths.

As with PSA screening, whether a clinician chooses therapy and which strategy to use involves case-by-case situations and a large dose of informed shared decision making. One of the studies states "findings from randomized [PSA] trials support a modest reduction in prostate cancer mortality."¹ To which, I say "modest indeed!".

Regarding therapy and prognosis, the outlook is quite good such that the old clinical saw remains true: "most patients with prostate cancer die with, rather than of, prostate cancer."

Patient follow-ups. The first patient subsequently saw two physicians, a urologist and radiation oncologist. After listening to the options and asking detailed questions from reading background material, he has chosen active surveillance. He will have periodic PSA measurements and clinical evaluation monitoring and knows there may be need to address progression later. He is very comfortable with this approach.

The second patient has a biopsy scheduled. Similar discussions with him reveal that should his biopsy be positive to whatever degree, low risk or no, he is uncomfortable with surveillance of a cancer diagnosis, which makes him nervous. He will proceed to immediate treatment in that event, most likely choosing radiation therapy.

What’s the Take Home? The major issues and questions regarding prostate cancer are:

• Screening: if, who, and when?
• Management and therapy: if, when, and how?

Since the 1990s, there has been a slow, but steady evolution to more cautious, conservative, and case-specific management of both issues. While every life saved is precious, mortality due to prostate cancer is low, which is something that should be considered when large numbers of screened patients are being exposed to the ordinance of biopsy, hormonal therapies, radiation, radical prostatectomy, and the mental anguish of being a "patient with cancer" even though they are unlikely to die of it, but with it.

There is a continuum of conservative to aggressive guidelines in management depending upon which physician's office one enters. Most aggressive regarding PSA screening is the American Cancer Society. Intermediates are the Urological Surgery Groups and most conservative are the General Practice, Internal Medicine and Medical Oncology Groups.¹ It is not generally understood that patient input, both explicit (age, family history, race, co-morbidities) and implicit (balancing morbidities of future therapy to patients' desires and lifestyles), is vital before making a treatment decision.

Once diagnostics are triaged for risk potential, there are three avenues of management: active surveillance, radiation therapy, and radical prostatectomy. Good data (e.g. large, randomized trials with long term follow-up), demonstrate no differences in overall survival or prostate cancer-related survival at least 10 years and likely 15+ years out, which must be a consideration for both screening and management in a condition usually diagnosed in men 65 years of age or older.

AUTHOR
Ronald N. Rubin MD^1,2

AFFILIATIONS
¹Lewis Katz School of Medicine at Temple University, Philadelphia, PA
²Department of Medicine, Temple University Hospital, Philadelphia, PA

CITATION
Rubin RN. Prostate Cancer Screening and Management: Two Men in Their Mid-70s Consider Their Path to Treatment. Consultant. 2024;64(9):eXX. doi: 

DISCLOSURES
The author reports no relevant financial relationships.

CORRESPONDENCE:
Ronald N. Rubin, MD, Temple University Hospital, 3401 N. Broad Street, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)

REFERENCES

1. Pinsky PF and Parnes H. Screening for prostate cancer. N Eng J Med. 2023;388:1405-1414
2. Weich HG and Albertson PC. Reconsidering prostate cancer mortality-the future of PSA screening. N Eng J Med. 2020;382:1557-1563
3. Eklund M, Jarderling F, Discacciati A, et al. MRI targeted or standard biopsy in prostate cancer screening. N Eng J Med. 2021;384:1-13
4. Wilt TJ, Jones KM, Barry MJ et al. Follow up of prostatectomy versus observation for early prostate cancer. N Eng J Med. 2017;377:132-142
5. Aparicio A. Biochemical recurrence in prostate cancer: tilting the scale. N Eng J Med. 2023;389:1522-1523.
6. Freedland SJ, de Almeida LU, Do Giorgi M et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Eng J Med. 2023;309:1453-1465.