IADT3since2000

Active Surveillance (AS) is growing in popularity among men with truly low-risk prostate cancer, but a recent article from Johns Hopkins suggests that only about 10% of eligible men take this approach. One likely reason is that many men still seem very concerned that their prostate cancers may jump from low-risk to higher risk suddenly and without much warning, despite research to the contrary!

Well aware of this concern, and no doubt wanting to check the facts for themselves, some of the major AS programs are carefully checking and publishing their results for the minority of their AS patients for whom their diligent monitoring reveals a need for radiation, surgery or other such major therapy to attempt to cure the cancer. The programs want to confirm their expectations that their AS patients will do about as well as their patients with similar truly low-risk cases who decide to have immediate therapy.

(These major centers, as I understand it as a layman, include at least the U. of Toronto - Sunnybrook (Dr. Laurence Klotz and others), Johns Hopkins (Drs. H. Ballentine Carter, Patrick Walsh, Jonathan Epstein and others), Memorial Sloan Kettering (Dr. Peter Scardino and others), Erasmus Medical Center (Netherlands, Dr. Fritz Schröder and others), MD Anderson (Dr. Babaian and others), and the University of California at San Francisco (Dr. Peter Carroll and others).

I thought this thread would be a good place to describe and discuss the research that is being published, including questions and doubts.

To lead off, here's one important study from Johns Hopkins, including comments from a 2005 talk by the renowned leader of the Johns Hopkins AS program, Dr. H. Ballentine Carter; renowned pathologist Jonathan Epstein, MD is the co-leader, as I understand it. (Here's the citation for the study: J Natl Cancer Inst.2006 Mar 1;98(5):355-7. Delayed versus immediate surgical intervention and prostate cancer outcome. Warlick C, Trock BJ, Landis P, Epstein JL, Carter HB. PubMed, at www.pubmed.gov, a site we can use on this board because it is Government sponsored, has a free link to the complete study.

They looked at 38 patients in their AS program who underwent surgery at an average of 27 months after diagnosis and compared them with 150 similar patients who had surgery within an average of 3 months after diagnosis. After reading the complete paper on June 14 after posting this, I would like to add that the groups compared looked highly comparable to me, as asserted in the study. The only difference that caught my attention was the maximum percent of cancer in a core: an average (mean) of 10.8% in the AS group versus 23.5% in the immediate surgery group. However, both percentages are fairly low, and in their analysis the authors found that these figures were not associated with the risk of incurable cancer; I'm thinking that men with substantially higher core percentages that were looked at in this study could be at higher risk of noncurable cancer.

What they were comparing was the number in each group estimated to have "noncurable cancer," which they defined as pathology characteristics that indicated a less than 75% chance of remaining disease-free for 10 years after surgery. As observed below, it appears that almost all of these surgeries were due to progression but that a few were elective. While "noncurable" cancer was determined in 23% (9 of 38) of the minority of AS patients who had surgery versus only 16% (24 of 150) in the comparison group that had more or less immediate surgery, after making adjustments to better match for age and PSA density, the Johns Hopkins researchers found strong statistical evidence that the risk of non-curable cancer was not different between the two groups. They concluded: "Thus, delayed prostate cancer surgery for patients with small, lower-grade prostate cancers does not appear to compromise curability."

Here's some more information about the Johns Hopkins AS program, which they refer to as "Expectant Management of Prostate Cancer," from a talk by Dr. H. Ballentine Carter at the National Conference on Prostate Cancer 2005 in Washington, DC. Their standards for eligibility - how they identify truly low risk disease - include, on the favorable, small-volume side, a PSA density of less than .1 (meaning the PSA divided by the volume of the prostate determined by ultrasound), and only 1 or 2 cores with cancer (probably out of 12 to 14 cores, based on other information), and less than ("not more than" in another publication) 50% of any core with cancer, and no high grade disease, meaning Gleason Score 7 or higher, and (not from the paper but published by Johns Hopkins elsewhere) stage T1c (can't be felt on DRE) as well as a free PSA percentage of consistently greater than 15 and a preference for older age men in their 60s, or men with other health problems that make active treatment less attractive.

On the flip side, considering unfavorable, not-small volume cancer, indicators included a PSA density of 0.1 or greater, or 3 cores or more with cancer, probably based on 12 to 14 cores based on other information, or 50% or more of any one core with cancer, or any high grade cancer (Gleason Score 7 or higher).

As of June 2005 talk to us, the Johns Hopkins program included 253 men. The program had been started in 1995, with confirmational biopsies to reduce the risk of undetected cancer started in 1998, and in its eleventh year in 2005 the program had more than 1 year of follow-up on 220 (87%) of the 253 men. The average age of men in the program was 65 years. Men with suspected small volume cancer as described above counted 178, and there were 42 men who classed in a group described as "comorbidity or other), indicating to me that they were somewhat higher in risk but with a life expectancy short enough that AS was deemed a reasonable option. The Johns Hopkins AS monitoring approach features PSAs and DREs every six months, with biopsies annually (with 12 to 14 core area-sampling biopsies recommended). (Note that at least one other major AS program, Toronto, does biopsies on all patients only for the first two years - baseline plus two years, with later biopsies based on judgment, by my recollection.) The program recommends curative treatment if there is "progression" of the cancer, defined as more than two positive cores found in a follow-up annual biopsy, or cancer involvement of 50% or more of any one biopsy core, or a Gleason Score of 7 or higher, or a change in the DRE. I suspect a suspiciously rising PSA would also trigger concern, but Johns Hopkins does not rely on that.

As of the 2005 talk, 213 confirmation biopsies revealed 31% unfavorable cancers (65 men), an equal percent and number revealed cancer with favorable characteristics (31%, 65 men), and 38% (83 men) resulted in no cancer found in follow-up biopsies (though it had, of course, been found in the initial biopsy). That means that 69% of patients remained eligible to stay in the AS program, consisting of the 31% with favorable follow-up but cancerous biopsies plus the 38% with no cancer found in subsequent biopsies. All of the work, I believe, was done at Johns Hopkins, known for its excellence in prostate cancer.

Let's look at the men whose follow-up biopsies were unfavorable. Regarding these 65 men, 48 (74% of 65) had Gleason Score 6 cancer found, which would be considered favorable except that the cancer was more extensive than originally found, 14 (22% of 65) were found to have Gleason Score 7 cancer, and only 3 (4%) were found to have Gleason Score 8 cancer. Thus, while the follow-up suggested a need for treatment, it would be quite unlikely for the cancer to turn out to be Gleason Score 7, and even far less likely for it to turn out to be Gleason Score 8. We should also keep in mind, in my view, that some of these higher risk cancers probably existed at the time of the original biopsy but were simply missed; that's significant, because it means that not all "unfavorable" cancers had turned unfavorable during AS: they were that way from the start. Dr. Carter also provided a chart showing that confirmation biopsies were very effective in reducing the risk of future unfavorable biopsy findings, with a miniscule percentage of unfavorable biopsies by the third biopsy, the first two having pretty much weeded out any detectable "unfavorable" cancer.

In another Johns Hopkins publication in 2005 to inform those interested in AS about the follow-up biopsies, they said this about their biopsy results:
- 12% of men whose first follow-up biopsy showed no cancer eventually experienced cancer progression, contrasted with just 5% of men whose first and second follow-up biopsies showed no cancer. That means you are entitled at least to a small celebration if that second follow-up biopsy is negative: you have a 95% chance that your cancer will not progress.
- 29% of men whose first follow-up biopsy showed cancer that was favorable eventually experienced cancer progression (flipping it, 71% did not progress!), while 22% of men eventually had the cancer progress despite showing only cancer that was favorable on both the first and second follow-up.
From these numbers, it's easy to see the importance of follow-up biopsies, not only to check for progression, but to get a handle of the likelihood of progression later on.

He also showed a chart with the percentages of men with non-curable disease by their years in the Johns Hopkins AS program, through the 7th year. A very encouraging finding was that the percentage with non-curable disease does not increase as men stay in the program.

He showed a chart in this talk that showed where all 220 men of the total of 253 in the AS program were who had at least one year of follow-up:

- 50% (109 men) then still active in the program with an average follow-up of 2.7 years;
- 7% (17 men) who decided to have treatment, despite having no cancer progression, after an average of 2.7 years in the program, 4 of them choosing RRPs (surgery) and 13 of them choosing radiation);
- 35% (77 men) experiencing cancer progression as caught in the diligent monitoring program, at an average follow-up time in the program of 2.7 years (26 men had RRPs, 32 had radiation, 7 were just watchfully waiting, and 12 were undecided);
- 2% (4 men) died from something other than prostate cancers (clear winners in one sense - lived their lives without any burden from prostate cancer treatment); and
- 6% (14 men) were lost to follow-up or withdrew from the program.
- ? (1 man) more than the 220, as the above numbers total 221 - I don't know why. I'm basing this on the printed slides for Dr. Carter's talk.

A thought - while the average follow-up figures are short, 2.7 years for example, quite a few men have much longer follow-up since the programs beginning in 1995. That enables the researchers to give longer term projections with confidence.

One of Dr. Carter's final slides from his 2005 talk gives us another cut at the curability comparison for those who choose AS instead of immediate treatment: 76% curability for men who got surgical treatment after having been in the AS program, versus 80% curability for all men treated surgically at Johns Hopkins who could have met all eligibility requirements for the AS program. Considering that the AS program has been improving, such as by adding follow-up biopsies in 1998, those numbers strongly suggest equivalence to me (and to Dr. Carter). (Here are the details for these percentages: for AS - of 94 men in the AS program who were treated - 77 with progression plus 17 who elected treatment, 30 were treated surgically - 26 after progression and 4 after deciding to have surgery, and curability was deemed 76%; for 11,600 men treated surgically at Johns Hopkins since 1983, 691 had T1 disease and otherwise would have qualified for the AS program, and 80% were deemed curable.)

Note that we are taking two looks at somewhat different times at the same AS program here. In the published 2006 paper, there are 38 patients from the AS program who had surgery, versus 30 in the 2005 talk. I'm thinking the difference is due to passage of time from the date of the statistics in the 2005 talk to the date of the 2006 paper. I'm not sure why there were 150 "similar" comparison patients in the paper versus 691 "T1c disease patients [who] met all criteria for expectant management.

In its information for AS patients Johns Hopkins addresses dietary changes but is tentative. Here are a couple of key lines. "The bottom line is that there is an association between intake of animal fat and the incidence of prostate cancer, and that fruits and vegetables can reduce the risk of many cancers. Thus, a diet that is mostly made up of food from plant sources (fruits, vegetables, soy) and that limits the intake of high fat foods makes sense for now." They also mention various vitamins. As of the 2005 document I have, their AS program did not mention the wisdom of taking a statin drug and either finasteride or Avodart.

As the Johns Hopkins AS "Expectant Management" program puts it in information for patients, "... Recent studies suggest that 30-50% of men over the age of 60 years diagnosed with prostate cancer today by PSA screening would never have known they had prostate cancer during their life if a prostate biopsy had not been performed. For these men, the news that they have prostate cancer will not be beneficial and their treatment will not add years to life.... The key is to be able to identify those older men who for now can safely forego treatment." The Johns Hopkins publication added this: "Thus, it would appear that when men are carefully selected for expectant management [meaning Active Surveillance], the window of opportunity for cure is unlikely to close with monitoring."

There's more published information about the AS program at Johns Hopkins and curability, but this is enough for now.

Take care,

Jim