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Might Negative Second Biopsy Procedures Indicate Spontaneous Regression?

There is an interesting Editorial in Uro Today PROSTATE CANCER RESEARCH INTERNATIONAL: ACTIVE SURVEILLANCE (PRIAS) STUDY . It is early days to draw any broad conclusions from this study, but one aspect caught my eye.

In the short time the study has been running (median follow-up a little over one year), a total of 261 men had repeat biopsies. To be accepted for the study, the initial diagnosis required was clinical stage T1c or T2 disease, PSA level 10ng/ml or less, PSA density of < 0.2ng/ml/ml, Gleason score 6 or less, and 2 biopsy cores or less involved with cancer. The repeat biopsies showed no PCa in 34% of the men and PCa in one or two cores with Gleason score less than 6 in 44%. In other words the biopsy showed no worsening of the situation in 78% of the men – quite the contrary, in most cases the result was significantly better. Presumably these men would lave had ‘favorable criteria’ since the other 22% of the men had what was termed in the Abstract as “unfavorable criteria”.

Of course, given the ‘hit and miss’ nature of prostate biopsy procedures, these results may mean that the needles just missed dangerous parts of the gland – but then again maybe not. I have long held the view that the development of the atypical cells that are labeled as ‘prostate cancer’ is a natural process. Like all other natural processes, there is no stasis: in nature there is always growth or retreat, nothing stands still. When cancers retreat the process is termed spontaneous remission or spontaneous regression. A definition might be A complete or partial, temporary or permanent disappearance of all or at least some relevant parameters of a soundly diagnosed malignant disease without any medical treatment or with treatment that is considered inadequate to produce the resulting regression. So could the absence of any sign of prostate cancer in the second biopsy needles, or the lower Gleason Grades be a demonstration of spontaneous regression?

Most men and medical people will tend to refute this thought with the reaction that there are no studies that demonstrate this possibility for prostate cancer. And they would be right, depending on their definition of what an appropriate study is – as far as I know there are no specific, prospective, double blinded, peer reviewed studies that demonstrate that prostate cancer can spontaneously regress. But that really means that the possibility may not have been studied. I don’t think it should mean we should ignore all evidence that points to a possibility of a spontaneous regression of prostate cancer.

When I first started my investigations of the possibility of spontaneous regression (SR), one of the first abstracts I found was this one which speculates on possible causes of SR. I found it particularly pertinent to note that SR is reported in virtually all types of human cancer and that one of the mechanisms proposed for SR was psychologic factors - an interesting thought for those who feel that attitude has nothing to do with healing. Immune mediation is another contentious issue since it was a long held belief that the immune system could not recognise tumour cells.

Papac RJ.: Spontaneous regression of cancer: possible mechanisms. In Vivo, 1998 Nov-Dec, 12(6):571-8.
Abstract: Spontaneous regression of cancer is reported in virtually all types of human cancer, although the greatest number of cases are reported in patients with neuroblastoma, renal cell carcinoma, malignant melanoma and lymphomas/ leukemias. Study of patients with these diseases has provided most of the data regarding mechanisms of spontaneous regression. Mechanisms proposed for spontaneous regression of human cancer include: immune mediation, tumor inhibition by growth factors and/or cytokines, induction of differentiation, hormonal mediation, elimination of a carcinogen, tumor > necrosis and/or angiogenesis inhibition, psychologic factors, apoptosis and epigenetic mechanisms. Clinical observations and laboratory studies support these concepts to a variable extent. The induction of spontaneous regression may involve multiple mechanisms in some cases although the end result is likely to be either differentiation or cell death. Elucidation of the process of spontaneous regression offers the possibility of improved methods of treating and preventing cancer.

Another study which seems to me to be pertinent is this one. I noted with interest that SR is said to be well documented and is said to be commonly attributed to the activation of the immune system. I was somewhat surprised to see the suggestion that tumours are inherently prone to SR since the odds of SR occurring have been calculated in one report as only occurring once in 80,000 cases. Mind you it is as difficult to identify how much SR there is as it is to calculate how many perfect murders occur. The definition of a perfect murder means that it was never identified as a murder. If a tumour occurs, is not diagnosed and is overwhelmed by the immune system, it could not be identified as a SR case. But I digress – here’s the second study:

Yakovlev A; Boucher K; DiSario J. Modeling insight into spontaneous regression of tumors. Mathematical Biosciences, 1999 Jan 1, 155(1):45-60.

The abstract opens by saying

The phenomenon of spontaneous regression of benign and malignant tumors is well documented in the literature and is commonly attributed to the induction of apoptosis or activation of the immune system. We attempt at evaluating the role of random effects in this phenomenon. To this end, we consider a stochastic model of tumor growth which is descriptive of the fact that tumors are inherently prone to spontaneous regression due to the random nature of their development.


When I have raised the issue of SR as a discussion point previously, the concept has either been ignored or shot down because of the stated lack of specific prostate related studies. I did find one study that referred specifically to prostate cancer:

Bissada NK; Kaczmarek AT. Complete remission of hormone refractory adenocarcinoma of the prostate in response to withdrawal of diethylstilbestrol. Journal of Urology, 1995 Jun, 153(6):1944-5.

Abstract: The phenomenon of regression of adenocarcinoma of the prostate after the withdrawal of antiandrogens is well documented. However, to our knowledge we report the first case of durable complete remission of hormone refractory prostate cancer after cessation of diethylstilbestrol. The drug was discontinued because the patient had disease progression while on diethylstilbestrol and withdrawal resulted in durable remission. In more than 3 years of followup since discontinuing diethylstilbestrol there has been no evidence of clinical or biochemical recurrence.

Of course this is not conclusive, but there are anecdotal reports of PSA not rising after intermittent ADT (Androgen Deprivation Therapy). This would, I think qualify as SR because the general view ADT is not curative. It is because of these incidents that I have wondered why early stage PCa is not treated with what I refer to as ADT Lite – limited shots of Zoladex for instance. If the colony is small enough, the combine effects of ADT and the immune system might wipe it out permanently.

I am not suggesting in any way that anyone should rely on SR as a potential ‘cure’ , but I think it is important to bear in mind that those men – the substantial majority in the US especially – who have a diagnosis that fits the criteria for this study would probably not lose anything – and might gain confidence in the Active Surveillance option if they followed the suggested PRIAS protocols.

Re: Might Negative Second Biopsy Procedures Indicate Spontaneous Regression?

Terry,

Very interesting information. Thanks for posting it.

The Stranger

Re: Might Negative Second Biopsy Procedures Indicate Spontaneous Regression?

Thank you for posting this Terry. You said: "I have long held the view that the development of the atypical cells that are labeled as ‘prostate cancer’ is a natural process". I have read a few comments by doctors recently (unfortunately I can't remember where) that suggest the majority of low Gleason, slow growing, insignificant prostate cancers, might properly not be labelled "cancer" at all. Perhaps that would explain the remarkable incidence of SR reported in this study.

Having had a robotic prostatectomy and still now doing active surveillance (like ALL men who have had any form of treatment, however successful), I increasingly wonder if the real research that needs to be done is first to be sure that what we have is cancer in the conventional meaning of the term. Second to decide which type is actually dangerous, as some undoubtedly are. Third learn how to watch it and survey it. Fourth develop a treatment protocol that preserves a quality of life that makes the treatment worthwhile.

I would lay a bet that if the science could tell us which atypical prostate cells would become cancerous in any meaningful sense and which not, there would be no rush to treatment!

Ted from England

Re: Might Negative Second Biopsy Procedures Indicate Spontaneous Regression?

Terry the notion of spontaneous regression for most types of cancer is not new. Essentially from early childhood the body does produce rogue cells, but the body'd immune system is very adept at identifying and destroying these. Even in advanced cases of Ca the immune system still functions to a certain degree, but it's efficacy is variable. In some lucky persons, modern therapeutics are able to switch back on, the rogue cell identifying, thus rallying the body's defences and hence SR.

Re: Might Negative Second Biopsy Procedures Indicate Spontaneous Regression?

John you say …the notion of spontaneous regression for most types of cancer is not new. I agree with you, but one of the available papers on the subject (published in September 1956 – fifty years ago!) said in it’s opening paragraph:

“Spontaneous regression of cancer is a very intriguing and challenging phenomenon, which has been mentioned as a probability or fact by numerous writers in the field of oncology, but proof of its existence is difficult to obtain..…….Some authorities have expressed serious doubt that the phenomenon ever occurs.”

And this is still the view today, at least judging by my experience in trying to get discussions going on the subject on a number of Lists and Forums over the years.

In one memorable (for me) exchange in about 1998, Dr Charles “Snuffy” Myers (who was recovering from his bad, self-selected treatment and who used to post a fair bit on the Internet) simply denied initially that SR existed. When challenged he moved to the position that it might occur in some cancers, but not PCa. Challenged on this (all challenges from me!!) with some evidence he said that IF it occurred in PCa it was so rare that no one should depend on it for a cure. My response that since most prostate glands are removed within six weeks of diagnosis this was might not be long enough for SR to occur, was not commented on.

Ted, as to your comments:

You say …first to be sure that what we have is cancer in the conventional meaning of the term.

Indeed this seems such an obvious point, and yet the definition of ‘prostate cancer’ has changed - even since I was diagnosed. Positive biopsy material with a Gleason Score of less than 3+3 is no longer tagged as PCa – at least in Europe or the US, yet 10 years or so ago, GS 5 and GS 6 were the most common scores! This decision has led to an upgrading of tumours – a migration as it is referred to. You can read about it here GLEASON GRADE MIGRATION if you’re interested.

The first time I came across the concept of ensuring a consistent definition was in a piece WHEN A CANCER DIAGNOSIS IS WRONG In that, Dr Christopher Logothetis a renowned specialist who deals with advance prostate cancer said (in 1993) in part:

One of the problems with prostate cancer is definition. They label it as a cancer, and they force us all to behave in a way that introduces us to a cascade of events that sends us to very morbid therapy. It's sort of like once that cancer label is put on there we are obligated to behave in a certain way, and its driven by physician beliefs and patient beliefs and frequently they don't have anything to do with reality.

This was echoed 15 years later by leading US pathologist Dr Jonathan Oppenheimer who says on his BLOG

For the vast majority of men with a recent diagnosis of prostate cancer the most important question is not what treatment is needed, but whether any treatment at all is required. Active surveillance is the logical choice for most men (and the families that love them) to make.

He also suggests:

It is time to reconcile the discrepancy of the term that pathologists assign to a microscopic finding to the historical and practical significance of that term. The most common significant finding made by contemporary pathologists on prostate biopsies cannot be adequately described by “tumor” (Greek: swelling), “cancer” (from the crab-like extension), or “malignant” (threatening to life or tending to metastasize). I propose the terms “prostatic tubular neogenesis” (creation of new epithelial tubes or acini) and “potentially malignant” to better describe the microscopic findings that we have in the past labeled “adenocarcinoma” “cancer” “tumor” and “malignant.”



You go on to say Second to decide which type is actually dangerous, as some undoubtedly are.

There is no doubt that some forms of PCa are indeed extremely dangerous, but those can be identified fairly easily and with a deal of accuracy. The problems that arise are, as Dr Logothetis and Dr Oppenheimer highlight, because ALL tumours are treated as if they are aggressive when it is very clear that they are most likely not. Dr Peter Scardino, one of the best surgeons in the US, was quoted three years ago in one of the newspapers as saying that we can now tell with a 95% certainty which tumours are likely to progress. That is not 100%, it is true, but is anything in life 100% guaranteed (apart from death and taxes)?

You go onThird learn how to watch it and survey it.

That is what the Active Surveillance studies around he world are doing – and they are demonstrating that what Dr Logothetis and Dr Oppenheimer and many others have been saying for years. Dr Thomas Stamey for example, said in 2001:

I believe that when the final chapter of this disease is written, which is unlikely to be in my lifetime, never in the history of oncology will so many men have been so overtreated for one disease.

And that is precisely what the latest studies are telling us with an estimated one million plus men who have been treated unnecessarily.

And then you say Fourth develop a treatment protocol that preserves a quality of life that makes the treatment worthwhile.

Despite the fact that there are no scientific studies to support the kind of concepts put forward by Dr Myers at COMPREHENSIVE MANAGEMENT OF PROSTATE CANCER there is unlikely that support for this kind of approach, with no great contribution to the income of those involved in the PCa Industry will get any meaningful support.

Ted you finally say I would lay a bet that if the science could tell us which atypical prostate cells would become cancerous in any meaningful sense and which not, there would be no rush to treatment!

The rush for treatment has slowed, to a certain extent and there are even some enlightened and informed doctors who will discuss Active Surveillance as an option for men with a suitable diagnosis, but if you read as many stories as I do, you will know that these are few and far between and the word “cancer” still has the power to push men into inappropriate treatment, helped by doctors who should know better.

All the best

Terry in Australia

Re: Might Negative Second Biopsy Procedures Indicate Spontaneous Regression?

Thanks for your detailed points, Terry. It was the Oppenheimer blog that I had not remembered.

It's true as you say that " . . . the word “cancer” still has the power to push men into inappropriate treatment, helped by doctors who should know better." I held off treatment for 8 months but was persuaded by a leading surgeon that if he put my prostate in a jar I would be able to put all this behind me and live the rest of my life without worrying if the PCa would develop.

As I have reported before, because of scar tissue I had from a previous TURP, he actually left 6 grams of the gland behind the bladder neck. This means that I am still doing the AS I was doing for 8 months before the op, only now I do AS with all the morbidities that follow a prostatectomy! (The musician Andrew Lloyd Weber is now in this position. Only his surgeon apparently blames scar tissue from an appendectomy at age 3!)

But in any case all men do AS after their ops and radiation anyway. The PSA tyranny never really goes away. You once said that men often choose surgery because if it fails you can move on to HIFU, for example, and if that fails you can go to radiation and if that fails on to ADT, etc.. You then speculated that it might be better to cut out all the procedures in the middle and simply keep an eye on things until, if necessary, go straight to ADT and the other palliatives.

It seems that for most men, with insignificant prostate "cancer", the survival outcomes are the same whatever you do or don't do. But at least by not storming in with heroic intervention too early, the patient will avoid all the morbidities of surgery or radiation.

Although the uro I see now is a HIFU expert, he tries to keep intervention to a minimum. He is helping me do AS. My PSA over the 2 years since my op, from my remaining 6 grams, has been up and down from as high as 1.62 (post op!) down through 0.81 to as low as 0.13 and most recently 0.61. In his last letter he said although there has been "quite a bit of fluctuation . . . I think it's fair to say there is no obvious progressive rise. I am reassured by this."

So am I. But even if there is a progressive rise, I shall now think very carefully, and slowly, before I allow him to unleash the Sonablate or whatever.

Ted from England

Re: Might Negative Second Biopsy Procedures Indicate Spontaneous Regression?

Terry I guess it just depends on one's perspective. Most health professionals can readily recall cases that defy existing medial knowledge. Health professionals use the term spontaneous regression, some patients see it as divine intervention. No doubt science will provide explanations over time, particularly when therapies are able to attack identified rogue cells.

Re: Might Negative Second Biopsy Procedures Indicate Spontaneous Regression?

I missed this article Study Suggests Some Cancers May Go Away in the New York Times series on Cancer.

It refers to a study in Norway – those darned Scandanavians!! – and it says in part ….new study, to be published Tuesday in The Archives of Internal Medicine, suggests that even invasive cancers may sometimes go away without treatment and in larger numbers than anyone ever believed. Well, perhaps no one other than me – and the dozens of men who chose not to have immediate conventional treatment for an insignificant tumour.

I know this isn’t any proof positive of anything, but it should be food for thought for those with an open mind.

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