Latest AS report by Dr. Klotz: Gleason upgrading with time

“Conclusions: This is the largest re-biopsy cohort, with long-term follow-up, described to date, enabling the first estimates of prostate cancer dedifferentiation in patients on AS. Dedifferentiation rates appear higher in patients with intermediate risk prostate cancer compared with those who are low risk at baseline.

593 of 862 patients in our cohort had at least one repeat biopsy. Median follow-up was 6.4 years (max. 20.2 years). The total number of biopsies ranged from 2 to 6. 20% of patients were intermediate risk, 0.3 % high risk, all others low risk. 31.2% of patients were upgraded during active surveillance. The proportion of patients upgraded increased with time, suggesting prostate cancer dedifferentiation occurred at a rate of 1.0%/year (95%CI -0.12 to 2.16%/year)”

In the recent past we discussed if is it possible that in a slow growing cancer such as prostate cancer, poorly differentiated tumor cells are produced in short periods of time? Or is this a stepwise process by which normal cells dedifferentiate at a variable rate as driven by genetic changes that cause them to gain or lose chromosomes? In time do Gleason Scores increase as tumors dedifferentiate?

This last report by Dr. Klotz seems to support that notion. It is true that the progression rate is variable and it can take many years to become lethal if ever, but the notion that GS6 is immovable and never or even seldom will progress to higher Gleason scores by dedifferentiation is negated by this report done at 6.4 years of followup.

Some 20 years ago Dr. Tribuikait demonstrated that fact by doing repeated fine needle biopsies during a 24 month period. He reported a 23% rate of dedifferentiation supporting the concept of a gradual dedifferentiation of prostate cancer. This is a caution notice for younger men with intermediate PCa risk disease considering AS.

A previous thread here dealt with this issue. See at:
www.healingwell.com/community/default.aspx?f=35&m=2284259

Source:
Suneil Jain, Danny Vesprini, Alexandre Mamedov, D. Andrew Loblaw, Laurence Klotz;
Gleason upgrading with time in a large, active surveillance cohort with long-term follow-up. Clin Oncol 31, 2013 (suppl 6; abstr 1)


RalphV

This is an important study, and for sure 31% patients who had Gleason scores upgraded during AS, speaks loudly to the fact that PC can become more agressive with time. Also, important that those with intermediate disease had a higher rate of "upgrade" increase than those with a low-risk disease. The obvious weakness of the study is the fact that the biopsies were blind - probably hitting a different area of the prostate during repeat biopsies. Still, the trend is "upward". Those on AS should take this study into consideration. Thanks Ralph.

Hi Phenom,
If by deformity you mean the gain and loss of chromosomes in cells, then the answer is yes. The process of dedifferentiation involves a change in the normal 23 pair of chromosomes. This can be by adding or reducing chromosomes. As this "deformity" becomes more pronounced, prostate cancer cells become more primitive or more poorly differentiated and have fewer of the characteristics they had when they were more normal. This is one of the reasons that poorly differentiated cells (higher GS) secrete less PSA per unit cell.

This report provides an indication that intermediate grade of the disease can progress faster than lower risk PCa. Understand that this progression is variable in individual patients. Some progress at a very slow rates during their lifetime and die of other causes rather than of PCa.

RalphV

Thanks for the update.  Dr Klotz has been pushing the research envelope (along with Carroll, see HERE ) to study some intermediate-risk PC cases, and over years of study has found a very predictable outcome, as reported here.  The programs that I know of (the non-research programs) only include low-risk men, unless there are appropriate extenuating circumstances.   (Both Klotz and Carroll, by the way, run standard AS programs with low-risk patients in addition to their research programs.) AS is very low risk for PC cases clinically staged as “low risk,” but the risk is somewhat higher for PC cases clinically staged as “intermediate risk”…I guess that the staging convention names make a lot of sense!   Duh!   PC is really two, and perhaps three, very different diseases which need very different courses of treatment.   AS is not for every case, but it is underutilized today for the pool of men for whom it would be the most appropriate solution.   This is shifting with growing awareness, and will continue shifting, but it will not shift overnight...and there will always be a percentage of men who "treat the name (cancer) rather than treat the disease."   Dr Klotz’s documented research continues to provide supporting evidence of the efficacy of AS as a viable alternative for low-risk PC cases. As has been written elsewhere, “Not only may it [active surveillance] defer the need for active intervention completely in many older patients, but in younger patients it may allow them to defer the need for treatment until a time when the consequences of treatment may be less traumatic in respect to the effects on sexual function while not significantly impacting the likelihood of a successful oncologic outcome.”   Some men will defer treatment forever, others perhaps for months or many years, but the successful treatment which follows deferred treatment—after a time when treatment skills and techniques have progressed—has already been shown to be as good as any immediate treatment.  Successful deferred treatment is defined as a success: AS success = (patients who require no aggressive treatment) + (patients who undergo curative deferred treatment) Klotz has published that the very best active surveillance programs consist of all four of these key components: 1.     Identification of appropriate patients 2.     Patient education and reassurance 3.     Close monitoring over time, with serial psa measurements, periodic biopsy, and (possibly) imaging studies 4.     Appropriate therapy for patients whose disease is reclassified as higher risk   The medical industry has too many incentives to push lucrative procedures, and the public has been taught to believe that more tests and more treatments are always better.  Good AS programs have helped debunk this notion.  But since there are no good incentives today that would tend to encourage the average clinician to present all of the management options in a neutral manner to appropriate candidates for active surveillance, exposing newcomers to a more complete understanding and patient education of all alternatives is a valued service that sites like HealingWell can provide...     Edit :   typo Post Edited (Casey59) : 2/18/2013 10:07:17 AM (GMT-7)

ralfinaz, thank you for your invitation to add clairty.  I have copied your last post into MSWord, and inserted clarifying comments (utilizing the "Track Changes" feature, which automatically selected red text for the comments I added): Casey, The fact that AS is underutilized needs clarification. At this point there is a tendency to highlight AS a solution to overdiagnosis and overtreatment. It might well be true that it is [I agree it is one of the solutions, but not the only solution] , but the problem is that urologists in general are not behind the idea because [yup, for several reasons; I already commented on the “incentives” aspects; one of the "solutions" to the existing PC overtreatment epidemic in the US is tied to changing incentives] in reality there is high uncertainty at the current diagnosis process [the degree of uncertainty is well documented in a percentage likelihood of being contained in the prostate, expressed in the Partin tables; it would be a stretch of the imagination to characterize the truly low-risk men as having a “high degree of uncertainty”] . A great number of men are upstaged after surgery from low risk to intermediate or high risk disease [different studies show have somewhat differing results, but Scardino published re-biopsy results of low-risk patients where about half (47%) were UNCHANGED, about a quarter (27%) went UP, and about a quarter (26%) went DOWN...you seem to have forgotten about the roughly three-quarters of men that stayed the same or went down] . This fact is one of the reasons many men decide for treatment. [upstaging is the right reason for men to exit an AS program and move on to curative treatment; studies show the outcomes to be about equal to immediate treatment]   More so if they are young with a long life expectancy.   [If they are upstaged, yes, I agree.  Dr Klotz has also written that "The longer a patient's life expectancy, the more stringent should be the criteria (for AS), but youth alone is not a contraindication for surveillance."] This post was not intended to detract from the potential value of AS for many men, but the intent was to show that PCa can in evolve from less aggressive disease to an aggressive form that can kill. This notion that GS6 in immovable and seldom progress has not been thoroughly established. [I think it’s been well established that some will move.   Deferred treatment is absolutely appropriate for them.]   Dr. Klotz is providing information that sheds light about this issue at a median followup of 6.4 years. You seem to imply that this result is due to a tendency by Dr. Klotz to push the envelope. [No, I am not implying anything; merely sharing information which is readily available, but takes some digging.   I pointed out that most clinician AS programs accept only patients with low-risk PC, verified with a re-biopsy.   Drs Klotz and Carroll have both had research projects which has included some men with intermediate PC (most of the cohorts are low-risk, though) to help define which, if any, men with intermediate PC might also be appropriate to include in AS.   It should also be pointed out that some of the intermediate risk men in their research studies have other comorbitities, but have elected to forego PC treatment, and perhaps re-biopsy also.]   This is his AS cohort that he has been following up to 20 years in some cases. Only 70% of this cohort have been subjected to a biopsy (2 to 6 times) in the median 6.4 years of followup. What is happening with the other 30%? [Understanding the math behind the median values, versus the longest (20 year) follow-up, it is clear that there are more new patients; the typical re-biopsy period is about 18-months after initial diagnosis.]   Without biopsies it is difficult to determine true progression given the kinetics of PSA in poorly differentiated disease.   [I don’t think Dr Klotz has forgotten or neglected any of his patients…but I’m sure they appreciate your concern.] Until there is a more clear picture about the way PCa can progress from an indolent form of the disease to an aggressive one if given enough time, we need to explain the possibility to all uninformed men and more so to the very young ones that come here seeking information.   [Agreed.   Time is the most relevant prognostic indicator.   For truly low-risk men, the risk is very low that their PC will leap-frog instantly from low-risk, beyond intermediate-risk, and into aggressive PC.   What the studies show is that almost exclusively, PC that progresses does so slowly.   Time is the most important prognostic indicator and it is on the side of the low-risk patient.   There are highly uncommon strains of PC which will progress essentially irregardless of treatments, though; neither of us should forget this.] The natural history of untreated PCa has a high mortality. [PC is one of the most common and least lethal of all malignancies.   It is really two, or perhaps three, different diseases that should be treated differently.   We should treat those that need treatment.   Most low-risk cases don’t need immediate treatment, although some will progress to needing deferred treatment later.   Most intermediate-risk cases need near-term treatment.   Most high-risk cases need aggressive, prompt treatment.   Three different diseases; three different approaches to treatments…NOT a one-size-fits-all.]   Why this has been ignored is very sad and goes to show that we tend to ignore valuable information because “it is too old” and does not apply in the age of the PSA test...a test that many of the experts consider the root cause of overtreatment but at the same time they negate its value in reducing PCa mortality. RalphV     Post Edited (Casey59) : 2/18/2013 3:32:28 PM (GMT-7)

And with the new protocols on general PSA testing, which the experts seem to agree is unnecessary and even harmful, this information helps us how? Seems to me that going forward there will be few low and intermediate risk patients presenting themselves for treatment, mostly those with symptoms and thus presumably already at a high risk stage.

John T,

A few things.

First a piddlin' quibble. With a progression rate of .75 percent per year you get 7.252 percent at ten years. Since you are looking only at first progression the men who progress in the first year are not candidates to progress in the second, and men who progress in the second years are not candidates for the third year, and so forth. A more accurate formula would be P=1-(1-R)^N where P is the total percentage progression in N years, R is the annual rate of progression expressed as a probability (percent/100) and N is the number of years, ie. 1-((1-0.0075)^10) = 1-0.9925^10 = 0.07252

Second, your distinction between correctly diagnosed Gleason 6 men and men misdiagnosed as Gleason 6 who actually have higher risk cancers seems to me to be a distinction without a practical difference. Given 10,000 men diagnosed as Gleason 6 this year, we can expect that next year's biopsy will show 75 of them a higher Gleason score. Some of those 75 will have progressed and some of them will have merely been misdiagnosed this year. Neither those 75 men nor their doctors will know which are which. They will never find out and it will make no difference in their treatment or their prognosis.

Better biopsy methods will reduce the number who are misdiagnosed (leaving the number who progress unchanged) and perfect biopsies would leave only progression for men whose Gleason scores change. But until better biopsies become the typical standard of care for AS patients or a perfect biopsy method is developed it is hard to see how men diagnosed today as GS6 can take any comfort from the fact that their 7.252 percent chance of progression in ten years is inflated by their chance of having been misdiagnosed.

Edit to fix my broken arithmetic. Math was OK.

John I suspect we can thank better screening and testing for that.

ralfinaz said...


JohnT,
You are assuming that the dedifferentiation process is linear so that a 7.5% increase in upgrading is an excellent result at 10 years. What if the process changes with time? In a stepwise carcinogenic process it usually does...
In the Klotz cohort, the median age is 68 to 70. That is why men die with PCa instead of PCa.

RalphV

I've been waiting for someone to point this out. How many men on this site have seen their doubling time increase... and often nearly exponentially? Progression is not linear and this is the component of this study that's being overlooked. It might take some time to get from G6 to G7, but after that, to more hard to manage cases, is a potentially steep slope, it seems. From the study, seemingly, things can go from bad to very much worse very quickly once the progression starts.

The real question for me is when "low risk" becomes "intermediate risk." Someone can give me textbook definitions of this and links galore, but I'm not interested in that. What I am interested in is: "when..." The time. The time this occurs. No one can answer that. Not even doctors. At best, it's an educated guess. You might biopsy at a G6, but there might be a "minor" G9 tumor that's missed. Pathological 4 and 5 cells are migratory. Pathological 3 cells tend to stay local. At least that's what I've read and how my uro counseled me.

I was concerned about this when I decided on treatment within 6 months of my diagnosis. Of course I had done a year of "non-active surveillance," (re. cruising as if nothing was wrong because I was asymptomatic) by that point because my GP wouldn't state what the PSA or a questionable DRE potentially meant.

I'm lucky that I'm a proactive person. I sought out an expert after the PSA rose after a year. It didn't double, but the uro felt a nodule, performed a biopsy, and counseled me accordingly.

There are several components in the pro-AS argument that are simply impossible to calibrate: the expertise of the professionals one deals with, what insurance will pay for, the exactitude of the tests... For me, one can argue all they want about how something should work under ideal circumstances, but we all KNOW there's many a slip between a cup and a lip... AS does not occur in a vacuum where things progress according to how some guy writing an article says they "should if managed properly."

That leads me to the philosophy: you get treatment when the problem is small, more manageable, and there's a higher likelihood of cure. It's not just that way with PCa, it should be that way for any ailment.

Post Edited (dude1969) : 2/18/2013 7:36:10 PM (GMT-7)

oy vey, the drama, Casey.

So now you're saying that the people on this forum are predators and that they should stay away from your son? I'm surprised you didn't post that in bright red.

Nobody here has said one size fits all, nobody.

John - a few things. No matter how small, the AS risk is not a risk a lot of men, specially my age, might want to take.

As for the risks of side effects, not sure about national numbers, but many surgeons advertise much higher success rates on both fronts. My surgeon for instance says he has an 85% success rate with ED issues, not 45%. So do many other surgeons.

You also have to compare success rates on younger men vis-a-vis older men. Younger men like myself will typically be able to mitigate potential SEs to a far greater degree than older men. That distinction, among others, is important to take into account, no?

Post Edited (davidg) : 2/18/2013 9:13:28 PM (GMT-7)

ralf - I think you presented an important piece for consideration. I think the part that struck the most in my mind and heart is when you said:

"Even here with the widespread use of PSA testing we continue have close to 30,000 men die of PCa every year. Is the second cause of cancer deaths in men the least lethal of malignancies?"

Especially the last sentence. PC is the second cause of cancer deaths in men, period. Even with our improved screening and treatments, the 30,000 men is 30,000 men too many. It's tragic in every sense of the word. I think this raw basic fact went right out the window with some that read your post.
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142 - I agree with your sentiments too. It is ludicrous that a prostate cancer starts out at a certain gleason rating, and stays that way, progression may be slow, but its definitely likely over time. That is still a big plus for surgery as a primary treatment, is having the luxury of having the entire prostate removed for study and biopsy, so that the patient knows what he is really dealing with. Even in our small circle of men at HW PC, look how many men were upgraded after surgery.
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Casey - you went overboard after making some valid counterpoints. I don't know of a single person here that ascribes to "one size fits all" as you accuse. that statement does a big disservice to the people here and their views. PC is PC, there are different degrees of course, but its not biologically 3 diseases as you keep saying, I simply don't believe that view is accurate, and is misleading to newcomers.

david in sc

Casey,
My purpose for posting the study was not to engage you or anyone else. When I read that GS6 is rarerly progressive in this venue I question what evidence is behind that and how that information affects younger men diagnosed with PCa.

There is no question in my mind that some men currently are treated prematurely and unnecessarily. That said, in a mostly slow growing malignancy the age at diagnosis is an important factor that seems to be ignored these days. When one tells an uninformed new PCa patient about AS one should not fail to mention that there are few physicians supporting the protocol these days and that men are left to fight on their own. This does not mean that AS should not be considered. It is the most valuable option we have to slow things down and hopefully be adopted by most practitioners.

I have been studying PCa for more than 20 years. I try to stay up on the barrage of information produced every day, but I never ignore what has happened in the past that we must not forget or overlook. Before the commercialization of the PSA test most men were diagnosed with advanced cases of the disease. This rate has been reported to be 70% to 80%. If that is the case, how to explain that? Was PCa a progressive disease then and not now? Of course not. PCa progression is very variable and seems to increase as the disease accumulate more gain or loss of chromosomes. This process of dedifferentiation drives changes that evolves in metastatic disease that can kill the patient.

RalphV