Rebuttal to “What’s the Truth About Prostate Cancer?” - 063

This newsletter is a rebuttal to an article, “What’s the Truth About Prostate Cancer,” posted by Howard Wolinsky on his Substack, The Active Surveillor. Dr. Bert Vorstman, a urologist, and Ron Piana, an investigative reporter, wrote the article.

If you haven’t read it, I encourage you to do so. My rebuttal will make a lot more sense if you read it first.

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Role of the contrarian

Although many of my Substack posts take a contrarian stance, I strive to provide a balanced perspective, even when I selectively choose data to support my viewpoint.

One-sided stories present a subtle danger, especially when discussing a cancer diagnosis.

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The article by Vorstman and Piana points out legitimate concerns in prostate cancer screening and care. I agree with their remarks about:

• The risk of overdiagnosis and overtreatment.

• The limitations of a 12-core systematic blind prostate biopsy.

• Patient anxiety linked to diagnostic processes.

• Treatment complications.

• A flawed healthcare system easily influenced by financial incentives.

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However, in their effort to offer a strong critique, they overlooked nuance. In prostate cancer, nuance is crucial.

My response is not just about offering a counterargument but a balanced perspective because men facing this diagnosis need clear information, not increased frustration.

If Vorstman and Piana were right about everything in their paper, then recommendations from my physicians that I've agreed to and the subsequent actions I've taken on my journey with advanced prostate cancer could be considered a waste of time.

But, I can tell you, without a doubt, had I not undergone a prostatectomy or radiation therapy twice, I wouldn’t be here today.

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Fighting yesterday's battle

The article is a polemic, framing the entire field of prostate cancer management as a financially driven "hoax." The problem in portraying it that way is that the authors are attacking a caricature of urology from 20 years ago.

Their accusations don't match the reality of how urologists practice prostate cancer screening and management today.

According to them, treatment is often worse than the disease, the prostate-specific antigen (PSA) blood test is useless, and surveillance doesn't save lives.

That kind of narrative might feel empowering to some. But for men who are interested in screening, are in active surveillance, or who are living with a diagnosis of advanced prostate cancer, it's like deleting the map while we're still deep in the woods.

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Nuance is crucial

Let's look at where Vostman and Piana's paper lacks nuance.

Vorstman and Piana state that "most prostate cancers are outlived." This concept applies to a specific subset of cases. Yes, indolent, slow-growing Gleason 6 cancers seldom become life-threatening.

But that statement doesn't represent the complete picture. It definitely doesn't represent the 394,200 men who died from prostate cancer globally in 2022.

Prostate cancer appears in very dangerous forms, such as high-grade Gleason 8–10 tumors. Without treatment, aggressive prostate cancer can rapidly spread to bones, damage organs, and shorten lives.

To suggest that treatment is "commonly worse than the disease itself" without discussing breakthroughs in therapy for men with advanced prostate cancer is misleading. Such a statement might unintentionally encourage inaction in men who urgently require treatment.

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Breakthroughs in therapy

Treatments for metastatic hormone-sensitive prostate cancer (mHSPC) had shown dramatic improvements in median overall survival since 2010, when monotherapy with androgen deprivation therapy (ADT) was the standard of care.

The CHAARTED trial demonstrated that for men with high-volume mHSPC, the median overall survival was 51.2 months when docetaxel was added to ADT, compared to 34.4 months with ADT alone.

Triplet therapy in mHSPC shows the deepest survival curves reported to date:

• In ARASENS, adding darolutamide to ADT + docetaxel lifted the 4-year overall-survival from 50.4 % to 62.7 %.

• In PEACE-1, median overall survival for the abiraterone triplet remains unreached after 68 months’ median follow-up, whereas ADT + docetaxel alone reaches ~53 months.

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Fear-based statistics or reality

The authors state, "Regrettably, the frequency of this cancer is exploited through the marketing of fear-based statistics such as 1 in 8 men will be diagnosed with prostate cancer in their lifetime and that it's the second leading cause of death in men after lung cancer."

The article links to those statistics on the American Cancer Society's (ACS) webpage. How is this marketing? It is the ACS's job to provide accurate statistics about every cancer, regardless of what fear it might induce.

The fact that prostate cancer is the second leading cause of cancer deaths in men is significant. That statistic represents a lot of men and their families. Whether people read those statistics and develop fear or not is irrelevant.

Facts are facts, and people want the truth.

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The 'false cancer' allegation and the reality of clonal evolution

The article claims that Gleason 3+3=6 "lacks the hallmarks of cancer, exhibits minor biochemical features,” and is a "false cancer." These claims are scientifically inaccurate and ignore the biological nature of these low-grade tumors and their proven potential to evolve.

First, let's establish the evidence that Gleason 6 is, by definition, a carcinoma. The authors claim it lacks cancerous features, but pathology and molecular biology tell a different story:

• Loss of basal cells is a fundamental characteristic that distinguishes prostate carcinoma, including Gleason 3+3, from benign glands. The absence of the outer basal cell layer is a key diagnostic feature of all prostate cancers. The exception to this would be intraductal carcinoma of the prostate (IDC-P) which retains the basal cell layer.

• Infiltrative growth pattern: Gleason pattern 3 glands exhibit an infiltrative growth pattern, haphazardly invading the surrounding prostatic stroma. Benign glands do not display this behavior, and this architectural difference serves as a crucial visual cue for pathologists.

Molecular changes: Even low-grade prostate cancers exhibit distinct genomics compared to benign tissue. These include:

• TMPRSS2:ERG gene fusions: Found in 40-50% of prostate cancers, though less frequently in Gleason 6. One study showed that ERG-positive Gleason 6 patients had significantly shorter cancer-specific survival. A "minor biochemical feature" doesn't shorten cancer survival.

• Copy number alterations (CNAs): Studies have shown that as the frequency of these chromosomal gains or losses increases in Gleason 6 tumors, the risk of recurrence and mortality also increases. A "minor biochemical feature" doesn't increase the risk of recurrence and death.

• PTEN loss: The loss of this protective gene, which is more common in high-grade cancers, is also found in a small subset of Gleason 6 tumors. This study shows “that PTEN protein loss in Gleason score 6 biopsies, although uncommon, is associated with an increased risk of tumor upgrading at radical prostatectomy.” A "minor biochemical feature" does not cause a pathologic upgrade at prostatectomy.

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Second, the authors’ claim that higher-grade cancer must be an entirely new tumor and that tumors cannot upgrade ignores decades of cancer biology research.

The molecular features above are part of the reason tumors can evolve.

That's not theory. That's biology.

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• A genomic study by Nurimen et al. analyzed DNA from 22 different tumor sites within two patients who had undergone radical prostatectomy and precisely mapped out how multiple prostate tumors in the same person originated from one rogue cell and evolved over several years.

• A 2013 study published in Cancer Research demonstrated that a small subset of Gleason 3 tumors can progress to Gleason 4 in a linear pattern of evolution, often driven by molecular features such as PTEN loss.

• A study by Bakbak et al. found that adjacent Gleason 3 and Gleason 5 patterns were often clonally related, meaning a pure Gleason 3+3 could represent an early stage of a lineage that can evolve into higher-grade disease.

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Calling Gleason 6 "false cancer" downplays the inherent potential for progression present within these clones. To claim there is "no evidence" for this evolution does a disservice to men on active surveillance whose rising PSA may indicate that a once slow-growing cancer is becoming more aggressive, possibly through clonal evolution.

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Using biomarkers to augment PSA and DRE

Attacking the Prostate-Specific Antigen (PSA) test and Digital Rectal Exam (DRE) as "wholly unreliable" disregards current diagnostic practices. No knowledgeable healthcare provider relies solely on these tests for diagnosis.

Clinicians following the National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA) guidelines may use individual risk factors, mpMRI, and adjunct biomarkers to help decide who needs a biopsy and who doesn’t.

The authors reference "prostate cancer markers," saying there's no evidence that any of these markers "...are accurate enough to estimate which prostate cancers are potentially deadly or may become deadly so as to alter care."

However, a study published in European Urology showed that the four-kallikrein panel (used in the 4Kscore test) is accurate in predicting the long-term risk of prostate cancer death, particularly in men with an elevated PSA, where uncertainty is highest.

This level of accuracy enables practitioners to “alter care” decisions by reducing unnecessary biopsies.

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Article claim:

“Amazingly, urologists' studies have concluded that at 12 years, 15 years and almost 20 years, radical prostate cancer surgery failed to save significant numbers of lives and had the same outcome as observation."

Evidence-based assessment:

To support this statement, the authors reference the Prostate Cancer Intervention versus Observation Trial (PIVOT) and the Prostate Testing for Cancer and Treatment (ProtecT) trial.

For the PIVOT trial, patient accrual occurred from 1994 to 2002, and for the ProtecT trial, patient accrual took place from 1999 to 2009. Both studies recruited men diagnosed using PSA testing and systematic, non-targeted TRUS-guided biopsies.

While these trials did accrue data over many years, their selection criteria and initial management strategies were based on the prevalent standards of their time.

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Those standards differ significantly from current approaches that incorporate advanced imaging, targeted biopsies, and more refined risk stratification and active surveillance protocols.

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It wasn't until the period between 2019 and 2023 that major international urological and cancer organizations incorporated multiparametric magnetic resonance imaging (mpMRI) into their guidelines for both the diagnosis and active surveillance of prostate cancer.

Today, when properly used, mpMRI acts as a critical filter. It improves the detection of clinically significant cancer (Gleason ≥3+4) and helps avoid the detection of insignificant cancer. A man with a high PSA and a negative (PI-RADS 1-2) MRI may avoid a biopsy altogether.

A man with a positive MRI (PI-RADS 4-5) will likely undergo a targeted biopsy, in conjunction with a systematic biopsy that is much more likely to find the aggressive cancer that benefits most from treatment.

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Therefore, men recommended for surgery today represent higher-risk patients compared to those in the ProtectT and PIVOT trial populations.

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Another issue to consider is that both trials included a very large proportion of men with low-risk disease.

• In the ProtecT trial, approximately 77% of participants had Gleason 6 cancer.

• In the PIVOT trial, after initial biopsy readings and a subsequent central pathological review, approximately 52% of men had Gleason scores of 6 or less.

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It's no wonder the studies didn't show that treatment saved lives. The majority of men in both trials had cancer that was unlikely to be lethal.

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These trials are not generalizable to today's clinical practice and cannot answer the modern question: After using mpMRI and biomarkers to filter out low-risk disease, does radical prostatectomy improve survival in men with well-characterized, clinically significant prostate cancer?

The authors failed to mention:

• An analysis of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) clinical trial showed that for younger men (<65) and those with intermediate-risk disease, surgery provided a significant reduction in prostate cancer death.

• The ProtecT trial itself demonstrated that men who received treatment experienced a 50% relative risk reduction in cancer progression or metastasis compared to those on active monitoring. When translated to absolute risk reduction, the figure isn’t nearly as impressive, but:

  • While the ProtecT trial’s primary endpoint showed no significant difference in prostate-cancer–specific mortality at a median 15-year follow-up, radical treatment (surgery or radiotherapy) produced an absolute reduction of roughly 4.6–5 percentage points in the cumulative incidence of distant metastasis — a statistically significant secondary outcome (hazard ratio 0.47-0.48 vs active monitoring).

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The purpose of active surveillance

The authors stated that "... there's no scientific evidence that active surveillance saves lives."

Their statement misrepresents the goal of active surveillance. Active surveillance aims to protect men from unnecessary treatment while monitoring the cancer for signs of progression. When that danger arises, that is the time to intervene.

Experienced and knowledgeable specialists, through consensus, design active surveillance protocols to detect signs of cancer progression at an early stage.

Large studies show that 5-year progression rates on active surveillance vary from 14% to 50%, depending on the specific criteria and monitoring intensity.

The most common cause of men transitioning off AS is a medical reason, either disease progression or recommendations from a doctor.

For those whose cancer does progress, timely treatment remains possible. When implemented correctly, active surveillance minimizes harm from overtreatment while preserving the option for curative therapy.

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A dangerous rejection of modern medicine

In another interview, Howard Wolinsky asks, "Should men skip PSAs?" and Dr. Vorstman answers, "Absolutely."

There is no mention of caveats or exceptions.

Then Howard asks, "Should they not go on AS?" And Dr. Vorstman says, "Yes. Stop PSA testing and active surveillance."

Dr. Vorstman's reason? "There is no irrefutable and reproducible scientific evidence for safety or benefits - we're not saving significant numbers of lives."

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I have some questions:

• What about the 47-year-old man whose father died of pancreatic cancer and his mother died of breast cancer, and he just found out he has a BRCA germline mutation? Should he get a PSA test?

• What about the 45-year-old African-American gentleman whose father died of prostate cancer in his fifties? Should he get a PSA test?

• What about the 53-year-old man on active surveillance whose last prostate biopsy showed an increase in Gleason pattern 4 from 10% to 20%, and his PI-RADS score increased from 2 to 3? Do you think he should stop active surveillance?

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Should we disregard all individual risk factors because the science isn't yet perfect?

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Medicine is the art and science of making the best possible decisions with the available data and tools rather than waiting for perfection while a disease progresses.

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Patients want doctors who are savvy and innovative

The most savvy and innovative physicians work with what they've got and do their best to thread the needle for patients even when they know the science isn't yet optimal.

They combine individual risk factors with tests like PSA, mpMRI, PSA density, and liquid biomarkers to develop the most effective screening and management approach for each patient.

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Professional guidelines incorporate risk stratification

A balanced assessment of the medical literature about prostate cancer supports a risk-stratified approach as recommended by the NCCN and AUA guidelines:

• Informed PSA-based screening based on individual risk factors.

• The use of adjunct biomarkers when appropriate.

• MRI-guided biopsy, when indicated.

• Active surveillance for Grade-Group 1 and many Grade-Group 2 tumors.

• Selective systemic therapy for higher-risk disease, when indicated.

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Conclusion

I welcome critiques of medical overtreatment and inadequate screening measures. However, those critiques carry more weight if they are precise, like a scalpel, and not wielded like a sledgehammer.

Vorstman and Piana's article raises important points, but its sweeping generalizations risk creating unnecessary fear and confusion.

We must never lose sight of the man at the center of this journey, who faces a series of difficult decisions. The foundation for an informed choice is not based on outdated criticism, but accurate information rooted in modern clinical practice.

This means providing a clear understanding of today's rigorous, evidence-based guidelines from the NCCN and AUA. By delivering this information clearly, we effectively support the men who rely on our guidance, enabling them to make informed decisions about their next steps.

Until the next newsletter, I wish you good health and much love,

Keith