Monday, December 30, 2024

The danger of doing your own research (or using AI)

In 1995, McArthur Wheeler and Clifton Earl Johnson robbed two banks in Pittsburgh. They believed they wouldn't be caught because they had researched how to render themselves invisible to bank security cameras. They learned that lemon juice could be used to write an invisible message on paper that could only be made visible by heating up the paper. Could lemon juice make them invisible to bank cameras? They conducted an experiment: they rubbed lemon juice on their faces and took a Polaroid picture -- their faces did not show up on the Polaroid!

They rubbed lemon juice on their faces, wore no masks, and robbed the two banks at gunpoint. The Pittsburgh Police showed the security camera images on local TV, and they were soon apprehended. They were nonplussed and insisted the police had no evidence. It is unknown why the Polaroid failed to show their faces - perhaps defective film or perhaps they pointed the camera in the wrong direction.

The Dunning-Kruger Effect

David Dunning read about the case. He hypothesized that if Wheeler was too stupid to be a bank robber, he may have been too stupid to know that he was too stupid. Dunning and his grad student, Justin Kruger, wrote a paper titled "Unskilled and Unaware of it: how difficulties in recognizing one's own incompetence lead to inflated self-assessments." This is known as the Dunning-Kruger Effect.

Dunning and Kruger found that people who first start to learn about any subject have an inflated perception of how much they know. Paradoxically, when people learn a lot about a subject, they think they know less about it than they actually do know. The following (exaggerated and comical) chart sums up their findings. Dunning-Kruger didn't use terms like "Mt Stupid" or "Valley of Despair." As people start to learn about a subject, their confidence in their knowledge is never higher. If they learn more, they quickly learn how little they know about it. If they stick with it and learn even more, they slowly gain confidence in their knowledge. But they will never have as much confidence as they had initially - they have humility because they have learned how much they don't know, and perhaps can never know.


A 2022 study by Light et al. published in Science found that across seven critical issues that enjoy substantial scientific consensus, individuals (n=3,249) who have the highest degree of opposition, have the lowest degree of objective knowledge and the highest degree of subjective knowledge (they feel strongly that they know more than the experts but fail on tests of established facts). They examined attitudes about anthropogenic climate change, genetically modified (GM) food safety, risk vs benefits of vaccination, importance of nuclear power, the lack of efficacy of homeopathic medicine, human evolution, the validity of the Big Bang Theory of cosmology, and Covid-19. 

A Personal Journey from the Peak of "Mt. Stupid"

I wanted to write a novel about an ancient virus that gets unleashed because of global warming. The idea was that the virus evolved before there were humans, so that we had no natural immunological defense to it. It was responsible for killing off all placental mammals in Australia, so it would kill many hundreds of millions of people, not to mention the animals humans use for food and pets. I wanted it to be plausible - how hard could that be?

I studied virology, epidemiology, genomics, and immunology, and found I understood only a small fraction of what I read. Just learning the basics in those fields with no educational background was difficult. After a year of studying, I hadn't solved the problem of making it plausible.

Retroviruses, endogenous retroviruses, virosomes, proto-oncogenes, endosymbiotic theory, maladaptive mutation, viral reservoirs and vectors, carcinogenic viruses, telomeres, zinc fingers, morpholinos, surface proteins, dysfunctional micro-RNAs, antagomirs, DNA sequencing, epigenetics, trophoblasts, choriocarcinoma... After a year, I was ready to give up. I put the book on the back burner, but continued to do research as time permitted.

Five years later, I finally finished Thaw's Hammer. My current feeling is that it is plausible if one doesn't know too much. I think a true virologist would have many valid objections. I would rate myself about 10% of the way up the "slope of enlightenment."

One benefit for me was that when the pandemic hit, I knew enough to respect the experts in the field like Anthony Fauci. I also knew enough to laugh at the dangerous stupidity of anti-vaxxers like Jenny McCarthy, RFK Jr., and Joe Rogan.

The Salience of Socially-Derived Knowledge

People are political and get their information from "epistemic bubbles" or "echo chambers" of people who are politically similar. Because politics are increasingly polarized, there is a social disincentive to get down from "Mt.Stupid" where their peer group is. The authors found no correlation with degree of education -- educated people were as likely to be wrong as less well-educated people. 

Humans are social creatures and get our opinions from our social peer group. Alienation from our peer group and their approbation is more important than error correction. Because of this, social media is now our primary source of knowledge. We have come full circle from the Stone Age when interpersonal gossip told us everything we had to know.Yuval Harari wrote about human evolution due to gossip in his book Sapiens:A Brief History of Humankind:

“Social cooperation is our key for survival and reproduction. It is not enough for individual men and women to know the whereabouts of lions and bisons. It’s much more important for them to know who in their band hates whom, who is sleeping with whom, who is honest and who is a cheat. This information about which individuals could be trusted — in other words, gossip — allowed early humans not only to survive, but also to expand their tribes. Long hours spent gossiping helped the early humans to forge friendships and hierarchies, which, in turn, helped to establish the social order and cooperation that eventually set them apart from the rest of the animal kingdom."

Homo Sapiens has always gossipped about people we know, come into direct contact with, or influence our survival (e.g., kings, lords, military, religious or political leaders).  In the 18th and 19th centuries, society gossip became fashionable. A new target of gossip emerged in the early 20th century -- movie stars. Photoplay, one of the first movie fan magazines, began publishing in 1911, and provided gossip about all the silent movie stars. Studios were happy to add content, often fictitious, if it drove fans to the movies. Mainstream media began unabashedly adding gossip columnists: Hedda Hopper and Louella Parsons were top journalists in the 1940s and 50s. Hedda Hopper was a fan of Joseph McCarthy and often exposed Communists in the film industry. Confidential (1952) offered fans salacious content, not provided by the studios, and had an even weaker link to truth. Tabloids emerged with The National Enquirer in 1962. When Carol Burnett sued them in 1976, the Supreme Court affirmed that libel was not protected speech, and the tabloids started being more careful about what the presented as "facts."

Television brought stars into people's homes. Talk shows became the media for celebrity gossip. Joe Franklin (1951) was the first. The Tonight Show began in 1954 with Steve Allen, followed by Jack Parr, Johnny Carson, Jay Leno, Conan O'Brien, and Jimmy Fallon. It is the longest running show on television, and there are too many imitators to mention. Not only TV, movie, music and political celebrities, but interviewers became celebrities in their own right. Talk shows made people watching feel like they personally knew whomever was being interviewed as well as the interviewer. All these people entered our "epistemic bubble" and became arbiters of "truth" because of the "availability heuristic" (see below).

Social media started on the Internet in the early 2000s. LinkedIn (2002), Facebook (2004), YouTube (2005), Twitter (2006), Instagram (2010), Snapchat (2011), and TikTok (2017) quickly became the source for gossip for about 5 billion people worldwide. Not only do they reach most people on Earth, most people look at multiple platforms frequently throughout each day. The average consumer looks at social media for about 150 minutes every day.

Unlike published media, social media is not constrained by libel laws in the US. In 1996, Congress passed the Communications Decency Act. Section 230 carves out an exception to libel laws for owners of Internet platforms. They cannot be sued for damages caused by erroneous content. After it came to light that Russia was using online disinformation to sway US (and other nations') elections, many social media companies made voluntary changes. Twitter, which canceled President Trump for his many lies, was then bought by Elon Musk who invited him back. Social media is a free speech "Wild West."

As Nobel Laureate Daniel Kahneman (based on research he did with Amos Tversky) pointed out in his book, Thinking: Fast and Slow, humans are lazy thinkers. Things we hear via gossip from people we know or via social media from people we sort-of know are more top-of-mind compared to dry statistics that we would have to search through incomprehensible journal articles to know. "Top-of-mind" means that we can often recall those "facts" much faster (in milliseconds) than anything we have to actually think about or research. They found that once we remember such "facts," we no longer search for facts that may contradict it. Instead, we usually find reasons to discount contradictory facts. They call this the "availability heuristic" and found it is the single greatest source of error in human decision-making.

Others have found that emotions drive our thinking. The Scottish Enlightenment philosopher, David Hume, famously observed in 1739:

"Reason is, and ought only to be, the slave of the passions and can never pretend to any other office than to serve and obey them"

Jonathan Haidt, the social psychologist, in The Righteous Mind,  describes human decision-making as an elephant with a small man riding on top. The elephant represents everything that Kahneman describes as fast thinking: our intuitions, emotions, moral underpinnings, subconscious memories, indoctrination in our political, social and cultural milieu, social and sexual evolutionary drives -- things we act on even if we are not consciously aware of them. The little man riding on top represents our intentional thinking, called "slow thinking" by Kahneman. The rider is under the delusion that he is guiding the elephant.











The rider uses reason (and google!) to justify all the elephant's actions. It is going exactly where the rider wanted him to go, or so he believes. The rider can guide the elephant, but Haidt finds that happening less than 10% of the time. We lie, cheat, and justify so well, we honestly believe we are honest. The built-in software that drives our reasoning and googling is called "confirmation bias" by Kahneman. We all have an instinctive drive to confirm our positive self image. Our reason must be consistent with and conform to that image.

Conspiracy Theories

Humans don't like to feel powerless, and actively seek to gain control over our environment and our own bodies. This is why the supplement industry is a $50 billion industry in the US. Cancer patients have been betrayed by their own bodies, so the loss of control is acutely felt. This is why cancer patients are so prone to conspiracy theories that explain why they are ill and why there is no cure for advanced cancers.

Because humans are social creatures, we believe people who we know and like, and don't believe people we don't know or don't like. It used to be the case that fringe theories were only believed by a small number of people. Now, with social media, google and AI, we are confronted by fringe theories we ordinarily wouldn't encounter. If we like those who convey fringe theories (e.g., Joe Rogan is very likeable), we may get caught in a self-justifying epistemic bubble.

People with cancer sometimes believe that there is a conspiracy on the part of Big Pharma and the FDA to keep curative drugs off the market. It has been estimated that the secret must be kept by 714,000 Big Pharma employees plus 18,000 FDA employees. Mathematically, the secret would get out inside of 3.2 years (see this link).

Conspiracy theorists believe that someone in power is preventing the most effective, safest, and cheapest drugs from getting to cancer patients. They believe there is a small number of people who know the real truth and they find the cognoscenti online. Consequently, many cancer patients die each year due to these beliefs. Smart people are perhaps more prone to such paranoid beliefs. Famously, Steve Jobs died sooner because he refused the standard of care. It has been found that cancer patients were 2.5 times more likely to die sooner if they used alternative therapies (see this link). Top oncologists evaluated the information available on social media. They found that about a third of the posts contained mostly harmful misinformation (see this link).

Some of the most widespread myths about cancer now on social media are:

"Sugar makes cancer grow faster.":  Based on a little knowledge gained about the Warburg Effect, proponents climb atop "Mt. Stupid" by claiming that they can slow cancer progression by cutting out all sugars from the diet. In reality:

  • Prostate cancer prefers to metabolize fats. This is why FDG (Glucose) PET scans usually don't detect prostate cancer, while choline PET scans do.
  • Insulin-like Growth Factor 1 (IGF1) inhibitors have had no effect on prostate cancer progression.
  • Cancer cells are indeed metabolically active, so active in fact that they will consume whatever food is available - fats, proteins,or carbohydrates. If no free nutrients are available, they will break down healthy cells for food. Cancer cells cannot be starved without killing the person. There is no clinical evidence that they can be starved.

"Ivermectin is the secret cure for cancer." Ivermectin, a anti-parasite drug, gained popularity as the secret cure for Covid-19. Although a large randomized double-blinded clinical trial proved it had no effect on Covid-19. Conspiracy theorists believed Big Pharma suppressed the results. They also believe it is a proven cure for cancer. There is a single clinical trial for its combined use with triple negative breast cancer (for which there are no effective medicines) but there are no trials for prostate cancer.

"Laetrile (B-17/apricot pits) cures cancer." This is one of the most dangerous myths to circulate on social media. It contains amygdalin, which in large quantities, is metabolized into deadly cyanides in humans. While healthy people can probably detoxify the cyanides, people with cancer can and have died (see this link).

"Fenbendazole cures cancer." Fenbendazole is a deworming agent for animals. Based on a single case (Joe Tippens) that has never been duplicated, it circulates on social media as a cure for prostate cancer. There have never been any clinical trials of the drug, only lab studies. Taken orally, it does not reach concentrations necessary to have an effect in animals or humans. It is hepatotoxic.

"Dukoral (cholera vaccine) cures prostate cancer." A Swedish study noticed that men who took this cholera vaccine were less likely to die of prostate cancer. Like all epidemiological studies, it is confounded by selection bias, so one cannot draw any cause-effect relations from it. A follow-up analysis of the same data set, found the same association, in fact, stronger, with all travel vaccines. Men who got travel vaccines were more concerned about health and were also more likely to catch their prostate cancer earlier. It had nothing to do with the cholera vaccine.

"Cancer cures can be found in nature." This is a quasi-religious myth. Some believe that God wouldn't have allowed diseases without also providing cures in Nature. Naturopaths are quacks who treat patients with natural cures. There are no legitimate clinical trials that back up this potentially deadly assertion. There is nothing salubrious about natural foods or medicines. Anyone with a background in the chemistry of natural products (as I have) knows how deadly nature can be and how many thousands of chemicals, innocuous, beneficial and harmful, can be found in "pure" natural products.

Believing the Worst

False negatives (called Type 2 errors) are more expensive than false positives (called Type 1 errors). For example, the rustling in the grass may be caused by a tiger; if you don't believe it (negative) and your negative belief turns out to be false (i.e.' there is really a tiger), then you are dead. However, if you do believe it, and it turns out to have been the wind (i.e., a false positive), you may feel foolish, but you won't be dead. This is called "negativity bias."


actual reason for grass rustling:

Tiger

Wind

imagined reason for grass rustling:

Tiger

true positive - safe

false negative - safe

(Type 1 error)

Wind

false negative - dead

(Type 2 error)

true negative - safe

Therefore, humans are programmed by evolution to believe things that we imagine but cannot verify. Imagining future outcomes is part of human mental equipment. We instinctively believe the warnings of our trusted social group.

Randomness/Statistics are Difficult to Comprehend

Dealing with randomness is emotionally difficult. Statistics (frequentist and Baysian) are incomprehensible to most people. Frequentist statistics rely on sample size to increase the probability that a hypothesis is false. There is never certainty because the chosen sample always has some possibility of being different from the entire population. As sample size increases, our confidence that it is a representative sample increases, and the probability of error decreases. With Baysian statistics, prior odds affect posterior odds. Someone well-versed in statistics may understand what a study means or doesn't mean, but someone new to the field is liable to misinterpret them.

Humans are always hunting for patterns. If a tiger appears even some of the time that the grass rustles, we will always look for a tiger when the grass rustles. We find patterns even where there are none. We filter out "noisy" data to find signals even if there are no signals (see Kahneman - Noise: A Flaw in Human Judgment). In an important mathematics proof this year by Sarah Peleuse at Oxford , she found that any chosen subset of random numbers will display a pattern even if only small subsets are chosen. We see patterns even if there are none.

When faced with statistics whose meaning is difficult, a typical reaction is "they can prove anything with statistics" or "it doesn't apply to me." Those who don't understand "levels of evidence" and grade, can certainly be fooled by statistics. Zaorsky et al. showed that common statistical techniques called "propensity score matching" or "inverse probability weighting" can be finagled to arrive at opposite conclusions from the same retrospective observational study. Similarly, Wang et al. showed that the analytic method used in diet studies could change red meat from having a positive effect on longevity to a negative effect (also, see this link). Others have shown that prior to 2000, journals allowed "p-hacking," specifying what the primary outcome should be after the research was analyzed. Post-hoc definition of sub-groups can lead to comical results. As a result of such problems, all major peer-reviewed journals have changed their standards. It's a work in progress, but it's improving.

For those who think the findings don't apply to them, they may be right. Clinical trials have very strict definitions of inclusion and exclusion criteria. The outcomes of such a trial may not apply to those who do not meet those criteria. Outcomes are conventionally reported as a median (the halfway point) with 95% confidence intervals (95% CI) around it. The size of the 95% CI is the result of both the statistical variance due to sample size and the natural variance among patients. For large sample sizes, most of the variance is natural variance. It is possible that a given patient falls outside of the 95% CI, but is highly unlikely. If one were to wager a bet, the median would be the best guess.

Logic Deceives Us

With imperfect knowledge, logic can deceive us. For example, Huggins and Hodges discovered in 1941 that testosterone is necessary for prostate cancer to grow. By turning off testosterone completely, prostate cancer progression can be slowed. "Logic" dictates that giving untreated men testosterone would cause progression. That turns out to be wrong much of the time. Morgentaler found that a man's androgen receptors are fully saturated at very low levels, so adding more has no effect and may even be useful in some cases. Human biochemistry is very complex (and different from mouse biochemistry!). We never fully understand human biochemistry, so always have imperfect knowledge. As far back as Aristotle, it has been known that inductive reasoning cannot be proved. Yet humans engage in inductive reasoning all the time.

We often rely on Occam's razor to make judgments. It says that all things being equal the simplest explanation is the best. But what if all things are not equal, or we just don't know if all things are equal?

"Levels of Evidence" and GRADE determine why a trial or review is dispositive

The neophyte climbs "Mt. Stupid" rapidly because he doesn't understand why one study is better than another. Only a large replicated well-done randomized clinical trial is beyond question. For a description of what constitutes a "well-done" trial, see: Systems for grading the quality of evidence and the strength of recommendations. For a list of what are the agreed upon levels of evidence, see: The Levels of Evidence and their role in Evidence-Based Medicine. All but Level 1 Evidence, that is, all observational studies are subject to confounding by "selection bias." Google and AI searches do not make such distinctions, which explains why their conclusions are usually wrong.

Dr. Google/YouTube

In 1998, Google became the most popular search engine for the Internet. It watched individual's searches and learned what each person was most likely to search for. It also looked at people who did similar searches. It democratized knowledge, but created epistemic bubbles. While it can be used to find information outside of the kind one's peer group looks for, it prioritizes the kind of information one and one's peer group has already looked for.

Google provides lots of information, but doesn't put it in useable form. It leaves it to the person to form that information into knowledge - the understanding and application of the information. It makes no distinctions about which studies are good or bad. A mouse study may be listed behind a prospective randomized clinical trial if the search terms are in the abstract.

I asked Google the same question about salvage radiation asked of ChatGPT below, and it did not come up with any of the three randomized clinical trials or their meta-analysis that patients should be making informed decisions based on.

In 2006, Google bought YouTube. YouTube videos on medical issues are particularly insidious. Because one sees the "doctor," the availability heuristic kicks in, building trust faster than reading a dry journal article with statistics and terminology one may not understand. The presenter often wears a white coat to create trust. 

  • There are seldom legitimate sources given for what is said; 
  • There is seldom a discussion of any controversial issues; and 
  • The presenter's qualifications are often not included. 

There are ways of doing a video presentation right, but many patients will not be able to distinguish misinformation from good information.

ChatGPT gets one to the top of "Mt. Stupid" faster

In 1975, researchers came up with a new method for compiling a lot of studies on the same topic. One always has more confidence in trials that have been replicated with similar findings and a  review and meta-analysis is always a higher Level of Evidence than a single trial. Cochrane Reviews is the top journal for publishing such meta-analyses.

To review multiple studies, the authors must go through the following steps:

  1. Define the research question as narrowly as possible, but not so narrow that only one trial is included. The question should include the relevant patient population and the problem examined, the intervention used in the trials, what it is compared to, and the which outcomes are used to evaluate the trials.
  2. Sources are chosen according to universally agreed upon quality. All reviews use the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed is perhaps the most used PRISMA source.
  3. Data are extracted from the sources in accordance with the question asked.
  4. The eligibility of the extracted data is assessed.
  5. The data are analyzed and combined. The analysis provides a hierarchy of reliability based on such quantitative and qualitative assessments as the sample size and how well the trial was conducted. The combination is often summarized in Forest Plots showing confidence intervals.

For anyone interested in a deep dive, here is the latest Cochrane Review Handbook.

In the last couple of years, machine learning algorithms that provide summaries in comprehensible language have gotten popular. All of the above issues still plague it. Unfortunately, it is called "artificial intelligence." Intelligence implies that it knows what it is spewing forth and wisely selects that information. It does neither.

  • It simply scrapes information from a popular variety of sources and provides a plain language summary very quickly. 
  • It has no judgment -- results of lab studies may have the same salience as Level 1 evidence. As Hume observed (above), emotions are required for reasoned judgment, and AI will never have that.
  • More recent trials are lumped together with older, no longer relevant studies. 
  • The output is only as good as how the query is phrased, and what is currently most popular in searches. 
  • It is insidious, because it sounds better than the raw data. 
  • One cannot check the reliability of its sources. 

I have found it is wrong more often than it is right, but it always sounds authoritative, and is therefore more dangerous than mere google searches. It only helps one climb to the top of "Mt. Stupid" faster.

Here's an example:

I asked ChatGPT a frequently asked question:"How do I decide when I should have salvage radiation therapy after a prostatectomy?"

ChatGPT said:

Deciding whether to pursue salvage radiation therapy (SRT) after a prostatectomy (radical prostatectomy) is a crucial decision that depends on several factors, including clinical, pathological, and radiological considerations. Here are the key factors to guide the decision-making process:

1. Biochemical Recurrence (BCR)

The most common indication for salvage radiation therapy is biochemical recurrence, which is typically defined by an elevated prostate-specific antigen (PSA) level following surgery. This is often the earliest sign of prostate cancer recurrence. The following are common criteria used to assess BCR:

    • PSA rise after prostatectomy: A PSA increase of 0.2 ng/mL or more is generally considered indicative of biochemical recurrence, but this threshold may vary slightly depending on the clinical guidelines and the situation.
    • PSA doubling time (PSADT): The rate at which the PSA level increases can provide insight into the aggressiveness of the recurrence. A faster doubling time (e.g., less than 6 months) may suggest more aggressive disease.

2. Timing of Recurrence

The timing of biochemical recurrence post-prostatectomy is important in guiding the need for salvage therapy:

    • Early recurrence (within 18-24 months post-surgery): This may indicate more aggressive disease, and salvage radiation therapy might be considered sooner, especially if the PSA is rising quickly.
    • Late recurrence (beyond 24 months): A slower, later recurrence may have a more indolent course, and radiation therapy can still be effective, but the decision might depend on other factors like clinical symptoms, imaging results, and patient preferences.

3. Pathological Factors

Pathology reports from the prostatectomy specimen can influence the decision to pursue salvage radiation:

    • Positive surgical margins: If cancer cells are found at the edge of the removed tissue, there is a higher risk of recurrence. This might make salvage radiation therapy more likely or beneficial.
    • Extracapsular extension: Cancer that has extended beyond the prostate capsule also increases the risk of recurrence, and this might favor earlier consideration for salvage radiation therapy.
    • Seminal vesicle invasion: Cancer involvement of the seminal vesicles is another risk factor that could prompt earlier use of salvage radiation therapy.

4. Imaging Studies

In cases where PSA is rising after prostatectomy, imaging studies may be used to assess the site of recurrence:

    • PSMA PET scan (Prostate-Specific Membrane Antigen positron emission tomography): This imaging modality is highly sensitive in detecting recurrent prostate cancer, particularly in patients with biochemical recurrence and low PSA levels.
    • Conventional imaging (CT, MRI, bone scans): These may be used if PSMA PET is unavailable or if there are concerns about distant metastasis.

If imaging shows local recurrence (in the prostate bed), salvage radiation is typically considered. If distant metastases are found, systemic treatments may be recommended instead of local radiation.

5. Clinical Status of the Patient

    • Overall health: The patient's general health, life expectancy, and ability to tolerate treatment should be factored in.
    • Performance status: If the patient is in good overall health and has a reasonable life expectancy, salvage radiation may be a good option to improve outcomes.
    • Side effect tolerance: The potential side effects of radiation, such as urinary incontinence, bowel symptoms, and sexual dysfunction, should be discussed.

6. Tumor Characteristics

The aggressiveness of the tumor (based on the Gleason score and other pathological features) will also influence whether salvage radiation therapy is appropriate. Higher Gleason scores (especially 8-10) and other high-risk features often suggest more aggressive disease that may benefit from early intervention.

7. Radiation Targeting

    • Prostate bed: If imaging shows localized recurrence in the prostate bed, salvage radiation therapy is often directed to this area.
    • Lymph nodes: In cases where imaging suggests lymph node involvement, the treatment plan may include radiation to these areas as well.

8. Post-Surgery PSA Levels

    • Low vs. high PSA at recurrence: A lower PSA (e.g., <1 ng/mL) at the time of recurrence is typically associated with a higher likelihood of success with salvage radiation. For patients with higher PSA levels, additional treatment options may be needed.

9. Potential for Cure vs. Palliation

If salvage radiation therapy is initiated early in the recurrence process, there is a higher likelihood that the disease is confined to the prostate bed and that radiation may lead to long-term remission. In later stages, when metastases may be present, radiation may offer symptom control and local palliation rather than curative treatment.

10. Multidisciplinary Team Discussion

It is often helpful for decisions regarding salvage radiation therapy to be made in the context of a multidisciplinary discussion, including the urologist, radiation oncologist, and medical oncologist. This team approach ensures that all options are considered, including the use of systemic therapies (e.g., androgen deprivation therapy) in conjunction with or instead of radiation.

Conclusion:

Salvage radiation therapy after prostatectomy is generally considered when biochemical recurrence (PSA rise) is detected, especially when it occurs in the first couple of years after surgery, and when there are no signs of distant metastasis. Decisions should take into account factors like PSA doubling time, pathological features, imaging findings, and the patient's health status. It's crucial to consult with your medical team, who can offer a personalized approach based on your specific case.

The answer it gave sounds good, but is somewhat right, somewhat wrong. It didn't seem (it doesn't provide sources) to know that there is a meta-analysis that is Level 1a Evidence and is dispositive. It is similar to what a doctor would have said in 2018, but not in 2025. It also did not evaluate the evidence and find the exceptions. The correct answers are:

Adjuvant Similar to Early Salvage Radiation in Meta-Analysis

Exceptions to Early Salvage Radiation Therapy after Prostatectomy

I suppose AI can be taught Levels of Evidence and Grade, but without emotions, it will never be able to provide reasoned judgments.

The Solution: Science and Experts

The solution to the problems in acquiring trustworthy information is "science." Science is a social construct whereby hypotheses are tested and a community of experts decides, provisionally, what truth is. It is provisional because science can later be proved to be wrong. It depends on having lots of hypotheses that may be falsified and usually are, and is only as good as the hypotheses tested.

For a fuller discussion, see: The Constitution of Medical Knowledge.

A patient goes to his doctors for their expertise. But doctors should be able to patiently explain why the suggested protocol is as it is. While many patients and doctors prefer a paternalistic decision-making model, there will be fewer regrets and recriminations if they engage in shared decision-making.

For a discussion of shared decision-making, see: Managing the Doctor/Patient Relationship.

All of the above should serve to let you know that you may be wrong in spite of clear instructions from Dr. Google, YouTube, or ChatGPT. I don't expect patients will stop using those readily available tools -- that genie is out of the bottle, but it should lead one to question that "knowledge."

Sometimes you will come across a research study online that seems perfectly relevant to your case. How should you handle it with your doctor?

  • The way I do it is, first of all, respectfully. 
  • I start by acknowledging that he probably has seen it or better information. 
  • My approach is collaborative and open, rather than confrontational and closed-minded. 
  • I try to share it, preferably via email, before my visit, if one is coming up. This gives him a chance to look at it and respond to it in a more considered way. 
  • I am also careful about sources. I would never send some “miracle cure” from a random Internet site. The articles to be discussed are always based on peer-reviewed medical evidence in highly-regarded journals. One can see if the study is highly-regarded if the study has had many citations in Google Scholar. Peer-reviewed journals all have an "Impact Factor" that shows how often articles in that journal are cited. The Lancet, the New England Journal of Medicine, and the Journal of the American Medical Association always have the highest Impact Factors. 
  • I am also open to refutation: I may not have understood why that case does not apply to my case; 
  • I may not know that there are more recent findings, possibly from a higher level of evidence; or, 
  • I may have misunderstood the findings or conclusions.

The only way to avoid "Mt. Stupid" is to have humility. Most attending doctors at teaching hospitals are experts in their fields. The empowered patient will tap into their expertise.

Friday, September 27, 2024

Protons vs Photons: No difference in Phase III trial

Finally, we have Level 1 evidence that proton vs. photon treatment of low-risk/intermediate-risk localized prostate cancer is no different in effectiveness or any quality of life domain (rectal, urinary, or sexual).

This prospective randomized trial, called the PARTIQoL trial, was an enormous undertaking, involving 450 patients from 30 recruiting centers, including 12 proton centers beginning in July 2012. Hormone therapy was not allowed. Patients were stratified on the following parameters:

  • risk level (59% intermediate-risk)
  • institution
  • age (median 68)
  • rectal spacer use (45%)
  • fractionation -79.2 Gy/44 fractions (49%) or 70 Gy/28 fractions (51%)
  • Pencil-beam proton scanning (49%)

After 2 years, there was no difference in rectal domain scores, with both showing minimal declines from baseline.

  • There were no differences at earlier timepoints.
  • There were no differences at later timepoints up to 5 years of follow-up.
  • There were no differences in urinary or sexual domains at any timepoint.
  • There were no differences in progression-free survival, which was 93%
  • There were no differences in any endpoint of the subgroups defined by any of the stratification variables. 
I suspect that many proton centers will have to declare bankruptcy after this, although there is still a use in pediatric tumors.

Thursday, May 16, 2024

Internet Myths about Red Meat

 "an odour assailed his nostrils, unlike any scent which he had before experienced." from "A Dissertation Upon Roast Pig" by Charles Lamb

Charles Lamb wrote that humorous fiction about the first time roast meat was accidentally tried. While the above quote describes the first accidentally roast pig, it could easily describe a grilled rib-eye steak. Grilled, bloody steaks are one of the great pleasures in life for many of us. 

There is enough evidence that saturated fat, and especially trans fats, are not heart-healthy. Cardiovascular disease is about 20 times the killer of elderly men compared to prostate cancer. Most of us take statins and exercise (I hope), so the occasional rib-eye won't clog our veins, as long as we eat it only occasionally. Of course, ask your cardiologist if you've already had evidence of obstruction.

There are many reasons to change diet, including cardiovascular health, and diabetes. Many men with prostate cancer use some form of androgen deprivation therapy (ADT) and are in danger of getting metabolic syndrome, especially if they are already overweight and sedentary. Men using ADT should monitor caloric intake and increase exercise, with their doctor's permission. Many patients like to change diets because it gives them a feeling of control in a situation where they have lost control of their own bodies. Others torture themselves (or are tortured by well-meaning loved ones) by depriving themselves (one more deprivation!) of their favorite foods. Eating and sharing meals with others is one of the pleasures of our lives, and is part of our social cohesion. But what is the evidence that diet plays a role in lengthening survival due to prostate cancer itself?

There are dietary fads. Current fads include plant-based/vegetarian/vegan diets, Mediterranean diet, ketogenic/low carb diet, alternate-day fasting, macrobiotic diets, microbiome diets, and so-called "cancer diets" that cut out sugars, animal fats, red meat, chicken, eggs, and dairy products, or that add foods with certain phytonutrients. It is extremely difficult to prove that diet has a causal effect in cancer progression. 

Associations between red meat intake and breast or colorectal cancers have been noted. Patients are highly motivated to seek out dietary changes they can do to regain control of their bodies.  Most patients search the Internet for clues but don't know enough about research methodology to distinguish gold from garbage. Many prostate cancer patients (and doctors, who should know better) have succumbed to the "conventional wisdom" that grilled red meat is bad for their cancer too. Is there any truth to that conventional wisdom? Here's the evidence.  

Only "Level 1" can prove that red meat consumption contributes to prostate cancer. (Follow these links to understand Levels of Evidence and GRADE). Higher levels of evidence, that are also high GRADE, replace lower levels of evidence. There is no Level 1 evidence (well-done randomized clinical trial), but there is some Level 2 evidence. A cohort study is Level 2 evidence only if it is prospective; i.e., the hypothesis to be investigated is formulated from the start. Longitudinal retrospective cohort studies are Level 3 evidence. See below for reasons why such studies almost always provide conflicting results.

Level 2 Evidence

The NutriNet Santé Cohort Study is a huge (61,476 adults over 35) prospective web-based cohort study in France. France has the highest rate of internet use of any large country, and it cuts across age and socio-economic classes. Participants fill out food questionnaires (3 random records of 24-hour food intake during a two-week period). They also provide information on physical activity, BMI, height, sex, age, lifestyle, health status, family history of cancer, and socio-economic conditions. They also may provide blood and urine samples and get a physical exam. Red meat can be beef, pork, veal, or lamb. Processed meat can be cured meats, sausage, bacon, ham, salami, spam, etc.

With a follow-up of 4 years, and 222 prostate cancers in the cohort, Diallo et al. reported:

  • Red meat intake was not associated with prostate cancer risk
  • Processed meat intake was not associated with prostate cancer risk
  • There was no association for any Gleason score.

Also, Level 2 evidence is provided by the UK Biobank Mendelian Randomization Study. They found the genomic mutations associated with red and processed meat intake and found the correlations with incidence of prostate cancer in over 140,000 people.

  • Red meat intake was not associated with prostate cancer risk
  • Processed meat intake was not associated with prostate cancer risk

Allen et al. reported the results of The European Prospective Investigation into Cancer and Nutrition (EPIC). It was a very large cohort study with 142,251 men and 2,727 cases of prostate cancer (none at enrollment) and 8.7 years median follow-up. It randomly sampled the cohort to ask for 24-hour dietary intake. They found that:

  • Red meat and processed meat intake was not associated with prostate cancer risk
  • There was no association for advanced or localized PCa or by Gleason score
Level 3 Evidence

Cross et al. prospectively reported on red meat associations with prostate cancer in the PLCO screening trial. They found no association with any meat products, but a small positive association with very well-done meat.

The CANARY PASS Trial proved that eating healthier did not affect progression. They defined eating healthier as either Dietary Guidelines for Americans (Healthy Eating Index - 2015)alternative Mediterranean Diet, or Dietary Approaches to Stop Hypertension.

Contradictory findings were reported in several observational cohort studies.

The MEAL Randomized Clinical Trial (RCT) - Level 1 Evidence

The MEAL RCT is the only Level 1 evidence we have on dietary causes of prostate cancer.

Parsons et al. randomized 478 low-risk men who were using active surveillance at 91 cancer centers to one of two groups:

  • The intervention group received telephone prompts to eat 7 or more servings of vegetables per day, including 2 servings of each of cruciferous vegetables and tomato products.
  • The control group only received written information

They all kept detailed food diaries, and plasma carotenoid assessment was used to prove compliance. After 2 years, the intervention group increased their consumption of vegetables and reduced consumption of red meat and animal fats. However, there was no difference in time to progression.

This trial proves that increasing vegetable intake has no effect on even the "lightest" prostate cancer. It also shows there is no "dose response" due to meat consumption. A "dose response" means that the more one uses some intervention, the greater the effect will be. We see this frequently with drugs - the higher the dose, the greater the response, up to a certain point; and the lower the dose, above some minimum, the lower the response. Some argue that meat-eating has no dose response but is binary -- eliminating all non-vegetable protein sources can make a difference. 

A typical dose-response curve:

Other Vegetarian Trials

It is worth mentioning Dean Ornish's  Prostate Cancer Lifestyle Trial (PCLT)  randomized 93 men on active surveillance to either:

  • A vegan diet with complex carbs and very low fat. They also exercised, took a variety of vitamins and food supplements, managed stress, and met in groups.
  • The other group just had usual care.

After 2 years of follow-up, fewer men in the treatment group had prostate cancer treatment. There was no difference in PSA. How much of the difference is due to exercise, may be speculated upon, and is the argument against unwarranted claims, such as this one. Early results of the ERASE trial suggest that exercise can make a difference. Cardiovascular parameters improved more in the intervention group.

A pilot trial among 36 recurrent men randomized them to either:

  • 11 weeks of mostly plant-based foods and oily fish, with no or less animal proteins. They also practiced mindfulness.
  • usual care

After 3 months, there was no difference in the rate of PSA change. 

There have been no other randomized studies in men with prostate cancer. There have been a couple of prospective trials without a control group to compare results.

Why Only Level 1 Evidence is Important to Patients

Level 2 or 3 studies are only hypothesis-generating for other researchers to conduct Level 1 trials. They should never be used by patients to make life-changing decisions. Observational studies suffer from "selection bias." This means that the patients who got the treatment (here, red meat) were in some ways different from the patients used as the control group (here, vegetarians). Researchers use statistical techniques like "propensity score matching" in the hope of correcting for this bias. But a new data analysis proves why they don't work. 

Wang et al. looked at 15 published studies on the topic of red meat and mortality, and at a huge dataset, The National Health and Nutrition Examination Survey 2007-2014 (NHANES), a longitudinal observational study (level 3 evidence) of over 10,000 persons. 

Their review of 15 published studies analyzed in 70 unique ways found:

  • Red meat intake was associated as originally analyzed with anywhere from a 37% reduced risk of death to a 131% increased risk of death.
  • They were able to re-analyze that data 10 quadrillion different ways (each way used a different set of variables like age, health status, etc.).

They randomly chose 1200 different ways that all seemed appropriate and applied them to the NHANES dataset.

  • Analysis of the 1200 methods for analyzing the data found:
  • There was no statistically significant association between red meat intake and death. With 95% confidence, it ranged from a 49% reduced risk of death to a 75% increased risk of death.
  • In total, 64% of analyses showed a reduced risk of death, while 36% showed an increased risk. Only 4% of analyses had statistically significant results. Of those, 83% showed reduced risk of death, and 17% showed increased risk of death.
  • Most analyses resulted in very little association (±10%)

Conclusion: with studies that are low-level evidence, the method chosen for the analysis changes the conclusion. Similar studies of analytic choice have similar results (see this link and this one).

Other Protein Sources

There is no Level 1 evidence for any protein source. Lower level evidence yields conflicting associations for every protein source. Below is just one example of each (note: negative associatiation means consuming more was beneficial, positive association means consuming more was deleterious).

Dairy: There are observational studies that have shown positive, negative, and no correlation with prostate cancer outcomes.

Chicken: Observational studies show no association, a positive association, or a negative association with prostate cancer progression.

Eggs: Observational studies show no association, or a positive association, with prostate cancer progression.

Fish: Observational studies show no association, a negative association, or a positive association with prostate cancer outcomes.

Vegan/Vegetarian: The complete protein source for vegans is high in carbohydrates (e.g., soy, beans and pasta). Observational studies with diets high in soy show no association, negative association, or a positive association. A small randomized trial designed to see if there was any effect of a diet low in carbs on PSADT. It was stopped early because of no effect.

Humans evolved to be omnivores. Our gut bacteria co-evolved and thrive on a varied diet. Plants are necessary for good gut motility.

ADVICE

There is no usable evidence that cutting back on red meat is beneficial. Given the lack of convincing evidence, it is a good idea to:

  • Vary one's protein sources (unless cardiologist dictates otherwise)
  • Don't deprive yourself! You have cancer -- treat yourself well, at least occasionally.
  • If you are on ADT, your metabolism is slower, so consume fewer calories and exercise more.
  • Eat plenty of vegetables, especially cruciferous and highly-colored vegetables.
  • Avoid vitamins, minerals and supplements unless you are deficient. Get your micronutrients from food. Your body will take what it needs and discard the rest. Don't try to outsmart your body -- you will lose. It has millions of years of evolution on its side.