Friday, December 16, 2016

Focal Ablation: Unresolved Issues

(frequently updated)

Focal ablation is the highly targeted destruction of cancerous prostate tissue, usually with some kind of heat or cold (called “thermal” ablation). There has been a lot of patient interest in focal ablation, spurred on by doctors and institutions promoting it and media reports. There has been much hype in the last year over focal ablation using high frequency focused ultrasound (HIFU) focal laser ablation (FLA), and photodynamic therapy (PDT). Cryoablation has been around for the longest time of any. There have been pilot trials of radiofrequency and microwave ablation as well. Irreversible Electroporation (IRE) may be the only form of ablation that is non-thermal, but so far seems to share characteristics with thermal ablation therapies. The promotional announcements for all of these therapies are often unbalanced, so it behooves anyone interested in pursuing it to get an understanding of the issues involved.

I am sincerely agnostic on this subject, and am very happy to see a potential prostate cancer therapy explored in tightly circumscribed clinical trials where patients are informed of the risks. I do believe that until we have learned more, clinical trials with strict protocols should be the only circumstances under which focal ablation is performed.

The Hope

Focal ablation has been touted as “the male lumpectomy.” This is a term borrowed from breast cancer. Breast cancer sometimes starts as a single tumor (called “unifocal”) that may be cured if it is removed with a negative margin. Just as the breast is preserved by such excision, the hope is that prostate function, and especially the function of nearby organs (bladder, rectum, urethra, bladder neck, neurovascular bundles, erectile function, and continence) can be fully preserved. Let’s understand why “lumpectomy” may be very different for the prostate.

Multifocality

Prostate cancer is overwhelmingly a multifocal disease. 80-90% of prostatectomy specimens have separate tumors distributed throughout the organ. Removing the largest, highest grade tumor (called “the index tumor”) does not remove all the cancer from the prostate.

Hemiablation

One way to get around the multifocality issue is to ablate half the prostate, either the right lobe or left lobe, but not both.This is called hemiablation. The hope is that the damage to nearby organs will be significantly reduced in so doing. Prostate cancer often appears to predominate in one lobe. But appearances are deceiving, even when saturation biopsies have been used to determine that the cancer was unilateral, it turned out to be bilateral in 3/4 of those cases (see this link), and may be as high as 90% (see this link). With traditional TRUS biopsies, unilateral cancer was misidentified in about 80% of men (see this link). Multiparametric MRI is not good at finding small tumors on the contralateral side. Pompe et al. showed that it missed cancer on the contralateral side in 58% of patients. The main issue is that it has not been proven that hemiablation is curative. In a study of 55 men in Belgium who received hemiablative HIFU, a quarter of the men relapsed and required further treatment. In a US study of 100 men receiving hemi-ablative HIFU, followed up with a biopsy after 2 years, a quarter had relapsed with Grade Group 2 or greater prostate cancer.

Index Tumor Theory

Proponents of focal ablation argue that it doesn’t matter if there are small amounts of prostate cancer that remain untreated. Prostate cancer, they believe, spreads by cloning daughter cancer cells from a single “parent” tumor within the prostate. This is called “Index Tumor Theory.” Under this theory, if the index tumor is removed by ablation, the prostate cancer will not spread further. In theory, the small untreated daughter foci of cancer are not malignant and will cause no further problems. In theory, the index tumor is identifiable as the largest, highest Gleason score tumor within the prostate.

Index tumor theory relies on the findings of two studies. Liu et al. and Mao et al. showed that metastases arise as clones from a single parent cancer cell. The Liu et al. study was based on cancers from 30 men who died of prostate cancer. The Mao et al. study confirmed the earlier study in a sample of 16 men. While both studies showed that metastases arose from a single prostatic parent cell, they did not show that the parent cell was in an index tumor. In fact, a case report from Johns Hopkins showed that lethal metastases at least sometimes could arise from a small, low grade tumor within the prostate, rather than from an index tumor. Adding to the complexity, Cheng et al. found that multiple tumors had independent origins. In 15/18 tumors, they found that they arose independently rather than from a parent tumor within the prostate, and in only 3/18 tumors they arose through intraglandular dissemination from an index lesion. Similarly, Wei et al. looked at prostate tumors taken from 4 patients, and found there was considerable genetic diversity within their index tumors as well as their other cancer foci. Ibeawuchi et al. discovered that a unifocal tumor could be as genetically diverse as multifocal tumors. Løvf et al. found that the various tumors in the same prostate only rarely shared genetic mutations, suggesting independent origins. Kneppers et al. found among 30 men with lymph node metastases that for 23%, their metastases were not clonally derived from the index tumor.

All of the above-mentioned genetic studies have been conducted in small numbers of patients. Genetic studies are tremendously difficult to conduct and interpret. Genetic breakdown is a characteristic of cancer, which complicates the subjective determination of what constitutes a clone from the index tumor.

None of this disproves index lesion theory entirely. In fact, there must be some truth to it or focal ablation would never be effective. Focal ablation trials with 5 years of follow-up demonstrate that focal ablation seems to halt progression in most men. However, because the studies have not been randomized, we cannot rule out that those mostly low risk patients were caught early and would not have progressed appreciably in that time frame anyway. We also know from long-term active surveillance trials that about half of all men with confirmed low-risk tumors will eventually progress – the smaller Gleason 6 tumors must be monitored. The most likely scenario is that there are index tumors in some men but not others. Unfortunately, we have no easy way of predicting which patients have index tumors and which have multiple tumors that are capable of malignant spread.

Targeting the index tumor

Assuming there is an index tumor, the next question becomes: can we precisely locate the tumor for targeted ablation? Our best current tool for doing so is using a multiparametric MRI (mpMRI) to target what seems to be the index tumor, and to confirm the location with a biopsy (either ultrasound fusion or in-bore). This poses special challenges.

Most patients who choose focal ablation are those who have predominant Gleason pattern 3 (either Gleason score 3+3 or 3+4). mpMRI is not at all sensitive at finding such low grade tumors if they are small; in fact, it is no better than a standard TRUS biopsy. In a study of mpMRI and Ga-68-PSMA PET/CT, both imaging techniques missed more than half the prostate tumors found after prostatectomy. Perhaps Color Doppler Ultrasound or transperineal template mapping biopsy perform better (see this link), but they are seldom used. However, mpMRI is a good tool for finding larger and higher grade tumors. In a study at UCLA, 80% of “index tumors” were found using mpMRI. In another UCLA study, mpMRI found that half of all men with intermediate or high-risk prostate cancer had satellite tumors in addition to their index tumor, but 2/3 of those same men were found to have satellite tumors when their prostates were surgically removed. Over half of the satellite tumors were Gleason score ≥ 3+4.

While mpMRI may detect index tumors, it is not a good tool for delineating even higher grade tumors. Priester et al. compared the dimensions of tumors found via mpMRI in 114 men to the dimensions of their same tumors determined via post-prostatectomy pathology. They found that the actual tumors were 3 times larger than their MRI estimates – they missed 80% of the tumor’s volume by relying on the MRI. It is worth noting too, that these MRIs were read by arguably the best radiologist in the business, Daniel Margolis at UCLA. He literally wrote the book (PIRADS 2.0) for interpreting mpMRIs. In a study of 461 lesions in 441 men, the average size of tumors was only 1.6 cm on the mpMRIs but was 2.4 cm after prostatectomy. The correlation between MRI and actual size was poor (0.13- 0.65). Pompe et al. found that mpMRI could not detect extracapsular invasion, and missed cancer in 58% of patients who had cancer in the contralateral lobe from the index tumor.

If satellite tumors are to be ablated as well as the index tumor, mpMRI performs even worse in finding them. Hollmann et al. found that satellite tumors were a median of 1 cm, and up to 4.4 cm, away from the index lesion, so they would not be destroyed within the ablation zone of the index lesion, and it would be difficult to locate them. (Update 5/2019) Stabile et al found that mpMRI missed 30% of the significant (Gleason score≥3+4) cancer outside of the index lesion, and the missed tumors had a median length of 2.6 mm, which is smaller than anything an mpMRI can detect.

Incomplete ablation in the ablation zone

Now let’s assume you do indeed have an index tumor, and you were able to accurately delineate it somehow, the next question becomes: Can focal therapy be used to completely ablate the tumor? So far, the answer seems to be – not completely. In some studies, treated patients had MRI-guided biopsies of the ablation zone within 6 months of treatment. Cancer was found in the ablation zone:

Focal Laser Ablation (FLA):  

(Update 5/2020) Feller et al. reported on the 10-year outcomes of 158 men and 248 cancer foci treated with MRI-guided FLA. All men had low or intermediate-risk prostate cancer. 122 had an MRI-targeted biopsy of their treatment sites after 6 months.
  • 26% were positive with clinically significant cancer
  • 15% were positive with clinically insignificant cancer
  • 59% were negative
(Update 5/2021) Mehrahlivand et al. reported that 3 years after MRI-guided FLA of 15 low and favorable intermediate-risk patients, almost half had residual cancer in, adjacent to, or in close proximity to the treatment area.

(Update 5/2019) Chao et al found that 8/32 (25%) had an mpMRI suspicious for cancer in the ablation zone within 2 years after FLA (Median time to positive mpMRI in the ablation zone was 6 months). All were confirmed by biopsy. Only one of those patients had low volume GS 6. 24/32 (75%) had an unsuspicious mpMRI, but biopsy at 2 years after FLA was nevertheless positive in 9 of the 14 men (64%) who had a biopsy. So 17/22 men (77%)  had a positive biopsy in the ablation zone after 2 years. Change in PSA did not predict a positive or negative mpMRI or a positive or negative biopsy.

In this study, MRI-detected cancer was found in 10/27 patients after 12 months, with cancer found in the ablation zone via biopsy in 3 patients. Cancer was found in the ablation zone in 2/9 patients (22%) in this study, 7/10 (70%) patients in this study that used a targeted biopsy, and 4/12 (33%) in this study. In one study, 2/13 (15%) had residual cancer within the ablation zone, but only 13 of 23 patients had a targeted biopsy. Knull et al. compared the pre-operative mpMRI images with MRIs obtained immediately after FLA in 23 lesions. They found that FLA did not completely overlap the intended ablation zone in about half of the lesions, and those tumors extended a median of 0.9 mm past the edge of the ablation zone.

High Intensity Focused Ultrasound (HIFU): Cancer was found in the ablation zone in 36% of the patients who had biopsies for cause in this study. In a hemi-ablation study, 28% had biochemical recurrence and 3/8 biopsied patients (38%) had cancer in the treated lobe. In another hemiablation study, 16% had cancer in the ablated lobe. In a large study of whole gland HIFU, 29% were given a repeat treatment. Cancer was found in 42% of high risk men in the ablation zone in this study - 10% were given a repeat treatment. In a US hemiablation study, 17% had Grade Group 2 or greater cancer in the treated lobe.

(Update 3/2020) Klotz et al. reported the 1-year outcomes of an MRI-guided and MRI-thermometry HIFU-ablated kind of thermal ablation called TULSA-PRO. The favorable risk men were all biopsied a year after whole gland treatment. Cancer was found in 35% of the treated men even though they barely had a prostate left (3 ccs.) and their PSA was very low (0.5 ng/ml). Full article here.

(Update 6/21/20) Lumiani et al. reported the 16-month outcomes of 52 consecutive TULSA-PRO patients, mostly focal. 27% were positive for recurrence on follow-up MRI, and the recurrence was confirmed by biopsy in all those who had a biopsy. Recurrence rates were similar for focal and whole-gland.

Photodynamic Therapy (PDT) /TOOKAD: In a hemiablation study, 11/21 men (52%)had a positive biopsy in the treated lobe.

Cryo: In a whole-gland study of cryoablation, 37% had residual cancer in the ablated prostate.

Irreversible Electroporation/NanoKnife (IRE): In a study of focal IRE, which is largely a non-thermal form of ablation, 4/25 patients (16%) were found to have residual cancer in the ablation zone. In another study that used mpMRI to detect residual cancer up to one year after treatment, 9/30 patients (30%) were found to have residual cancer in the ablation zone. Colletini et al reported in-field treatment failures by 18% of low and intermediate-risk patients detected via mpMRI-targeted bioosy after 6 months.

So we observe that ablation is sometimes incomplete within the treated area. There are thermodynamic and biochemical reasons that may explain those failures.


Heat Sink Effect

Most kinds of ablation (e.g., FLA, HIFU, cryo & PDT) are thermal, which means they rely on the local application of heat or cold to ablate the tumor tissue. The second law of thermodynamics guarantees that heat (or cold) will never stay exactly where it is put. This is true for the thermal energy generated by laser beams, by ultrasound, contact with cold, or by any kind of electromagnetic energy. Water is a very good conductor of thermal energy, and prostate tissue is mostly water. The thermal energy always flows away from where it is placed, leaving the ablation zone with less ablative energy, and areas around it with more ablative energy. This translates to sub-lethal killing of cancer cells within the ablation zone, and killing of healthy tissue outside of the ablation zone.

Biochemical Effects

Human cells, especially cancer cells, have self-preservation mechanisms that may defeat efforts to ablate them. One such mechanism is “heat shock protein (HSP).” Whenever cells are threatened with heat, they enlist HSPs to protect themselves. (There are actually separate “cold shock proteins” that have been identified.) HSPs play an important role in protecting cancer cells, and scientists are developing HSP inhibitors that may one day help other medicines to treat cancer. HSPs are known to play a special role acting as chaperones in bringing the androgen receptor to a more protected place inside the cell. They also encourage cells to enter a dormant phase where they are less subject to destruction. Cell cycle dormancy may play a role in ablation therapy. It is possible that in malignant cells that are not destroyed, cell cycle arrest may delay cell replication for some time. Paradoxically, activation of HSPs may turn cancer cells more aggressive. (See this link and this one). This has not been studied in regard to focal ablation, but should be.

We are coming to recognize the effects that cancer cells may have on nearby “bystander” cells. In a recent lab study, prostate cancer cells stressed by PDT released nitric oxide that caused bystander cells to become more aggressive. The role of extracellular vesicles/proteasomes in promoting malignancy in nearby cells under ablation conditions has yet to be elucidated.

Organ-at-risk damage/toxicity

Because of the heat sink effect, there will always be some impact on surrounding healthy tissues. Depending on where within the prostate the index tumor is, and how large the ablation zone is, ablation may damage the urethra, the rectum, the bladder neck, or neurovascular bundles. In most modern trials of focal ablation, side effects have been low, but are not zero.

At the same time, there has been much progress made in reducing the toxicity of radical (whole gland) radiation therapy. Take for example, a report of HDR brachytherapy as a monotherapy for treating intermediate risk patients, and compare it to the recent report by the Ahmed/Emberton group of (mostly) intermediate risk patients treated with focal HIFU in the UK, the largest study of focal HIFU. Both studies had 5 years of follow-up.


HDR brachy
HIFU
Recurrence-free survival
94%
72%
Potency preservation
82%
84%
Percent pad-free
97.5%
97.6%
Serious rectal injury
none
2 patients

Oncological control was 30% better with HDR brachy and only required a single treatment. Sexual, urinary, and rectal late term side effects were equivalent for both treatments. What is the advantage of focal ablation, then?

Re-do rates

As we’ve seen, some recurrences occur within the ablation zone, but most recurrences occur outside of the treated area. In the above-cited report on HIFU, 28% of patients had a recurrence. This is typical for focal ablation. An advantage often cited for focal ablation is that patients who have a recurrence can be retreated with a second round of focal ablation therapy. In the Ahmed/Emberton HIFU study, 25% of all patients were treated with HIFU multiple times (others chose radical salvage therapy (7%) or permanent hormone therapy (1%)).

“Re-do’s” incur extra costs and may increase morbidity of treatment. There’s no guarantee that they will be effective. As we’ve seen, recurrences are common even when the whole gland is ablated.

Lack of long-term data

The longest running studies of focal ablation, other than cryotherapy, have only 5 years of follow-up. While 5 years may be enough for therapies that are simply an improvement over existing therapies, focal ablation requires longer follow-up because of all the open questions that may affect long-term results. Because many of the focal ablation patients so far have been low risk patients who are likely to enjoy long progression-free times anyway, it is not at all clear that the remissions are lasting ones. Both the AUA nor the EAU consider focal ablation to be experimental and unproven.

Tracking progression after therapy

After radical prostatectomy, we hope that PSA will become undetectable permanently. If it rises afterwards, we suspect recurrence. After radical radiation therapy, PSA reaches a nadir, usually less than 0.5 ng/ml. If it rises 2 or more points above that, we suspect recurrence. However, with focal ablation, there is no reasonably expected PSA nadir, and there is no rise in PSA we can label as a biochemical recurrence. The PSA changes will be different for every patient. Because only the index tumor has been ablated, we don’t expect PSA from small foci of cancer outside of the ablation zone to vanish, nor PSA from BPH or prostatitis. The Chao et al trial showed that change in PSA is not a good predictor of recurrence. Because PSA cannot be used to monitor remission, we have to use imaging and periodic biopsies. Such imaging and biopsies requires experienced radiologists and pathologists because ablated tissue is qualitatively different from unablated tissue. Again, the Chao et al trial showed that while a positive mpMRI always predicted a positive biopsy, a negative mpMRI led to a positive biopsy in most cases treated with FLA. If found to be true of other kinds of focal ablation, periodic biopsies will have to be part of routine follow-up.

Salvage after ablation

If ablation doesn’t succeed and further ablation is either futile or dangerous, what are the salvage options? Salvage prostatectomy is complicated by the ablative tissue alterations, and may lead to increased morbidity. There is no reliable data on whether or not salvage radiation is effective after ablation failure. There are no experts in such salvage therapies.

Comparison to active surveillance

Focal ablation is often put forward as a middle ground between active surveillance and radical treatment. However, unlike active surveillance, there is some risk of morbidity after focal ablation. There is no long-term clinical evidence for the index tumor theory, and we have learned from long-running active surveillance trials that up to half of all Gleason 6 cancers eventually progress. Because of this, the patient is actually on a lifelong active surveillance protocol anyway: he must continue to have periodic imaging and biopsies to track progression, but is disadvantaged by not being able to use PSA to track progression.

Some focal ablation proponents, notably Ahmed and Emberton, argue that focal ablation should only be offered to intermediate risk patients and to those low risk patients who refuse active surveillance. This seems reasonable.

Inexperienced practitioners and practices

Focal ablation is still very new in the US, there are few practitioners who have adequate experience, and the learning curve is steep. There are no standard protocols. It may be years before there is consensus on best practices.

Danger of procedures

Ablation often requires anesthesia, local or general. IRE, for example, requires artificial paralysis and respiration throughout the high-voltage process.

Cost/Insurance

No form of ablation is covered by insurance or Medicare, and out-of-pocket costs are typically in the $20,000 range. Because “re-do’s” are often required, future costs are unpredictable. There will be ongoing costs of periodic imaging (usually mpMRIs) and biopsies.


As with all new therapies, methods and outcomes will undoubtedly improve over the years. This first wave of practitioners and brave patients are taking risks that may eventually benefit many others. It is important that patients understand those risks before making their treatment decision.



3 comments:

  1. Thank you for your detailed analysis with numerous citations from relevant medical literature.

    I'd like to make a few counter points:
    1) HIFU, as currently practiced in the US, is almost always whole gland HIFU--this is not focal ablation.
    2) Incomplete ablation for FLA: we have learned to take larger zones of ablation to get a better margin. The studies you cite were very early in the learning curve.
    3) Your evaluation of the heat sink effect is somewhat accurate, but if I may say, misleading. Within the prostate (unlike the liver for example), there are not very large blood vessels that act as a heat sink. Several studies looking at laser ablation in the prostate have demonstrated complete cell death within the zone of ablation as well as a very sharp transition between ablated and unablated tissue. With laser, this transition is much sharper than with cryoablation or HIFU. This is one of the main reasons that I am using laser for prostate ablations.
    4) Focal ablation has been long used in kidney and liver cancers with excellent long term outcomes for appropriately selected patients. This approach is new in the prostate because prostate MRI has only recently allowed superb imaging within the prostate.
    5) MRI guided focal laser ablation does not limit future treatment options (unlike radiation). Should the cancer show signs of progression despite our best efforts, other treatment options are still on the table.
    6) Breast cancer is often multifocal. Lumpectomy proponents were literally called "assassins" in the medical literature by the radical mastectomy proponents. It turns out that there is breast cancer that is clinically significant and breast cancer that is not clinically significant. Most men I speak with would like to balance treatment aggressiveness with treatment side effects if appropriate for their situation.

    A key point: MRI guidance (with the patient inside the MRI during the procedure) is superior to ultrasound guidance or fusion guidance/MRI ultrasound fusion guidance.

    This recent study published in Lancet demonstrates MRI has a 93% sensitivity for clinically significant prostate cancer:
    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32401-1/fulltext?rss=yes
    This is much higher than the 80% from the UCLA study.

    Again, thank you for your thoughtful analysis.

    Best regards,
    Ara Karamanian, MD

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    Replies
    1. Dr Karamanian,

      Thank you for taking the time to write such a detailed response. I'll try to address what I can.

      1) Since the FDA allowed HIFU ablation of prostate tissue, there are practitioners using that loophole to treat patients focally for prostate cancer. A quick google search of "focal HIFU prostate cancer" came up with websites touting focal HIFU from Drs. Michel, Suarez, Pugach, Scionti, etc. The unresolved issues I raised are not mentioned on their websites, or in media reports.

      2) I trust that practitioners will get better with experience, and I look forward to reading about the improvements you have made when they are published in peer-reviewed journals.

      3) I cited above 4 focal FLA studies in which ablation was incomplete in the ablation zone in 15%-38% of patients. Perhaps you have a new method that increases the completeness of the ablation while protecting healthy tissues. I look forward to reading about how you accomplished that.

      4) mpMRI is very good at detecting higher grade and larger tumors (at least 4 mm), but is very poor at detecting GS 3+3 and small foci of cancer.

      5) We know little about the completeness and side effects of salvage therapy after focal ablation. Surgery is usually a poor salvage option after radiation because of the tissue changes (focal brachytherapy or focal ablation may be better salvage options). But how much do we know about salvage of the necrotic tissue after focal ablation?

      6) Breast cancer lumpectomy is usually followed by radiation and/or chemotherapy to destroy the remaining foci of cancer that were not removed. I don't think anyone is proposing those as adjuvant therapies following focal prostate ablation.

      mpMRI is indeed very good at detecting "clinically significant" prostate cancer, but Dr. Klotz's 20-year active surveillance study shows us that only about half of clinically insignificant cancers remain so, even with frequent follow-up biopsies. I don't think anyone is prepared to conclude that GS 6 will always remain as a GS 6, although that is certainly the case in the short term. I haven't yet seen the comparison of in-bore MRI guidance to US fusion guidance.

      I'm glad that doctors like you are experimenting with new therapies, and improving existing ones. I think that experimental therapies should always be done in the context of IRB-approved clinical trials. It is essential that patients be fully informed of the risks, and the unresolved issues. The results of clinical trials should always be published in peer-reviewed journals, and the trials should be replicated.

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  2. My response does not focus solely on FLA, but on any PCa treatments for G3+3, G3+4.

    Below is my shortened "stump speech". I fear many newly diagnosed get rushed into whole gland or focal treatment without seeing both sides of the coin.
    I am not a clinician nor doctor.
    ScottD

    Hopefully, the info below provides the confidence to ask your PCa doctor 2 KEY questions - if they are recommending treatment as IMHO they offer the foundation for ANY treatment, or doing AS.

    1. Who has died from Gleason 3?
    2. Who has died because their Gleason 3 metastasized into higher grade PCa?

    The ANSWER to BOTH QUESTIONS is almost NO ONE.

    DO NOT take my word - Read on and discover

    1. Almost NO ONE (< .1%) dies from G3's.
    2. Our G3's do NOT (< .1%) progress/metastasize into deadly G4+3 =7.
    3. As the "volume" or size of a G3 SLOWLY grows, it does NOT also metastasize into G4+3
    4. G3's do not leave the prostrate and metastasize elsewhere in the body.

    On 11/28/16, Dr Mark Schloz "The biggest change has been the discovery that Gleason scores of 3+3=6 or less are not malignant… not cancer."
    https://www.verywell.com/elevated-psa-from-screening-next-steps-4104456?utm%20_campaign=healthsl&utm_medium=email&utm_source=cn_nl&utm_content=8320149&ut%20m_term=Fluent

    Dr. Laurence Klotz, presenting his data June 2016 at Duke University with data from 17-20 YEARS of studying over 20,000 PATIENTS on AS. Watching time 17 minutes:
    https://vimeopro.com/erasmusgr/focal2016/video/182781353

    Dr Peter Pinto at that same June 2016 convention.
    > "The Gleason 6 slide shows that only 10% of gleason 6 prostate have an abnormal PTEN…and if your PTEN is not intact then your foot is on the gas. If the PTEN is intact than the gleason 6 would not metastases."
    >Slide1: https://www.dropbox.com/s/f8hn6krhk1vkr8m/Dr%20Pinto%20presentation%206-201 6.jpg?dl=0

    > "Slide #2 shows G3’s in 12,000 PATIENYS only 0.2% died:
    https://www.dropbox.com/s/cnpmrfksuwk4ohv/Dr%20Peter%20Pinto-2.jpg?dl=0

    Dr Bert Vorstman's calls G3+3 a " Bogus Cancer" in 2015. He is also "sick and tired of seeing men in his office mangled from RP's side effects - mental (depression) and physical (ED & incontinence). Especially for men with only G3+3 or G3+4" .
    http://www.urologyweb.com/bogus-gleason-6-prostate-cancer

    Dr Epstein on 12/16/16 “…In the new system, the GS 6 corresponds to the Grade Group 1, in which these are typically tumors that haven’t grown beyond the prostate. In this case, treatments, such as radical prostatectomy or radiotherapy, are NOT NECESSARY for most men because prostate cancer grows slowly."
    http://www.hopkinsmedicine.org/news/media/releases/new_condensed_grading_sy stem_shown_accurate_for_predicting_prostate_cancer_outcomes

    Can G3's escape the prostrate and enter into our bodies? NO, per Dr John Epstein's study prostate. http://urology.jhu.edu/newsletter/2014/prostate_cancer_2014_19.php

    Mark Emberton, an esteemed PCa doctor from tOctober 2015. He says at the 8-minute mark: "if the MRI was normal (no G pattern 4 or 5) 2 studies (over 1200 men) show survival rate of close to 100%. https://www.youtube.com/watch?v=t6_OH9VQWTg


    From another fine online resource the Cancer Network from January 2014 - Gleason 6 Prostate Cancer: Serious Malignancy or Toothless Lion?
    http://www.cancernetwork.com/oncology-journal/gleason-6-prostate-cancer-ser ious-malignancy-or-toothless-lion?

    In November 2012, urologist Anthony Horan published his book: How to Avoid the Over-diagnosis and Over-treatment of Prostate Cancer

    Just 12 years ago, pre-2005, PCa physicians were treating ANY Gleason 2's as CANCER. Then after an International vote, THEY STOPPED. Fast forward to today and they were right! Many doctors have been saying the same about treating G3’s.

    Our goal is to make INFORMED vs emotional decisions. Yes, 28,000 men die each year from PCa (G4 or higher) in the USA; just not from Gleason 3's.

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