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Is the overtreatment rate of PCa overstated?

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Posted 10/26/2011 10:03 PM (GMT 0)
If there is that much overtreatment of indolent disease how to explain the ever ignored 41.8% reduction of PCa deaths since the inception of PSA testing? Surely those overtreated with indolent disease are not impacting this number since they were never destined to die of prostate cancer. What could have possibly reduced the number of deaths during this period? This is a well ignored mystery that doesn't fit the USPSTF recommendations and signals to an overstated overtreatment rate.

SEER Database. U.S. Prostate cancer mortality rate. All races included.*

1992 39.2245/100K
2008 22.8198/100K
Varience: 16.4047/100/K

16.4047 x 100/39.2245 = 41.82% reduction in prostate cancer deaths. Male life expectancy increased from 72.3 years to 75.3 years**

*Mortality source: US Mortality Files, National Center for Health Statistics, CDC.

Rates are per 100,000 and are age-adjusted to the 2000 US Std Population (19 age groups - Census P25-1130).

** CDC - U.S. Life Tables 2003

RalphV
Posted 10/26/2011 10:08 PM (GMT 0)
it sure is.

it also ignores the simple fact that many men simply cannot live with knowledge of cancer being present in their body and need to try to extract it. That's actually a quality of life issue too and the reason why 20% of men on AS drop out and seek othe rtreatments.
Posted 10/26/2011 10:27 PM (GMT 0)
Well, if we haven't totally confused the general public and the average male by now, I don't know what more we can do to add to their confusion:

We say prostate cancer is one of the leading killers of men...maybe 30 thousand each year.  But we can't even agree whether or not men should routinely be screened for the malignancy.

We say the PSA test saves lives, but many "experts" say it doesn't.

So, don't get routinely PSA tested because you'll likely be overtreated, and most prostate cancer is indolent and won't kill you anyway.

But if you choose to get treated, you'll almost certainly end up incontinent and impotent.

Oh, and the surgeons are money-grubbers, treating guys who don't need treatment.

And a huge percentage of guys who do get treatment end up wishing they hadn't because of the ED issues and the incontinence.

And blah, blah, blah.

The population is being bombarded with so many mixed messages that we've probably confused them to the point that most men will just stick their heads back in the sand, avoid their uro's, tell their GP's they don't want the PSA test or the DRE....and I can fully understand why.  Even here on this forum it's hard to find anything like a consensus regarding what men should do. 

I don't see how this can be a good thing.  All I know for sure is that without the annual and rising PSA test, I would have never had the biopsy; the palpable tumor would never have been palpated; the G7 cancer would have continued to fester and probably would have soon metastasized; and not a day goes by that I don't thank God for the PSA test and vigilant doctors.

 

Post Edited (clocknut) : 10/26/2011 4:41:02 PM (GMT-6)

Posted 10/26/2011 10:48 PM (GMT 0)
Based upon my limited observations, where I live in the NE US, I believe overtreating is pretty extensive. However, not testing PSA's is clearly not the answer. When I went for I pre-surgery group meeting to prepare men that were scheduled for surgery 80+% of the 20 men inthe room were G6's, and I at 58 appeared to be one of the youngest. Some appeared to be late 60's/early 70's and several indicated that the were taking blood thiners for heart problems. Several months later I bumped into a friend and discovered that he recently had surgery for PCa. I was very surprised when hetold me he was a G5.
Posted 10/27/2011 12:11 AM (GMT 0)
Ralf, once again, I give a thumbs up to your post and line of thinking on the subject.
Posted 10/27/2011 12:33 AM (GMT 0)
Estimates for PC overtreatment fairly consistently hover around 1 million men over the past 20 years.
Posted 10/27/2011 1:18 AM (GMT 0)
what is your source for that figure, casey?
Posted 10/27/2011 1:42 AM (GMT 0)
That would average 25%...too low! They like the 60% to 70%. That makes overtreatment a significant issue

RalphV
Posted 10/27/2011 3:06 AM (GMT 0)

ralfinaz said...
That would average 25%...too low! They like the 60% to 70%. That makes overtreatment a significant issue

RalphV

Ralph, I think it's significant, but the research I've read say it's much lower than you do. 

The estimates I've read for overtreatment are close to the estimates for those likely to be eligible under the newer, more rigid guidelines for Active Surveillance...in the 20-30% range.  Makes sense that these would be close to the same.  Today we are overtreating, and under-utilizing AS.

Everyone has an anecdotal story about how their choice of aggressive treatment was correct (and they wouldn't have lived until next Christmas without it), but out there is a million men overtreated.  Lets not overtreat another million men...

Posted 10/27/2011 5:11 AM (GMT 0)
Casey, you still have failed to give a source for your "one million" overtreated men. Where are you coming up with that number, and who determined that all one million men were overtreated? I think we are entitled to an answer to this question since your quoted it.

david in scc
Posted 10/27/2011 11:07 AM (GMT 0)
"In the European Randomized Study of Screening for Prostate Cancer, screening did confer a benefit but was also related to a high risk of overdiagnosis. The study, published in The New England Journal of Medicine, found “that 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer.”

Of course for that one person it was worth it
Posted 10/27/2011 4:43 PM (GMT 0)
We all keep thinking that PC is a single disease; it's not, it's three different distinct types, low risk, intermediate risk and high risk. Studies show that diagnosed low risk patients have a better 10 years survival than non diagonosed patients, because they are now into the medical system and other things like high blood pressure and other important health factors are being monitored. Walsh, " Prostate Cance Screening may have an unintended efffect on mortality- the camel's nose effect" Journal of Urology, april 2007.
When we make statements about PC we need to remember that all PC is not created equal and goes from harmless to very deadly. A G6 will not act like a G10 and lumping all PC together does not help anyone in these discussions.
JohnT
Posted 10/27/2011 5:23 PM (GMT 0)
Ezra18 stated:

"In the European Randomized Study of Screening for Prostate Cancer, screening did confer a benefit but was also related to a high risk of overdiagnosis. The study, published in The New England Journal of Medicine, found “that 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer.”

Of course for that one person it was worth it

-------------------

Exra,
The ERSPC trial reported in the NEJM along with the US trial has been somewhat reconsidered and the number needed to be treated dropped from 1 in 48 to as low as a projected 1 in 28. See below...

prostatecancerinfolink.net/2011/02/13/truth-in-screening-how-many-men-to-screen-and-treat-to-save-a-life/

The Europeans study had a median of 9 years at the original release, 8 years for the US version. Many consider these to be a major flaw to both studies. When including a G6 patient, who hardly ever die of PCa in ten years, this skews the numbers by having the early cutoff at the time of reporting. As my contention has always been here, 10 year studies are common in prostate cancer. Helpful only to the median aged at Dx prostate cancer patient. Not to the younger patients. I firmly believe that the screening benefit for younger men is going to show a different picture than what these two studies show, and the ERSPA study shows a survival benefit regardless of patient ageC

Tony
Posted 10/27/2011 6:04 PM (GMT 0)
Tony,
I do not say 60% to 70%. THEY DO! These over treatment figures are based on computer models. I personally believe the problem here and in most of the world is UNDER TREATMENT...and the over treatment figure is more modest.

If you have read the results of the Tyrol, Austria experiment where all men diagnosed with PCa are treated, the yield of over diagnosis in surgically treated men is 8.7%. WOW! How can that be true? These men had their prostates removed and analyzed. This is not is not a computer model figure...maybe these computer models were designed by the same folks that designed the global warming computer models. Yeah, that sounds possible!

RalphV
Posted 10/27/2011 6:17 PM (GMT 0)
LOL.
Maybe epidemiologists should decide everything in life. That's what the USPSTF is a panel of. They analyze numbers. In my opinion these one's----> $$$$..

Tony
Posted 10/27/2011 6:37 PM (GMT 0)
The way they come to this conclusion in mind boggling.

"In the European Randomized Study of Screening for Prostate Cancer, screening did confer a benefit but was also related to a high risk of overdiagnosis. The study, published in The New England Journal of Medicine, found “that 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer.”

If they extend the study beyond 8.8 years, then the statics on their own will be usefull, but any comparision between the screening group and the control group is misleading at best;

They compared a screening group that was offered a PSA test once very 4 years (with 82% compliance) to a control group that had regular medical care. The control group was not barred from having the PSA test yet in the report they don't take that into account. This study is not showing us the difference between having a PSA test or not, it's the difference between regular care PSA tests and being offered a PSA test once very 4 years.

How they reached the numbers in their conclusion, is that the screening group had a death rate that was 0.71 per thousand less than the control group. That works out to a difference of one death per 1,410 men in the study between the two groups. It makes no sense to jump from there to saying that 1410 men need to be screened to save a life.

Same thing with the 48 cases need to be treated. In the study there was a difference in PC detection (not treatments) of 32 per thousand, or 48 per 1,410 between the two groups.



 

Posted 10/27/2011 7:39 PM (GMT 0)
John T says above that "We all keep thinking that PC is a single disease; it's not, it's three different distinct types, low risk, intermediate risk and high risk."

I've been thinking about this all morning. If a 40-year-old is diagnosed as a Gleason 6, isn't it likely that his cancer started out as PIN or HGPIN, progressed to G6, and that it will allmost inevitably progress to G7, G8, or even G9 if he lives long enough? Are there really distinct types, or is it simply that the cellular changes continue until they resemble normal prostate cells less and less and become characterized as higher grade cancer?

If there are actually distinct types, are there various "types" of Gleason 7, and various 'types" of Gleason 6? Or is it simply that in some men, whatever triggers the development of the cancer results in faster progression than it does in others, and that there's nothing that physically distinguishes a more aggressive cancer from one that does not progress?

I'm simply asking. It's something I would like to know more about, and would welcome any link or reference that can explain this.
Posted 10/27/2011 8:50 PM (GMT 0)
From Dr Klotz, Journal of Clinical Urology, march 2004:

"While the lifetime risk of being Dxed with PC is one out of 6, prior to the advent of psa screening the risk of death from pc was one in 40. Dispite this large discrepancy, 94% of men with low risk pc are still receiving radical treatment. In the rare instances where a life is saved by surgery, thought to be one out of 100 men, that one man's early death occurrs an average of 16 years after Dx and only 4 years prior to expected death from other causes. At best surgery extends life expectancy by 1.2 months."

Dr Klotz from Sunnybrook in Toronto has spent his entire life as a surgeon studing low risk PC and runs the longest AS program around going on better than 12 years.

Clocknut,
Another way of looking at PC is the PSA doubling time which remains fairly constant through the life of a tumor. It takes 40 doublings for pc to become fatal. Low risk cancer is defined by Klotz as having a doubling time greater than 3 years, many are in the 10 to 12 year range. By simple math one can calculate how fast the tumor is growing. At an average doubling time of 5 years it would take a 1 mm tumor 20 years to get to 16mm. To put this into perspective the best scans can pick up a 5mm tumor.
We also know from lots of evidence that those on an AS program about 60% will not progress in 12 years and about 40% do progress, either from a rapidly rising psa or from a upgrade to a G7. So the majority of G6s don't progress at least in the 12 year time frame.
There are unquestionably different types of pc with different growth rates and different abilities to metastasize. A G6 has difficulty in metastastizing even with a capsule breach and a G10 doesn't need a breach to metastasize. The cancer cells DNA are different and they act completely different.
We see very large volume G6's that have been growing a long time without mutating to higher grades and we see very small amounts of G8 that seem to appear in a very short period of time, so they must start as G8s. So to answer your question; it would be rare for a G6 to turn into a G8 during one's lifetime. There is a reasonable chance to a G6 to mutate into a G7 and this occurrs fairly early in the process, within the first three years. It is much more common for a G6 to continue to grow very slowly or not grow at all as we see consistantly in 60% of AS patients from various programs. The vast majority of matastais occurrs in the higher grades even when treated. Given the exact same treatment the cure rates for the different grades are radically different. G6 at 95%, G7 at 70% and G8 and above 60% or less. If these cancers acted the same the cure rates would be identical since they get the same treatment and are identified by the same psa tests and biopsies. All prostate cancer is not the same, the dna of the cells will determine the grade and the growth rate. All the higher grades will grow and grow rapidly; it's in their dna. In the low grades some cells will continue to grow at their predetermined rate, some will mutate to a higher grade, but most will grow slowly or not grow at all. The only way we have now to determine what a low grade cancer will do is to watch it over time.
I hope this helps.
JT
Posted 10/27/2011 9:45 PM (GMT 0)
John T

What is the estimated average doubling time for the different Gleason grades?   Does the doubling time of tumor volume correlate with PSA doubling time?

In my case I had different Gleasons and included 3+3,3+4,and 4+3 and was treated as an aggressive 7.   My tumor was estimated to be about one cm across.   I have assumed the G7 doubles  yearly, and thus can estimate at what point my cancer became detectable and could also estimate at what point it would likely be fatal given your rule of 40.   I could then apply the average lifespans from the point of treatment to determine whether the treatment would be likely to be life extending.   In my case I am confident that treatment was appropriate and will be life extending versus no treatment.

I remember reading (but I don't know where) that, left untreated, the cancer could become metastic in 5-7 years from the point of detection, and be fatal in 3-5 years after that.   I don't know what grade this referred to, obviously not 6.   Thus PCa can kill in 8-12 years under this scenario, assuming an intermediate to high risk setting.   The treatment statistics indicate high probability of extended longevity.  

The question perhaps shouldn't be whether treatment is life saving, rather is it life extending? 

Posted 10/27/2011 10:39 PM (GMT 0)
JNF,
Treatment for intermediate and high grade pc should always be undertaken unless one's expected life span is well under 10 years. I also had a G3+3, G 3+4 and G4+3. I had a very long time to see what my tumor did. My psa started rising before 1997; it maintained a doubling time of 3 years through out the 11 years that it was monitored. The fact that it most likely mutated to a G 4+3 over the years did not change it's doubling time. In fact when I changed my diet the last 4 months it actually dropped by 25%. I have over 50 psa data points. The doubling time accurrately reflects how fast the tumor is growing. The gleason grade and the total psa reflect the volume of the tumor. You can calculate tumor volume fairly accurrately by subtracting the benign prostate psa (.066Xprostate size) from total psa which then leaves the amount of psa generated by only the tumor. There is a mathematical formula that determines the amount of psa per cc of tumor by Gleason grade, so if you know the grade and the psa you can calculate the tumor volume. G6s generate more psa per cc than G9s. The PCRI website used to have a tumor volume calculator in their PC tools section that used these formulas. Doubling time, gleason grade and volume are different; you have to look at all three plus psa velocity and total psa to get an idea of what risk catagory you are in. Low risk PC always has a very long doubling time and agressive PC has a fast doubling time. A psa that goes from 2 to 4 in 6 months is much more dangerous than one that goes from 5 to 10 in 5 years.
Posted 10/27/2011 10:58 PM (GMT 0)
JohnT,

Your explanation is good, and overall makes sense. But still seems like there are too many exceptions to the rule, and that's the part that's puzzling to me, still 3 years out.

Pre-treatment, my PSA went from 4.2 to 5.8 in 2007, then from 5.8 to 12.3 a year later, then in just 2 months, went from 12.3 to 16.x. Yet my post-surgery pathology was T2C, nothing found in the lymph nodes that were taken, no SVI, and 1 tiny positive margin. Also, I was downgraded from a G7 4+3 to G7 3+4.

As you know from my story, my surgery failed in 9 months. And even after 72 Gys of SRT, the radiation failed in actually less than 9 months, and from my signature, you know that my PSA has been skyrocketing ever since. Last time the doubling time was calculated, was in the 8-12 week range, depending on who did the numbers. Based on my 5.8 PSA in June, my oncologist and I are expecting a new number in December >10, but hoping upon hope that the rise may have slowed and might be sitting at <10.

My real point, using your line of thinking, how would you explain the obvious aggessiveness of my own PC situation. On paper, I shouldn't have seen any recurrance for years, yet my reality says that the cancer is very agressive, despite the supposed 3+4 Gleason.

There must be some other factors here to consider, but I don't know what they are. Of course, Sonny's situation is very similar to mine, except that he had immediate recurrance after surgery, and he didn't have the extreme PSA velocity issues I had prior to primary treatment.

My current oncologist says that cases like mine are really hard to control, where you have BCR at every level, and at such a fast rate. I am about to get some state of the art PET scan in the next couple of weeks, but neither of us are convinced it will show anything, though my doctor doesn't put much faith in readings from conventional bone scans or MRI's. But he admits, that the cancer was probably long gone from the prostate bed before I ever had SRT (which doesn't make me feel good considering all the damage it did to me). He feels that too many men jump, or get talked into SRT when in many cases, it will do no good to stop the cancer. And that they jump into it with very minimal PSA numbers. I know doctors have very opposing views on that subject, as well as when to introduce HT to the mix.

Would like your take on this, using me as the example.

David in SC
Posted 10/28/2011 1:17 AM (GMT 0)
David,
Without a lot more information like ploidy and some other tumor markers or even a PCA3 it would just be a guess what was happening. You could have had a varient that wasn't discovered on your pathology. In any event your doubling time was less than a year, this is an indication of a very agressive fast growing cancer regardless of the Gleason grade. Because of the agressiveness of the cancer it appears that some cells got into your blood stream and are setting up shop and growing somewhere in you body. They are probably still to small to be detected, but are throwing off psa. Because of your failed radiation you can assume that some cancer cells were already beyond the immediate prostate region and were not affected by the radiation.
AS Zufus says "welcome to the twilight zone" as there are some cases that just don't follow the common path. There are 24 identified varients of PC that all behave somewhat differently.
My case was also rare, but it followed a very predictible pattern that only became apparent when a very knowledgable expert discovered it and explained it to me. I would say that your case also follows a very predicitable pattern of very agressive cancer which have a high rate of reoccurrance regardless of treatments.
JT
Posted 10/28/2011 2:06 AM (GMT 0)
thanks for the answer. if only there were a better way to know about these variants, how they react, and how best to treat them. so far, my original urologist has had this pretty well figured out. he told me from the very first, at dx, that i might be in for a difficult time, and when my first psa post surgery came back, he was pretty upset, and knew there would be trouble ahead.

i wish i still had the link from a couple of years back, it had to deal with how Gleason 7's can sometimes be more dangerous than Gleason 8/9.  The jist of the article was that many Gleason 8/9 run a predictable course, where there are Gleason 7 cases that have a mind of their own, and can run very aggressive and stubborn to treatment.  While other Gleason 7's act more indolent like most Gleason 6 cases.  As far as the argument of 3+4 being better than 4+3, I have read experts that believe that, and other experts that disagree that it doesn't make any difference.  They referred to the quality of the "4" component in the mix, not just the quantity difference between the "3" and the "4".  If my pathology was correct, it would add some credence to that last thought.

david

Post Edited (Purgatory) : 10/27/2011 8:11:22 PM (GMT-6)

Posted 10/28/2011 2:33 AM (GMT 0)
JohnT,
I do not know what is the data behind Dr. Klotz statement. What follows is the data from the Holmberg randomized clinical trial. It demonstrated a 32% benefit in death reduction for surgery at 12.8 years of follow up as compared to no treatment. At this time, 52% of surgical patients were still alive while 42% of untreated men were also alive representing a 19% improvement in overall survival for the surgical cohort. Definitely a better survival than 1.2 months...

I respect and admire Dr. Klotz for his work and his support of active surveillance. It is something needed to stop cutting corners and treating men who would derive little benefit from treatment.

At the same time, I do believe that treatments in general done at the proper time can change the natural course of the disease and provide a survival benefit. Why misinform a man that has decided for surgery? I try not to be involved in their personal preferences to decide. Just pass on information.
Source:
Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, Busch C, Nordling S,
Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Steineck G, Adami
HO, Johansson JE; SPCG-4 Investigators.
Radical prostatectomy versus watchful waiting in early prostate cancer.1. N Engl J Med. 2011 May 5;364(18):1708-17.

BACKGROUND: In 2008, we reported that radical prostatectomy, as compared with
watchful waiting, reduces the rate of death from prostate cancer. After an
additional 3 years of follow-up, we now report estimated 15-year results.
METHODS: From October 1989 through February 1999, we randomly assigned 695 men
with early prostate cancer to watchful waiting or radical prostatectomy.
Follow-up was complete through December 2009, with histopathological review of
biopsy and radical-prostatectomy specimens and blinded evaluation of causes of
death. Relative risks, with 95% confidence intervals, were estimated with the use
of a Cox proportional-hazards model.

RESULTS: During a median of 12.8 years, 166 of the 347 men in the
radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died
(P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to
watchful waiting, death was due to prostate cancer. This yielded a cumulative
incidence of death from prostate cancer at 15 years of 14.6% and 20.7%,<SNIP>

CONCLUSIONS: Radical prostatectomy was associated with a reduction in the rate of
death from prostate cancer. Men with extracapsular tumor growth may benefit from
adjuvant local or systemic treatment. (Funded by the Swedish Cancer Society and
the National Institutes of Health.).

PMID: 21542742 ]

In reference to your statement that GS8 are created as GS8, I believe that you believe that to be true by using what you feel is supportive data from AS studies. I presented Dr. Tribukait’s study about the change in ploidy associated with the dedifferentiation progress in 24 months by consecutive needle aspirations.

Studies using data from the ERSPC-Rotterdam trial provided epidemiological evidence of dedifferentiation as a major mechanism of progression in prostate cancer. Tumors dedifferentiate during the screen-detectable phase and consequently screening with PSA and early treatment can possibly prevent dedifferentiation.
Source:
Draisma G, Postma R, Schröder FH, van der Kwast TH, de Koning HJ.
Gleason score, age and screening: modeling dedifferentiation in prostate cancer.Int J Cancer. 2006 Nov 15;119(10):2366-71.

You also need to question why wouldn’t low-grade disease patients on AS would rarely progress in a matter of years while low-grade patients treated with surgery do fail treatment and progress within 1 to 5 years. Such is the case of 34% of patients that fail surgery done by Patrick Walsh at Johns Hopkins and develop metastatic disease.
Source:
Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC.
Natural history of progression after PSA elevation following radical
prostatectomy. JAMA. 1999 May 5;281(17):1591-7

RalphV
Posted 10/28/2011 3:52 AM (GMT 0)
Ralph,
I think that Klotz was referring to low risk cancer. There is no doubt that treatment effects mortality in the intermediate and high risk cases. I do believe that in many cases aggressive PC is not treated agressively enough in many patients who choose a mono therapy where a combination treatment may have been more effective. My belief is that one one end of the PC spectrum we are over treating and on the other end we are under treating.
My issue with the studies you cited is there is no risk classification associated to the patients. If all the selected patients were classified as low risk as defined by the Epstien criteria then it would have meaning in this discussion. We don't know the patient selection only that it was early pc.
I define low risk PC as gleason 6, psa density <1.5; psa < 10; no more than 30% cores positive; no core over 50%; psadt> 3 years; no nodule. Given this criteria most patients don't progress. Very low risk is 1 or 2 cores less than 5% and these rarely progress,; in fact these are most likely indolant cancer clusters that will never form into a tumor. If this criteria were used to select patients for comparison studies I believe that Klotz's number is correct.
Proper risk classification of patients is imperitive for any study because the results are significantly different for the different classifications because we are dealing with different types of cancer. You can't compare intermediate risk patients to low risk patients or low risk patients to very low risk patients. It's like comparing apples to oranges and lumping risk classifications together in a study makes it worthless.
Walsh's own records indicate that his success rate for G6 (not defined as low risk as all G6's are not low risk) is 85%. If the tumor was contained the cure rate was in the high 90%. His surgical failures were due to the cancer already being outside the prostate at time of surgery. If a tumor has breached the capsule by defination it is a large growing tumor and not low risk. Klotz also indicates from his research that 1.7% of cancers that appear to be low risk at biopsy are in fact varients that will result in death within 5 years regardless of treatment.
JT
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