Sunday, September 11, 2022

Short-term androgen annihilation in non-metastatic recurrent men delays progression

 A difficult question for patients who still having rising PSA after prostatectomy and salvage radiation is: Is there any advantage to starting advanced hormone therapy before metastases are visible?

Rahul Aggarwal presented the early results of the PRESTO trial. Patients (n=504) were chosen who had the following characteristics:

  • Failed prostatectomy and salvage radiation (85%). Half of those who had salvage radiation, had adjuvant ADT at the time
  • PSA>0.5 ng/ml
  • PSA doubling time (PSADT) ≤ 9 month
  • no metastases on conventional imaging (bone scan/CT/MRI)

Patients were randomly assigned to one year of any of the following treatments:

  1. ADT only
  2. ADT+apalutamide
  3. ADT+abiraterone+apalutamide

With follow-up of 21 months, biochemical progression-free survival (bPFS, PSA stayed under 0.2 ng/ml) was:

  • 20 mos. in Group A
  • 25 mos. in Group B (48% improvement vs Group A)
  • 26 mos. in Group C  (52% improvement vs Group A)
  • No significant differences attributable to PSADT
  • Group C wasn't significantly different from Group B (Zytiga added little)

Other findings:

  • Testosterone recovered in 4-5 months in all groups
  • More hypertension with abiraterone

Other trials have looked at adding a limited term of 2nd line hormonal medicines when there is rapid PSADT but before metastases have been discovered on conventional imaging.

  • Spetsieris et al. added abiraterone for 8 months. Afterwards, bPFS was 27 mos vs 20 mos. for ADT-only.
  • Madan et al. reported substantial PSA control with intermittent use (two 3-month cycles) of enzalutamide alone without ADT. PSA didn't rise for 6-7 months after the first and second cycles.

With detection of metastases with PSMA PET scans, the advantage of early intervention will become clearer. There is also a clearer advantage for men with a higher Decipher score. It is likely that even intermittent use will be advantageous. Men with rapid PSADT after salvage radiation should consider a short-term intervention with one of the advanced hormonals.

Friday, July 15, 2022

The Constitution of Medical Knowledge

Patients are often confused by seemingly conflicting findings of studies, or equally good doctors recommending different treatment plans. How are we to decide? Medical science is a process created by a “reality-based community” to help decide such questions. Science isn’t just hypothesis-testing with empirical observation, although that is a big part of it. It is also the consensus of a community of experts. In 1660, scientists led by Isaac Newton formed The Royal Society as the first institution designed to collect, encourage, and evaluate scientific knowledge. They published the first scientific journal in 1665 (which is still in publication). Were they ever wrong? Often! For example, for 250 years everyone wrongly believed Newton’s theory that gravity was a fundamental force of nature. And that is the point – knowledge is fallible and not subject to the personal authority of any one person. But over time, the arc of the universe of scientific knowledge bends towards truth.

There have been many improvements to the system of medical science since the Scientific Revolution. The first peer-reviewed journal was published in 1731. But peer-review as we now know it didn’t begin until the 1970s. The first randomized clinical trial occurred in 1747 (citrus for scurvy), but the rules for running double-blinded randomized clinical trials, and progressive Phase 1-3 trials weren’t systematized until Austin Bradford Hill and Harry Gold in the post-WWII era. Statistics entered medicine in the 1970s. Systematic reviews began in the late 1970s. Evidence-based medicine, as we know it today, was taught in medical schools since the 1980s.

Jonathan Rauch in “The Constitution of Knowledge: A Defense of Truth” describes knowledge as a funnel. At the top are all the guesses, the hypotheses, that drive scientific investigation. This would include (in order of increasing reliability) much of what is posted on any patient health forum every day: anecdotal “evidence” from patients; YouTube videos posted by Snuffy Myers, Mark Scholz, etc.; lab studies (mouse or test-tube); observational/epidemiological studies of patients; retrospective case-controlled studies, and systematic reviews/meta-analyses of them; cohort studies (people followed from before disease occurrence; e.g., Health Professionals Follow-Up Study, Mendelian Randomization Study). All of them are just hypothesis-generating. Most hypotheses are, and should be, wrong. Science depends on evaluating lots of hypotheses. There is no shame in guessing wrong; the only problems are when guessing stops and when one confuses a guess for a fact.

Large, well-done, and confirmed randomized clinical trials are at the bottom of the funnel; they are not just hypothesis-generating, they constitute truth in medical science. These categories were universally agreed upon after looking at which kinds of studies are likely to have conflicting results, and which almost never have conflicting results. All scientists believe in these categories; “pseudoscience” occurs when people claim to be doing science but ignore these categories. Here’s a fuller description:

Some institutions regularly GRADE prostate cancer research (NCCN, AUA, ASTRO, ASCO, SUO, EAU, CUA, PCF, and others). The institutional opinions (and not anyone’s personal opinion) are the standard-of-care. Until disproved, they constitute current medical truth. While even the best research doesn’t predict for the individual, one is foolish to ignore our best estimate.

There is no science without consensus by experts - science is a social construct. One can argue that there are and always have been objective truths, but we can only know what is in some way perceivable by humans. Did the Earth always revolve around the sun? Of course. But it did not enter the realm of science until Copernicus hypothesized it (1543), and Galileo (1609), Tycho Brahe (1573), Johannes Kepler (1609), and Isaac Newton (1687) proved it and showed how. That’s when astronomy became a science. There is no science without hypothesis-testing and empirical observers. 

 Loss of Respect for Expertise 

How do we know what is true? None of us has the time or the inclination to test everything for ourselves. We rely on trusted experts to tell us. Few doubt that the heart pumps blood to our lungs and other tissues, although few have seen our hearts do that. We know that William Harvey discovered that fact in 1628, and it is now universally accepted as true and foundational to all cardiology. Even fewer know how the nerves cause the heart to beat, how arrhythmias are diagnosed, or how plaques can cause heart attacks. We rely on cardiologists to know all that, and within cardiology are sub-specialties (e.g., heart transplant specialists, sports cardiology, etc.). There are dozens of medical specialties, each with several sub-specialties. There are even specialists in cutting across categories, and assuring that the latest innovations become available to patients; this is called “translational medicine.” In this era of specialization, few know much outside of their specialty, and as patients, we must, at some point, rely on the experts for our knowledge about disease, diagnosis, and treatment. 

Medical science became probabilistic in the 20th Century. All medical institutions agreed that statistics are the only way to reject hypotheses, judge superiority or inferiority, infer causality, and to analyze and reduce errors. Statistics are difficult to understand and are non-intuitive, even for many doctors. As sophisticated statistical techniques were adopted by the medical institutions and their publications, lay people, who did not have their arcane knowledge, were increasingly left out of the truth community. 

The Dunning-Kruger Effect is a cognitive bias on the part of incompetent people overestimating how much they know. In medicine, a little knowledge is a dangerous thing. When I started writing my novel, Thaw’s Hammer, about a killer virus, I thought I knew enough about the subject to write a credible novel. Four years later, I knew how much I didn’t know. I grew to admire the experts who had to understand the biochemistry of the replicative apparatus, the interactions with host cells, and the immune system. Viruses are the most numerous and diverse forms of life on Earth. Anyone who thinks they understand them is wrong. The experts differ from lay people in knowing they don’t completely understand them. Still, an expert understands a lot more than any lay person who thinks he knows more. I know enough to reject any advice from a Jenny McCarthy or a Joe Rogan in favor of advice from the CDC. 

Overconfidence in subjective assessments, when contrary to scientific consensus, is also influenced by alignment with political and religious social groups. The Dunning-Kruger Effect is particularly strong on the issues of vaccination (particularly Covid-19 vaccination), genetically modified foods, and homeopathic medicines (see this link).

Fundamentalism in Medicine

Knowledge is progressive and cumulative. Newton said, “If I have seen farther, it is because I have stood on the shoulders of giants.” Opposing this kind of humility, are people who think, based on a few facts or “alternate facts,” that they have arrived at the truth hidden from the rest of us. What they are really doing is inhabiting what Rauch calls an “epistemic (knowledge) bubble.” They are only allowing into their knowledge bubble those data, and persons, that confirm their biases. They take studies out of context and fail to rigorously analyze studies they agree with while finding reasons to disqualify studies that don’t agree with their preconceived notions. They reject the methods of analysis developed by the institutions they reject. They are usually smart and think that they are fully capable of judging the data for themselves. This takes a certain kind of narcissism – as if the whole world is full of “sheeple” and only they know the real truth. They are also lazy – it would be too much work to learn and evaluate the whole body of knowledge. 

Fundamentalism has been around in religion at least since the Protestant Reformation. But it emerges in all other areas of human knowledge – politics (as populism), law (as originalism/ anti-stare decisis), and folk/Internet medicine. It is usually short-lived: the fundamentalists of one generation eventually give way to the acceptance of an orthodoxy and hermeneutics for interpretation of texts. Fundamentalism substitutes personal authority for institutional authority. Personal knowledge is acquired rapidly and doesn’t require input from others. Because personal ego is at stake, it excludes all information that doesn’t confirm. Institutional knowledge, on the other hand, builds on a foundation of knowledge of the “truth community,” and includes conflicting data. The conflicting data create new hypotheses and the opportunity for knowledge to expand. If enough conflicting data accumulate, they may cause what Thomas Kuhn called a “paradigm shift.” 

Google is a wonderful thing. Knowledge is potentially at our fingertips, but information out of context can mislead. Instead of knowledge, we can be left with information that only confirms what we think we know. Social media ideally expose us to all sides of any issue. But if we are not open to all sides, social media can only reinforce the knowledge bubble we have built around our pre-determined beliefs. Without challenges to what we think we know, there is no progress. 

Distrust of Institutions 

There has been growing distrust of institutions among lay people, sometimes with good reasons. There were abuses like “p-hacking” that fostered distrust. Until recently, publications did not require authors to be transparent about potential conflicts of interest. Often, negative findings were not published (the US government now requires all registered clinical trials to publish their findings). Budget cutbacks at the NIH decreased funding for medicines and technologies that did not have profit potential. Mistakes and abuses were publicized in the media and over the Internet. Institutions are valuable not because they don’t make mistakes, but because they correct mistakes and abuses. Retractions and corrections are published. Researchers who lie are found out and excluded from future publication. 

The other threat to truth came from an unlikely source – conspiracy theorists. Before the Internet, they were just isolated “nut jobs.” But social media provided the means for them to find others with enough common beliefs to form a “non-truth” community. On the patient forum, HealthUnlocked, I’ve seen several who point to a supposed Big Pharma/FDA conspiracy. Although they are still a minority, they can have outsize influence by dominating conversations, mixing truth and lies, purveying lies so outrageous that some believe there must be some truth to them, and by blinding the conversation with so much bullshit that reasonable people despair of ever discerning the truth. On Facebook, Twitter and YouTube, bad actors can stage a concerted campaign to “like” and “share” content they want to use as propaganda. They can “troll” serious posts to render the conversation harder to follow. 

Because institutional knowledge was not readily comprehensible to laymen, and because distrust mounted as abuses were well-publicized, the Internet (Dr. Google) became a substitute for expertise. Laymen believed they understood the subjects as well as experts and their institutions, and they were able to find others on social media willing to tell them so. When biases are confirmed by media personalities they become particularly pernicious. We always believe relatable people we know and like (from TV, videos, and podcasts) versus strangers who author incomprehensible studies full of numbers and jargon we don’t understand. This cognitive error is called “the availability heuristic” – it’s why you may believe the claims of someone you know on an Internet forum over high-level statistical evidence. The danger of substituting personal knowledge for institutional knowledge in medicine became apparent with the anti-vaxxer movement. It had always been a fringe group, but in the US, a third of the population did not get vaccinated against Covid-19.

What can be done?

What can be done to restore faith in institutional truth? Rauch sees hope in the measures Facebook took after it came to light that bad actors from Russia manipulated Facebook’s algorithms to change what was seen by Facebook members. Facebook changed its algorithms and created software to eliminate bots. They also labeled and demoted content of dubious veracity. They established an independent oversight board with transparent rules. It reports to and is financed by independent trustees, who can remove its members if they act in bad faith. The board’s decisions are binding on Facebook and anyone who uses Facebook. Its decisions are published. It acts much like an independent court. The problem for a patient health forum like HealthUnlocked is that unless the oversight body is a panel of doctors, they cannot privilege the content of one post over another without risking lawsuits.

The most any patient forum can do is establish rules for civil discourse. I would suggest the following rules and guidelines for anyone posting in a patient forum:

(1) No ad hominem remarks. Ad hominems are remarks that insult the person. “You’re wrong about that and here’s why…” is entirely appropriate. “Jane, you ignorant slut!” is entirely inappropriate. Responses must speak to content, not the supposed intentions of the poster. If you don’t have anything good to say about a person, say nothing. This should eliminate trolling. Trolls thrive on attention and virtue-signaling, so don’t feed the trolls by responding in kind. Alert a moderator immediately. If you feel you have to make personal remarks, do it in private mail.

(2) Members cannot post dangerous or illegal content (e.g., a recipe for a known toxic substance or instructions on how to obtain it). They may post unproven or experimental therapies, and especially their own experience with them. Members are encouraged to identify experimental therapies as experimental. Hypotheses are entirely appropriate and encouraged.

(3) Avoid strawman arguments. Strawman arguments are ones that replace what the poster is actually saying with a false one which is then refuted. If you are starting a reply with the words “"So what you're saying is ... ?" or “Then you must also believe that…” you are probably setting up a strawman. The opposite is a steelman argument, where you restate what the poster said in the strongest form. It shows you are listening and want to resolve the issue.

(4) Avoid sarcasm. Sarcasm doesn’t work on the Internet. It usually only works if one can see your facial expressions and hear it in your voice. There are no sarcasm emojis, and the original poster will probably believe you meant it seriously. Making fun of a person is just a form of ad hominem. Humor is fine, but not as a rhetorical technique.

(5) Be aware that consensus is rare. Patients may get a lot of conflicting advice or anecdotes, and that’s okay. Discuss with a doctor you trust.

(6) Don’t take it personally if someone disagrees with you. Consider the issue as dispassionately as you can. It’s not necessary to reach agreement, just to flesh out the issue from all sides.

(7) Caveat emptor! No one on a patient forum is a doctor, and no one’s advice or personal experience should be taken as definitive. Anecdotes are not evidence. Check everything with your doctor. It is entirely appropriate to ask for source material for advice that goes beyond the standard-of-care, and to discuss those sources with your doctor. But remember that doctors may have little patience for sources that do not come from peer-reviewed journals or are low-level or low-quality evidence (see above).

Tuesday, June 21, 2022

Adjuvant Interventions for Active Surveillance

As of 2015, for men with low-risk prostate cancer (PCa), active surveillance (AS), is now the most popular "treatment" at 42%,  tripling since 2010. Its use was followed by radical prostatectomy (31%) and radiotherapy (37%). NCCN now lists AS as the preferred "therapy" for most men with low-risk PCa. They include these possible exceptions:

  • high PSA density
  • high number of positive cores
  • high genomic risk (e.g., on Decipher test, especially PTEN loss, TMPRSS2:ERG fusion, MYC activation,  or tp53 mutation)
  • known BRCA2 germline mutation

Other risk factors that are non-exclusionary but may suggest caution include family history, African-American ethnicity, and perineural invasion. Men with small amounts of Gleason pattern 4 are accepted in some AS programs now.

Memorial Sloan Kettering reported the following rates of AS patients who experienced grade progression:

  • 24% by 5 years
  • 36% by 10 years
  • 43% by 15 years
With the growing popularity of AS, and improved patient selection with mpMRI-targeted biopsies, there is interest in ways to extend time on AS. Several "adjuvant interventions" have been proposed to accomplish this. Adjuvant interventions can be categorized as systemic hormonal therapies, focal treatments, immunotherapies, and diet/supplements/lifestyle interventions.

It must always be recalled that the purpose of AS is to maintain guality of life (QOL) for as long as possible. Some interventions are minimal, do not harm the QOL or may (like exercise) even enhance the QOL. Some interventions harm QOL but only for a limited period.

AS without intervention performs very well for most low risk men, especially those with fewer risk factors. Interventions geared towards men on the less risky end of the AS spectrum must be less intrusive than interventions designed to prolong treatment-free survival among men who have greater risk.

In the end, the patient must weigh the risk and benefits of the intervention against the potential for AS prolongation.

I. Systemic Hormonal Therapies

5ARis (Proscar or Avodart)

Proscar (finasteride) and Avodart  (dutasteride) belong to a class of medications called 5-alpha-reductase inhibitors (5ARis) that are often prescribed to lessen symptoms of BPH. They prevent the metabolic conversion of testosterone to dihydrotestosterone (DHT), which is a much more powerful activator of the androgen receptor. It is the only known drug that can prevent prostate cancer. While there were initially some hints that it might cause high-risk PCa, many studies have now refuted that (e.g. this one or this one). When there is BPH, 5ARi use lowers PSA by about half and shrinks the prostate, which facilitates cancer detection. 

Fleshner et al. reported on a prospective clinical trial in which 289 men at 65 centers who chose to be on AS were randomly alocated to get dutasteride or a placebo. They were checked with a biopsy at 18 months and at 3 years. After 3 years of follow-up, they reported:
  • 38% of men using dutasteride and 48% using placebo  experienced progression, a statistically significant difference
  • 24% of men using dutasteride and 15% using placebo reported sexual adverse effects or gynecomastia
  • No prostate cancer-related deaths or metastases 

Finelli et al. retrospectively reported on 288 men on AS at Princess Margaret Hospital in Toronto. After median follow-up of 7 years, they found:

  • Pathologic progression (increased grade, increased # of core>3, or any core involvement > 50%): 28% of men using 5ARis vs 56% of non-users.
  • Grade progression: 22% of men using 5ARIs vs. 40% of non-users
  • Volume progression: 18% of men using 5ARIs vs. 43% of non-users
  • Definitive treatment: 27% of men using 5ARIs vs. 51% of non-users
  • Frequency of progression to Gleason 8-10 was the same for both groups: 2% of men using 5ARIs vs. 4% of non-users

Kearns et al. retrospectively reported on 107 men who used a 5ARi and 902 men who didn't while on AS in the multicenter PASS trial.
  • There was no statistically significant difference in the percent of men reclassified
  • Men using 5ARis were less likely to undergo definitive treatment (19%) vs. non-users (24%)
  • There was no difference in adverse pathology among men opting for prostatectomy
Shelton et al. at Carolinas Medical Center reported that among 82 men who had very-low-risk PCa and BPH who were given a 5ARi for one year, over half had no cancer in a subsequent biopsy. This is especially encouraging, because with prostate shrinking, we would expect the cancer to be easier to detect.

It is also worthwhile to note that 5ARis improve the sensitivity of PSA to detect prostate cancer; rises while taking the drug are more likely to be due to prostate cancer progression than to BPH (see this link). Chiang et al. proposed that 5ARis can be used to render PSA doubling time a good indicator of progression for men on AS.

Tan et al. at UCLA reported that 5ARis, because they reduce urinary symptoms, may reduce the anxiety associated with AS. This may encourage men to stick with AS longer. In 2011, the FDA approved daily Cialis for LUTS and BPH. Cialis (tadalafil) is now available as a low cost generic. Taking it with a 5ari may mitigate some of the sexual side effects too.

Androgen Deprivation Therapy (ADT)

Cussenot et al. reported on a French Phase 3 clinical trial among 115 men on AS randomized to get one 3-month shot of  Lupron or not. After a year, they were biopsied:

  • 53% had negative biopsies, if they'd had the Lupron vs. 32%, if not
  • Prostate symptoms improved at 3-9 months among those who took the Lupron
  • Sexual function was similar in both groups after a year
  • Other endpoints were no different: % with grade progression, progression on MRI, PSA progression, anxiety

The problem with such clinical trials is "lead-time bias." That means that the Lupron may have shrunk the cancer while it was effective, but after testosterone returned to normal, the cancer may have resumed growth at the same pace. To control for lead-time bias, the biopsy in the Lupron-using group should have occurred 12 months after their testosterone returned to its baseline level. If all the Lupron did was defer progression for 3 months, there was no benefit and probably some quality-of-life harm while taking it.

Apalutamide (Erleada)

Erleada is a powerful 2nd generation anti-androgen. It is useful in newly-diagnosed men with metastases and castration-resistant men without metastases. The major toxicities are fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.

Barrett et al. reported on a single-arm pilot trial called TAPS-01. Nine men on AS were given 3 months of apalutamide.

  • At the end of treatment, prostate volume shrank by 38%, tumor volume shrank by 54%, and the ratio of tumor volume to prostate volume shrank by 27%
  • 3 months after treatment, prostate volume returned to baseline, while tumor volume and the ratio were 32% and 29%, respectively, less than at baseline
  • 15 months after treatment,  tumor volume and the ratio were 18% and 24%, respectively, less than at baseline
  • QOL scores decreased during treatment but returned to baseline 6 weeks after treatment

They are planning to recruit 335 patients for a Phase III randomized trial.

Michael Schweizer presented the results of another small  (n=22) trial at the 2020 SUO meeting. Patients were mostly low risk (64%), but a few were very favorable intermediate risk (36%). They were given 3 months of apalutamide.

  • At the end of treatment, 59% had negative biopsies.
    • 35% had negative biopsies 9 months later
  • All 4 patients who were biopsied at 2 years had positive biopsies
  • PSA returned to baseline level 9 months after treatment

There is a randomized Phase 2 trial in France (see this link).

Enzalutamide (Xtandi)

Shore et al. reported the results of the ENACT clinical trial in which 227 men at 66 sites were randomized to get 1 year of enzalutamide monotherapy+AS (enza) or AS-alone. None had very low risk PCa, 53% had low-risk PCa, and 47% had favorable intermediate risk PCa.

  • Disease progression: 28% on enza vs 37% on AS
  • Pathologic or therapeutic progression was lower with enza at the end of therapy (8% vs 23%), but there was no difference a year later (16% in both arms)
  • By 2 yrs after randomization, there was no significant difference in the % with positive biopsies, % of positive cores, or the % with a secondary rise in PSA.
  • Among intermediate risk patients, therapeutic progression was 25% for enza vs 39% for AS-only
  • Adverse events (AEs) were experienced by 92% for enza vs. 55% for AS-only
  • Drug related AEs were fatigue, breast effects, ED, baldness, libido loss, hot flashes, and GI disturbances

This trial exhibited significant lead-time bias. PSA progression occurred precipitously at 15 months, when the enzalutamide wore off (Fig 2B). If the enza patients were monitored starting when the enza wore off and they were compared to the AS-only patients from the date of randomization, there would be no effect ever seen for enza therapy. Patients suffered the side effects of enza for nothing. There may be some opportunity for its use in favorable intermediate-risk patients on AS, but that requires further trials.

II. Focal therapies

We looked at photodynamic therapy (PDT) using sensitization with TOOKAD previously (see this link). After 4 years of follow-up, 24% of TOOKAD users and 53% of AS-only users converted to radical therapy (RP or RT). But 5-yr conversion rates were similar at MSK (24%) and Klotz (28%). There are several apparent reasons for this discrepency:

  • Very low risk patients were excluded in the TOOKAD trial
  • TOOKAD retreatment was given if a 1-yr biopsy indicated progression.
  • All of the TOOKAD group had mpMRI, while none of the AS-only group did. Many in the AS-only group would have been excluded from AS if mpMRI had been used to confirm their low-risk cancer.

The other major finding was that 49% had a negative biopsy after TOOKAD treatment and retreatment vs 14% with AS-only. In another study, 52% had no evidence of disease on a confirmatory biopsy with AS-only. In a UCLA study using mpMRI to find suspicious sites, the apparent remission rate was 40%. The reason for the discrepancy is that the AS-only group in this trial included many men who should never have been on AS if mpMRIs had been used initially to find their cancer.

As we've seen (above), an apparent remission rate of 54% can be achieved by simply taking a Proscar or Avodart pill (see this link).

For a discussion of treatment toxicity, see the previous article. Also, see the comparison with SBRT at 2-years post-treatment. It shows the patients would have been better off had they been given definitive treatment with SBRT.

The FDA has rejected TOOKAD as a treatment for low-risk prostate cancer, but a longer follow-up study is expected in 2025.

Ehdaie et al. conducted a clinical trial of an MRI-based HIFU technique (see this link for analysis of a whole-gland TULSA-PRO trial). They only treated intermediate-risk patients (78% Grade Group 2, 22% Grade Group 3). The goal was to see if HIFU could maintain such patients on active surveillance and forestall radical treatment. There were 101 patients treated at 8 institutions. At 2 year follow-up:

  • 20% still had cancer in the ablation zone, 12% Grade Group 2 or higher
  • 60% still had cancer in the prostate, 40% Grade Group 2 or higher
  • PSA reduced from 5.7 to about 3.1
  • Among men with good erectile function at baseline, erectile function dropped by 40%, but only by 10% with ED meds.
  • Urinary function was maintained.
  • Transient hematuria (24%) and urinary retention (15%) were common immediately following treatment

We see results similar to TOOKAD above. There, about half still had cancer 4 years after treatment; Here, 60% 2 years after treatment. With 40% still having Grade Group 2 or higher, this treatment failed for many at keeping them on active surveillance and forestalling treatment. It doesn't matter how low the toxicity is, if the treatment doesn't do job #1. With significant PSA remaining after HIFU, patient anxiety and regret (not measured) may still be high. It's hard to see what was gained by putting patients through this operation.

It would be nice to see a comparative trial in intermediate-risk patients randomized to either HIFU or SBRT.

There is a clinical trial in Norway among intermediate-risk men with MRI-detected lesions on AS to be focally treated with HIFU (see this link).

III. Injections

Several one-time injections have been tried or proposed that could possibly extend time on AS.

Fexapotide Triflutate (FT)

FT was previously reviewed (see this link). It is injected only once into any quadrant of the prostate where Gleason 6 has been detected. It causes apoptosis of all prostate cells, benign and cancerous, but has no effect on other tissues. It was only used in men who had only one core that had <50% GS6 cancer. To recap:

After 4 years of follow-up:

  • 42% of AS patients progressed, and 39% were treated for progression
  • 19% of high-dose FT patients progressed, and 11% were treated for progression
  • Median biopsied tumor grade was Gleason 3+4 among those assigned to ASvs Gleason 3+3 among those who received high-dose FT. At 18 months, the median tumor grade for the high-dose group was benign (no cancer detected) vs GS 3+3 in the AS group.
  • At 18 months, estimated tumor volume in the quadrant with cancer increased by 69% for AS vs decreased by 59% for FT.
  • The effect of high-dose FT was greatest at 18 months, and still had an effect at 48 months.
  • PSA reduction was maintained in the FT group (-21%) 
  • There were very few and transient side effects attributable to the injections (blood in urine, sperm or stool), diarrhea or nausea from antibiotic.
  • There were no serious adverse effects - no increase in urinary symptoms
  • There were no significant sexual problems associated with FT treatment

Again, the treatment rate for AS progression is very high, especially in this very low risk population. The FDA has delayed approval pending 2 years more follow-up data.

Liproca (2-hydroxyflutamide)

Liproca is an intra-prostate injection for men on the riskier end of the AS spectrum. Klotz et al. reported on a dose-finding clinical trial of the one-time injection of a large volume (doses were varied) of the anti-androgen into the prostates of 61 men on AS who had the following characteristics:

  • GS 3+3 or 3+4, and
  • PSA > 6 ng/ml and PSA density > 0.15, or
  • PSA between 10-20 ng/ml, or
  • Any core >50% cancer, or
  • PIRADS 4 or 5, or
  • Men of African descent

After 6 months of follow-up:

  • After a transient PSA increase due to the large volume of liquid,  about half had a PSA reduction >15% by 6 months post-injection
  • Testosterone was at baseline by month 6
  • About ¾ of patients had a decreased prostate volume
  • No worsening of PIRADS csores were seen
  • Systemic leakage of the anti-androgen was low and transient
  • No adverse events were attributable to the anti-androgen

If  they expand the trial, the 16 ml dose will be used, and biopsies will be given to determine efficacy.

Prostatic Artery Embolization

Frandon et al. reported on a pilot trial of 10 patients with a single positive GS6 biopsy core. The artery leading to that prostate lobe was embolized.

  • 4 of 10 patients had negative biopsies
  • No MRI-visible lesions in 3 of 10
  • Prostate symptoms and erectile function were unchanged from baseline
  • 9 of 10 patients were still on AS after a year. The 1 who progressed had his positive core outside the target lesion

With the majority still having positive biopsies, it is a doubtful treatment.

IV. Immunotherapy

There are three clinical trials of immunotherapies to extend active surveillance.




V. Supplements, Diet, & Exercise

Vitamin D

Marshall et al. reported on 46 patients on AS given 4000iu/day Vitamin D. After a year:

  • There were no significant changes in PSA
  • In terms of Gleason scores or positive cores: 55% decreased, 11% stayed the same, and 34% increased

Although there was no control group, these results were unspectacular.

There are 2 clinical trials. One in Australia, and one among US Veterans.


There are two clinical trials for curcumin. One at the University of Rochester; one at UTSW. Curcumin has been found to interfere with PSA assays (see this link), which makes its use on an AS program problematic.

Green Tea

There is a large, randomized, multi-institutional trial of green tea catechins for active surveillance.


The MEAL RCT proved that adding more vegetables to the diet did not extend time on active surveillance.


The ERASE RCT randomized 52 Canadian men on AS to either 12 weeks of high intensity interval-training exercise or usual care. At the end of the intervention:

  • Peak blood oxygenation increased significantly in the exercise group and decreased in the usual care group
  • Compared to usual care, PSA decreased significantly and PSA velocity slowed
  • Histology demonstrated that in the exercise group, cancer cells shrank by at least 5% in 15 of 23 men (65%) vs. in only 7 of 23 men (30%) in the usual care group. 
  • In the exercise group, growth by 5% or more only occurred in 2 of 23 men (9%) vs 5 of 23 men (22%) in the usual care group.

Early results seem to favor staying on AS. Even if these early effects do not eventually translate into less conversion from AS, there was a health benefit. There may also be a benefit in terms of decreased tumor hypoxia if radiation therapy is eventually chosen.

Guy et al. reported on a retrospective study among men on AS at Sunnybrooke Hospital in Toronto and Royal Marsden Hospital in London. They found that men who participated in weekly vigorous physical activity were 58% less likely to reclassify vs. those who did not.

Friday, June 3, 2022

Abiraterone+PARP inhibitor better than abiraterone alone for mCRPC

PARP inhibitors have been approved for men with metastatic castration-resistant prostate cancer (mCRPC) who have certain defects in their DNA-repair mechanism, mainly defects in their BRCA genes. So far, two PARP inhibitors have been approved: olaparib (Lynparza) after progression on abiraterone (Zytiga) or enzalutamide (Xtandi), and rucaparib (Rubraca) after a second-line hormonal medicine and docetaxel. Two other PARP inhibitors, niraparib (Zejula) and talazoparib (Talzenna) are not yet approved. (See this link). PARP inhibitors prevent cancer cells from fixing DNA mistakes that are more prevalent when one already has the defective BRCA gene.

Hypothetically, PARP inhibitors can delay progression in cancer cells whose DNA is already being disrupted by radiation: Xofigo or Pluvicto. Lynparza has been found to have no benefit when used with Keytruda. A trial of bipolar androgen therapy (BAT) with Lynparza found that the combination delayed progression considerably in men without DNA-damage repair defects. They may also be useful when cell replication is being slowed by docetaxel+carboplatin or second-line hormonals, even in men who do not have DNA damage repair defects. Enzalutamide may be able to prevent cross resistance between docetaxel and PARP inhibitors (see this link)

The PROpel clinical trial randomized 796 mCRPC patients in 17 countries to get either:

  • abiraterone + olaparib, or
  • abiraterone + placebo
  • a quarter had already had docetaxel
  • none were previously treated with a second-line hormonal
  • all were tested (Foundation One) for DNA damage defects which were found in ~28% of patients

With about 21 months of follow-up, radiographic (any kind of imaging) progression-free survival (rPFS) was:

  • 25 months in the olaparib group vs 17 months without olaparib (HR=0.66)
  • Benefit did not differ significantly by type of metastasis, previous docetaxel, or whether they had pre-existing DNA damage repair defects

Follow-up was not long enough to detect significant differences in overall survival, but other secondary endpoints showed benefit for the combination:

  • PSA response was 79% with olaparib vs 69% without it
  • Time to PSA progression was not reached for olaparib vs 12 months without it
  • Tumors shrank in 58% with olaparib vs 48% without it
  • Time to next therapy was reduced by 26% due to olaparib
  • Time before progression on the next therapy was reduced by 31% due to the olaparib therapy

Some adverse events were markedly increased among those taking olaparib:

  • any grade 3 was reported by 47% with olaparib vs 38% without it
  • interruption of the drug among 45% taking olaparib (33% interrupted abiraterone) vs 25% taking placebo (22% interrupted abiraterone)
  • dose reduction of the drug among 20% taking olaparib vs 6% taking placebo
  • discontinuation of the drug among 14% taking olaparib vs 8% taking placebo
  • anemia  among 46% (15% grade 3) taking olaparib vs 16% (3% grade 3) taking placebo
  • fatigue among 37% taking olaparib vs 28% taking placebo
  • nausea among 28% taking olaparib vs 13% taking placebo
  • diarrhea among 17% taking olaparib vs 9% taking placebo
  • decreased appetite among 15% taking olaparib vs 6% taking placebo
  • pulmonary embolism among 7% taking olaparib vs 2% taking placebo

The MAGNITUDE clinical trial randomized 423 mCRPC patients with DNA repair defects and 233 without DNA repair defects to: 

  • abiraterone + niraparib, or
  • abiraterone + placebo
  • 23% had prior abiraterone

After 19 months of follow-up:

  • There was no benefit in rPFS among those lacking DNA repair defects

Among those with DNA repair defects:

  • rPFS was 17 months with niraparib vs. 14 months with placebo
  • if they had BRCA defects, rPFS was 17 months with niraparib vs 11 months with placebo
  • time to chemotherapy was increased by 41% by niraparib
  • time to symptomatic progression was increased by 31% by niraparib
  • time to PSA progression was increased by 43% by niraparib
  • tumors more than doubled without olaparib vs with nirparib
  • discontinuation of the drug among 9% taking niraparib vs 3.8% taking placebo
  • Grade 3+ adverse events occurred in 67% taking niraparib vs 46% taking placebo
A more granular analysis of specific DNA repair genes suggest there may be a benefit (sample size is low) in men with defects in:
  • ATM
  • PALB2
  • CHEK2
  • CDK12
I don't know why men without DNA repair defects benefited from the PARP inhibitor in the PROpel trial and not in the Magnitude trial. I can conjecture that:
  • Olaparib is a stronger PARP inhibitor (based on worse side effects)
  • The olaparib group was less progressed
  • The previous docetaxel use by ¼ in the olaparib trial sensitized the cancer, whereas the previous abiraterone use in the niraparib trial had no sensitization effect. 

Tuesday, May 31, 2022

SPPORT trial: whole pelvic salvage radiation + short-term ADT after failed surgery can be a curative option

 In 2018, we saw the early results of the SPPORT randomized clinical trial (see this link). Now Pollack et al. has published the full results. To review:

They randomly assigned 1,792 men with a recurrence after prostatectomy in 2008-2015 at 460 locations in the US, Canada, and Israel to one of 3 therapies:

  1. PBRT (prostate-bed radiation only)
  2. PBRT + STADT (prostate-bed radiation + short-term ADT)
  3. sWPRT + STADT (salvage whole pelvic radiation + short-term ADT)
  • ADT consisted of 4-6 months of a combination of an anti-androgen and an LHRH agonist starting 2 months before salvage radiation.
  • Radiation dose to the prostate was 64.8-70.2 Gy at 1.8 Gy per fraction.
  • Radiation dose to the pelvic lymph nodes was 45 Gy at 1.8 Gy per fraction.
  • The treated pelvic lymph node area was per RTOG guidelines and did not include the recently recommended expansion. (There is also an expansion of the prostate bed, as discussed here)
  • The sample size was powered to detect progression-free survival, but not metastases, prostate cancer mortality, or overall survival. 8 years of follow-up is insufficient for those other endpoints.
The oncological results were:
  • 8-year freedom from progression (biochemical or clinical) was 77% for sWPRT+STADT, 72% for PBRT+STADT, and 61% for PBRT (all significantly different, regardless of initial ADT, Gleason score, or stage). They used a nadir+2 definition of biochemical progression because it correlated best with clinical progression.
  • At lower PSA (≤ 0.35), Group 3 did no better than Group 2, so widening the treatment area had no effect. Both groups did better than Group1, so ADT had a significant effect.
  • At higher PSA (> 0.35), Group 3 was better than Group 2, but the difference was not statistically significant. Both groups did better than Group 1, indicating ADT effectiveness.
  • 4 vs 6 months of ADT did not matter. It reduced the occurrence of local and regional metastases.
  • Widening the treatment area reduced the long-term rate of local and regional metastases.
  • 8-year incidence of metastases was 69 (12%) for PBRT (HR=0.71), 56 (10%) for PBRT+STADT (HR=0.74), and 41 (7%) for sWPRT+STADT (HR=0.52). sWPRT+STADT was significantly better than the other two.
The physician-reported acute toxicity results show some small early adverse effects of ADT and the wider treatment area:
  • GI grade 2 or higher: 7% for sWPRT+STADT vs. 4% for PBRT+STADT vs. 2% for PBRT
  • GU grade 2 or higher: 12% for sWPRT+STADT vs. 12% for PBRT+STADT vs. 9% for PBRT
  • Bone marrow grade 2 or higher: 5% for sWPRT+STADT vs. 2% for PBRT+STADT vs. 2% for PBRT
  • Bone marrow grade 3: 2.6% for sWPRT+STADT vs. <1% for PBRT+STADT vs. 1% for PBRT
The physician-reported late toxicity results show that late toxicity was not influenced by ADT or whole pelvic RT:
  • GI grade 2 or higher: 9% for sWPRT+STADT vs. 10% for PBRT+STADT vs. 10% for PBRT
  • GU grade 2 or higher: 40% for sWPRT+STADT vs. 35% for PBRT+STADT vs. 37% for PBRT
  • Bone marrow grade 2 or higher: 4% for sWPRT+STADT vs. 2% for PBRT+STADT vs. 4% for PBRT
This RCT proved that whole pelvic salvage radiation with 4-6 months of ADT is the preferred salvage treatment.

In contrast to a previous trial (RTOG 9601) that told us that ADT can be safely avoided if PSA<0.7, this trial suggests at least 4 months of ADT and whole pelvic treatment. The reason for the difference in recommendations is due to the choice of endpoint. SPPORT is telling us that if we are willing to put up with 4 months of ADT and some extra short-term toxicity from the wider field of radiation, a cure is likely. RTOG 9601 tells us that if your PSA<0.7, you aren't likely to die if you don't get the extra short-term hormone therapy, but you may have to have lifelong ADT eventually. It will always be a managed disease. Patients should acknowledge these trade-offs and discuss with their doctors.

Results may possibly be improved further with:
  • Better patient selection using PET scans (PSMA, Axumin, or NaF)
  • Extra radiation to the prostate bed
  • Boost doses to cancer detected with a PSMA PET scan (if PSA> 0.5 - but do not wait!)
  • Selection of patients who would benefit from treatment intensification using a Decipher test
  • Hormone therapy intensification in select patients (as in this clinical trial)

Thursday, April 28, 2022

The importance of radiotherapy dose escalation and long-term ADT for success

 Localized prostate cancer (PCa) is highly curable. We usually divide localized PCa into 3 risk categories: low-risk, intermediate-risk, and high-risk of recurrence after treatment. Even high-risk PCa is highly curable - 80+% of patients are cured in clinical trials of various radiation therapy regimes (see this link, for example). With new PET scans recently approved for high-risk patients, patients who truly have localized PCa have every hope of achieving even better cure rates.

This begs the question: what do we mean by "cured." What most patients mean is that no recurrence will ever be detected. The first sign of recurrence is a rising PSA more than 2.0 ng/ml over the lowest PSA achieved (nadir). This is called a "biochemical recurrence" (BCR). Other deleterious events may happen. An undetected ("occult") metastasis may grow. The patient may die due to some other cause. If the former never happens, it is called "metastasis-free survival (MFS)." It is highly dependent on the technology used to detect occult metastases. If the latter never happens within the time patients are tracked after treatment, it is called "overall survival (OS)." It is highly dependent upon other diseases ("comorbidities"), treatments given, and the length of follow-up. Often, there are undetermined variables (called "confounders") that tilt OS in one direction or another. Only BCR is relevant for the patient making a therapy choice for his localized prostate cancer.

As we saw previously (at this link), the MARCAP consortium has found that the duration of androgen deprivation therapy (ADT) given along with ("adjuvant to") radiation therapy depends on how the radiation is delivered to high-risk patients - either 12 months for brachy boost therapy or 26 months for external beam radiation therapy. Kishan et al. has analyzed a large number of clinical trials to answer the following questions:

  1. What is the role of radiation dose escalation in minimizing BCR?
  2. What is the role of long-term vs short-term ADT in minimizing BCR?

  • They defined "high dose" radiation as any dose equivalent to greater than or equal to 74 Gy (or its equivalent)
  • They defined "long-term" (LTADT) as any duration longer than 18 months, while "short-term" (STADT) was defined as 3-6 months.

For high-risk patients, compared to treating them with low-dose RT without ADT:

  • Adding high dose RT (without ADT) reduced BCR by 26%
  • Adding short-term ADT reduced BCR by 36%
  • Adding high dose RT and STADT reduced BCR by 55%
  • Adding low dose RT and LTADT reduced BCR by 61%
  • Adding high dose RT and LTADT reduced BCR by 69%

Intermediate risk patients were treated before NCCN distinguished "favorable" intermediate-risk from "unfavorable" intermediate-risk (see this link). For intermediate-risk patients, taken as a whole, compared to treating them with low-dose RT without ADT:

  • Adding high dose RT (without ADT) reduced BCR by 21%
  • Adding short-term ADT reduced BCR by 32%
  • Adding high dose RT and STADT reduced BCR by 46%
  • Adding low dose RT and LTADT reduced BCR by 55%
  • Adding high dose RT and LTADT reduced BCR by 74%
In both risk groups, long-term ADT provided greater benefit than high dose RT, but combining LTADT with high dose RT provided the best cure rates. 

There are some seeming contradictions between this meta-analysis and the DART 01/05 randomized clinical trial. The purpose was to see if there was a difference in biochemical disease-free survival (bDFS) among intermediate and high-risk patients treated with high-dose radiation and either 28 months or 4 months of ADT. At 5 years of follow-up (see this link), the LTADT group had a significantly higher bDFS than the STADT group. The difference was particularly noticed among the high-risk subgroup. However, with 10 years of follow-up, the difference was no longer significant. 
  • For the total, the bDFS was 70% for LTADT vs 62% for STADT (not statistically significant)
  • For the high-risk subgroup, the bDFS was 67% for LTADT vs 54% for STADT (not statistically significant)
At least for the high-risk subgroup, the difference was large but not statistically significant. What happened?

What happened was a quarter of the men in the study died in the interim (median age was 72 at the start). Only 3% died of prostate cancer. Many of the men who would have shown no biochemical progression had they lived were eliminated from the trial because they died of other causes. This is called "survivorship bias." The high dropout rate due to death from other causes tells us that follow-up of such trials beyond 5 years will introduce bias into our most important endpoint. It is also another reason that "overall survival" is not a useful endpoint when patients are older. Men with less than 10 years of expected survival due to age or comorbidities should consider watchful waiting rather than any kind of radical treatment. Patients can determine their actuarial expected survival with this calculator: (scroll down to "Male Life Expectancy").

Saturday, January 22, 2022

Optimal duration of adjuvant ADT depends on the type of radiation used for high-risk patients

No one wants to have androgen deprivation therapy (ADT), even if it is for a limited time. It has been known for a long time that it improves oncological outcomes when given with ("adjuvant to") radiation therapy in patients with high-risk prostate cancer. Several randomized clinical trials (RCTs) have tried to find the best duration to use it, but it is difficult to arrive at reliable optimization points- it would involve varying the duration for a large number of high risk patients. Kishan et al. have taken an innovative approach to solving this problem by combining several RCTs and a multi-institutional observational study. Unlike typical "meta-analyses," they compared similar patients across three studies.

The three studies they used in their analysis were:

  1. The high-risk patients in the DART 01.05 GICOR RCT (see this link), which randomized patients to 28 months or 4 months of adjuvant ADT in patients getting high dose external beam radiation (EBRT-only). They found that 28 months is better than 4 months, but is there a duration that is less than 28 months for EBRT-only?
  2. The patients in the TROG 03.04 RADAR RCT (see this link), which randomized patients to 18 months or 6 months of adjuvant ADT in patients getting varying doses of EBRT or high dose rate brachy boost therapy (BBT). They found that 18 months is better than 6 months for BBT, but is there a duration that is less than 18 months for BBT?
  3. The patients in a multi-institutional (retrospective, non-randomized) study who received varying durations of adjuvant ADT and EBRT-only or brachy boost therapy for their high risk PCa (see this link).

They used distant metastasis-free survival (DMFS) as the endpoint of interest because it has been found to correlate well with eventual overall survival. They went back to the original patient-level data to extract comparable patients when comparing them across studies. This retained many of the advantages of each of the three studies. While this innovative approach does not constitute the highest level of evidence (Level 1), it offers a degree of reliability that goes beyond simple observational studies.

They used two statistical methods to look at the data. In one analysis, they divided the durations into three parts: 

  • ≤6mo.
  • >6 - 18 mos
  • >18 mos

In another analysis (called "cubic splines") they found the best fit for the continuous data. Both analyses led to similar conclusions.

The best estimates for the best minimum adjuvant ADT duration are:

  • at least 26.3 months for EBRT-only
  • at least 12 months for BBT

But, one might object, didn't Nabid's PCS IV trial show that 18 months is as good as 36 months (see this link)? Kishan points out that only about half of the cohort in that trial who were supposed to get 36 months of ADT actually got that much. And nearly a quarter of the 36-month cohort actually received less than 21 months. The only data we've seen so far has been analyzed by the dose they were intended to get, not by what they actually got. Also, why were the drop-out rates so high? The DART RCT had 95% compliance with the full 28 months, even though the radiation doses given were much higher.

There is a trade-off: BBT can come with severe late-term urinary side effects (among 19% in the ASCENDE-RT RCT), while the late-term urinary side effects are milder for EBRT-only (only 2.5% in DART). Only the patient can decide if he is willing to take on 12 months of ADT with BBT vs over twice as long for EBRT-only, given the higher expected radiation toxicity with BBT.

There are several unanswered questions:

  • As we have seen (see this link), brief intense use of abiraterone or other advanced hormone therapy may obviate the need for longer ADT.
  • Decipher genomic analysis may indicate which patients may be able to get away with less hormone therapy, and which need more. The PREDICT-RT RCT will eventually answer this question.
  • Does SBRT monotherapy or HDR brachy monotherapy still require adjuvant ADT? Those therapies can have almost as high a biologically effective dose as BBT but with fewer side effects. This study suggests that 12 months of ADT is beneficial with even the highest dose radiation, but future clinical trials will give a more reliable answer.
  • Standard-of-care dictates 2-3 years of adjuvant ADT when enlarged pelvic lymph nodes are found by CT or MRI. What is the optimum duration when cancerous pelvic lymph nodes are only detected with a PSMA PET scan and not by CT? What about when they are too small to be detected by any kind of imaging, and their presence is only suggested by risk characteristics?
  • What duration of adjuvant ADT minimizes biochemical recurrence-free survival and the need for any salvage treatment?
  • Will these estimates hold up if tested in an RCT?