Klotz latest numbers on AS program

In an important new paper in Current Opinion in Urology (available free as a full-text article), Dr. Laurie Klotz has provided an excellent summary of his perspective on the current application of active surveillance in the management of low-risk prostate cancer, based on the 20-year experience of the Sunnybrook group and other data.
This is a paper that most support group leaders and other advocates will want to print out for their files. Here is a summary of some of Dr. Klotz’s key statements:
There is now extensive clinical evidence supporting the near to complete absence of metastatic potential in the vast majority of pure Gleason pattern 3 cancers.
There is a truly tiny number of rare case reports of patients with apparently pure Gleason 3 + 3 disease in which metastasis was observed. (Klotz states that this is just two known cases among tens of thousands now evaluated.)
Cardiovascular disease is the commonest cause of death in men with favorable risk prostate cancer and such patients are 10 times more likely to die of causes other than prostate cancer than they are to die of their prostate cancer.
Among men initially diagnosed with Gleason 6 prostate cancer and who meet other appropriate criteria for active surveillance
PSA testing should be performed every 3 months for 2 years (to establish a baseline of PSA kinetics) and every 6 months indefinitely after that.
A confirmatory biopsy is mandatory within 6 to 12 months of the initial diagnostic biopsy.
The confirmatory biopsy should target the areas that are typically under-sampled on the initial diagnostic biopsy (the anterior prostate, the prostatic apex, and the prostatic base).
If the confirmatory biopsy is negative or confirms microfocal Gleason 3  +  3 disease, subsequent biopsies should be performed every 3 to 5 years until the patient reaches age 80, or has a life expectancy of less than 5 years because of comorbidity.
The increasing use of MRI and molecular markers will further reduce biopsy requirements in men with favorable results (i.e., negative MRIs).
PSA kinetics are now used by the Sunnybrook group only as a guide to identify patients at a higher risk, but not to drive the decision to recommend treatment.
about 25 percent of men on active surveillance will be upgraded on confirmatory or repeat biopsies.
The vast majority of such upgrades are a consequence re-sampling (i.e., finding areas of cancer that were not sampled at the time of the original diagnostic biopsy).
98 percent of these patients will be upgraded to Gleason 3  +  4 = 7.
Upgrading to Gleason 8 or higher is uncommon.
Biological grade progression (i.e., Gleason 3 cells giving rise to Gleason 4 or 5 progeny) does occur over time, but is uncommon.
In the Sunnybrook cohort cohort, biological grade progression occurred at about 1 percent per year from the time of the original biopsy.
Low prostate volume (i.e., a high PSA density) is a predictor for risk progression.
African Americans on active surveillance have a higher rate of risk reclassification, and PSA failure when treated, than Caucasians — but active surveillance is still an appealing option for African Americans who have been appropriately risk-stratified.
Tests such as the Prolaris test, the Oncotype DX test, and others have the potential to interrogating the microfocus of Gleason 6 found on biopsy for accurate information about the presence of higher grade cancer elsewhere in the prostate, or the future likelihood of progression to aggressive disease.
Multi-parametric MRI has an important emerging role in the management of men on active surveillance (and Dr. Klotz discusses this at some length).
Patients with favorable-risk Gleason 3  +  4  =  7, in which the component of pattern 4 is < 10 percent, have a very similar natural history to those with Gleason 3  +  3 = 6, and Klotz states that such patients “are surveillance candidates”.
There is now general consensus on the principles of surveillance but the optimal surveillance strategy and triggers for intervention are still not completely agreed upon.
Klotz also notes that
The results of active surveillance, embodying conservative management with selective delayed intervention for the subset who are reclassified as higher risk over time based on repeat biopsy, imaging or biomarker results, are associated with a 5 percent cancer-specific mortality at 15 years.
What this mean is that out of 1,000 men who are appropriate candidates for active surveillance based on the original Sunnybrook criteria — either true low risk disease (with Gleason 3 + 3 = 6, PSA < 15 ng/ml; and clinical stage T1c to T2a) or favorable intermediate-risk disease (with Gleason 3 + 4 = 7, generally small volume in older patients and the same PSA and clinical staging criteria) — about 25 percent or 250 men will actually progress over time and meet criteria for localized treatment. Of those 250 men whose disease does progress, about 5 percent (i.e., 12 or 13 men) will actually die from prostate cancer within 15 years.
More recent Sunnybrook criteria have placed tighter limits on eligibility for active surveillance among men with Gleason 3 + 4 = 7 to try to reduce the number of men who would actually progress to have metastatic disease. However, even based on the currently available data, what this means is that, at 15 years of follow-up, about 95 percent of men placed on active surveillance and managed according to the Sunnybrook criteria are not going to die of prostate cancer, and about 75 percent will never require treatment at all.
This level of ability to avoid unnecessary treatment and the associated adverse effects of such treatment over time in appropriately identified and well-monitored patients seems to The “New” Prostate Cancer InfoLink to represent extraordinary progress from where we were in the mid-1990s, when immediate treatment was almost de riguer for every man diagnosed with prostate cancer of any Gleason grade. It is also interesting that these data are so very closely correlated with the data first published by Albertsen and his colleagues in the late 1990s; those data had shown that risk of prostate cancer-specific mortality in men with a Gleason score of 6 or less was significantly less than 30 percent if they had no treatment at all until some form of androgen deprivation therapy became necessary.
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GeetarMan,

Are you enroled in AS program , and how did you get the PSA dropping so much? With that low PSA, do they even recommend another biopsy?

Thanks.

This is good stuff indeed. I have one question, being in the 35% who biopsied as G 3+3 and had surgical pathology of 3+4, and that is this: Is there a good, commonly available, and well trusted tool that can identify the "true" G6? (or alternatively identify those of us, pre-surgery, who were not going to stay G6?)

I saw this from Laurie.

This is more data that is showing us that AS can be safe and a logical choice for many. We still need better data on the right candidates but it's getting easier to define AS candidates and it's improving the quality of care.

LOL, John you can say I told you so anytime you like.

I know it's a touchy subject for a few but that crowd is shrinking. And the acceptance in the physician community has changed drastically. Still quite a few hold outs, though.

Chris,
We've gotten a lot better at identifying guys that should stay on AS. Laurie's work has established a very good protocol to identify those that need at least a delayed therapy approach. Many urologists have adopted early observation protocols that use the mpMRI approach and the confirmatory biopsy approach. If the PSA continues to rise then there is evidence that the disease is not behaving like a true Gleason 6.

We still could use better tools, and they are definitely better than when I start out over 8 years ago. But NCCN, AUA, ASCO, ASTRO, ALL the major organizations have recognized observation as a key in curbing over treatment. I agree that cancer is still frightening and has a shroud of mystery to it. But like breast cancer, cervical cancer, and others, the definitions are changing and more observational approaches are coming down the pipeline.

I was one of those with favorable risk 3+4...

...never should have jumped so blindly into (over) treatment.


Too late for me (5years later), but glad to see that men today are not so fast to make that same mistake. Will continue to spread the word for men to pull their heads out of the sand, and look/think beyond what their diagnosing urologist tells them to do!

Thanks for the info, JohnT.

turpT1a said...

The point of AS is that we don't NEED a foolproof tool to identify the "true" G6 before using AS. If you are not "true" G6, it will show up some years later (usually within the first two to three years) and you can be treated then just as successfully as you would have if you had been treated right away. To me, the key point of the results published by Klotz is that the death rate from PCa for those on AS is very little different from the death rate for those with low risk disease who have been treated right away.

"...and you can be treated just as successfully as you would have if you had been treated right away."

True. If all one cares about is "...how long have I got?"

But...if one cares about QOL...ie...HT, etc to keep you alive vs. zero treatments at all (ie..."cured") for the rest of one's life, I'm not so sure. (Even though the life spans are the same for cancer specific deaths).

where does Klotz's study refer to the % of biochemical recurrence (I don't see it here).

If one compares what Klotz is finding to cancer specific death, then the study mimics what the Sloan Kettering nomogram predicts. 10 and 15 year survival both at 99% for 3+3 and 3+4 disease.

But nomograms show a difference in the recurrence rate between 3+3 disease vs. 3+4 disease.

3+3 Progression free probabilities @ 5 and 10 yr. Respectively is...94% and 89%.

But...

3+4 progression free probabilities @ 5 and 10 yr. Respectively is...86% and 76%.

Where does Klotz mention this?

turpT1a said...
island time,

I'm not sure what you are saying? Are you arguing that QOL is higher for those who undergo radical treatments such as surgery and radiation than for those who use AS?

I'm saying recurrence rates are higher with 3+4 vs. 3+3 by statistically significant rates. And I'm also stating that this study doesn't mention this (from what I'm reading).

Not that it has to. But, the conclusion of this study leaves out the part that one must still make a deeply personal choice about odds, and what their own personal definition of QOL means to them In regards to those odds.

In other words...it reads.to me as if AS is a "no brainer" (physiologically). When....it is not.

Post Edited (island time) : 5/17/2015 9:55:06 PM (GMT-6)

turpT1a said...
island time,

I'm not sure what you are saying? Are you arguing that QOL is higher for those who undergo radical treatments such as surgery and radiation than for those who use AS?

Put another way...

3+4 may not be any deadlier than 3+3. But 3+4 does increase the odds mets over 3+3.

So one must ask themselves...are the odds of living with mets worth not having treatment?

I'm no expert...just a.ga.guy trying to make sensof.it all. And what I'm seeing.is that Klotz is leaving this question alone in this study.

Which brings us back to my basic question, put another way:

The data suggests that "true" 3+3 G6 should be treated with AS, hands down. The rare cases where G6 does something besides just sit there would be caught in plenty of time to deal with it. The challenge could be stated this way: We do not seem to have, at this time, a definitive tool to identify the true G6 early in the game. I believe that the day will come when that test does exist and is in common use. Just not yet. From what I've seen the only way to differentiate between the G3+3 and the G3+4, in today, is to either go into AS for a period of time and see if it progresses...or do the surgery and do the detailed pathology post surgery.

This, then, is the dilemma.

I'm a poster child for this outcome. My 12 core biopsy showed only one side involved at a maximum of 20%, G3+3. Post surgery, I showed 15-20% involvement in all 4 quadrants, G3+4. From that, I conclude that the surgeon was correct when he said, "you could go on AS if you like, but we'll be having this conversation again in a year or so."

island time,

Here are the numbers from Klotz's study  (Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol 33:272–277):

 

Results Among the 819 survivors, the median follow-up time from the first biopsy is 6.4 years (range, 0.2 to 19.8 years). One hundred forty-nine (15%) of 993 patients died, and 844 patients are alive (censored rate, 85.0%). There were 15 deaths (1.5%) from prostate cancer. The 10- and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases (n = 9) or have died of other causes (n = 4). At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance. The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1.

Conclusion Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame. In our cohort, 2.8% of patients have developed metastatic disease, and 1.5% have died of prostate cancer. This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention.

In an accompanying editorial in the same issue of J Clin Oncol, Dr. Matthew Cooperberg writes:

Klotz et al⁶ report an overall rate of metastasis of 2.8%, occurring at a median of 9.6 years after diagnosis. Before this figure is argued by proponents of immediate treatment for low-risk disease to represent the risk of active surveillance, it should be stressed that it is not dissimilar from the risk of lethal disease among men treated immediately for low-risk tumors (ranging from 1.4% to 5.9% at 10 years depending on primary treatment in one large, multicenter series)

 

Halbert,

You wrote:

I'm a poster child for this outcome. My 12 core biopsy showed only one side involved at a maximum of 20%, G3+3. Post surgery, I showed 15-20% involvement in all 4 quadrants, G3+4. From that, I conclude that the surgeon was correct when he said, "you could go on AS if you like, but we'll be having this conversation again in a year or so."

 

Although the surgeon was correct in your case, this implies that he would be correct in all cases. This is not what Klotz reports. In Klotz's study, "At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance."

Hi TurpT1a,

-- Re: "progressing to Gleason 3+4 is not a reason to disqualify [from AS]"

I should have been clearer. I'm not considering AS. I was enrolled in AS at Johns Hopkins for only a month or two late in 2014, and then, upon very strong urging from my surgeon, OK'd him doing a RRP four months ago. I believe a big part of his reason for wanting to do the surgery, and my acceding to his doing it, was a problematic MRi which the MRI summary said showed "large volume, non-organ confined disease with extraprostatic disease present ... extracapsular invasion is present on left." That analysis was hokum. Maybe other pieces of information were persuasive.

A DRE in summer 2014 by my original urologist revealed the presence of a palpable hard lump inside my prostate. Can't ignore that. Then, too, six of twelve cores on original biopsy had 80-90% disease. My original surgeon said "that's a lot of cancer." I can understand the argument to take my prostate out. I don't know if my cancer was aggressive or not. Should I draw any conclusion from my Gleason 3+3 (orig biopsy) turning into Gleason 3+4 (post-op final pathology report after RRP)?

I had the surgery in January, the incontinence is almost done, but the ED is not going away.

ChrisR wrote on this thread, "...once you are G6 organ confined you have about a 0 chance of dying from PCa..." I'm G7 organ confined, and not sure that statement applies to me.

The drift I got from the post that started this thread is Gleason 6s and Gleason 7s, depending I guess on what a DRE shows, and what the PSA is, and what the MRI says, all that forms a sense of what's going on in the mind of the surgeon. And of course, as always, the hardest decision to make is always to do nothing. It's too late now to "unring the bell" and not have my prostate taken out. But I do wonder about the wisdom of my decision to operate.

And I do love my current, post-op PSA, 3/15 <0.01. I'm focused this moment on getting Medicare to pay for a steady supply of Cialis, which odds of that happening are slim to none, I reckon.

Bill Positive

______________________________
[Sig Block revised 3-27-15]

age 70
diagnosed 8-8-14

RRP 1-12-15, Johns Hopkins.

Prostate cancer "capsule contained"
per final JH pathology report, 1-14-2015.

PSA history:
1/08 4.6
4/08 6.4
7/08 3.5
12/09 2.5
2/11 4.4
4/12 3.2
4/14 5.4
8/14 5.1
9/14 4.9
10/14 5.7
3/15 <0.01

Pathology Report (9/12/2014, Johns Hopkins,
Jonathan Epstein) on 7/28/2014 biopsy slides.
6 cores Gleason 6 (3+3),
A. prostatic adenocarcinoma, 90%, 80%
B. prostatic adenocarcinoma, 90%, 90% ("perineural
invasion identified in this case") [Interesting the final
pathology report below found no actual "invasion"
beyond the prostate capsule, very glad of that!]
C. prostatic adenocarcinoma, 90%, 90%

1-12-15 RRP at Johns Hopkins
1-14-15 Final JHH Surgical Pathology Report
Interpretation & Diagnosis
1) pelvic nodes, left (excision); three lymph nodes and
associated fibroadipose tissue, negative for tumor
2) anterior fat pad (excision), negative for tumor
3) prostate and SV (prostatectomy): histologic type:
adenocarcinoma (conventional, NOS)

Gleason score - dominant nodule: 3+4 = 7
Tumor extent: moderate
location: (dominant nodule): left, posterolateral, apex, mid
location: (secondary nodule): [none noted]
Local extent: organ confined
Margins: negative
Seminal vesicle invasion: none
Lymphatic invasion: absent

Pelvic lymph nodes (includes all parts):
all 3 lymph nodes are negative for tumor

Extent of invasion (7th Edition, AJCC, Staging):
Primary tumor: pT2: organ confined throughout

Summary margins: negative

A representative tumor block is 3-LBP
A representative normal block is 3-LDA

Post Edited (Bill Positive) : 4/2/2015 8:38:24 AM (GMT-6)