PRIMARY THRPY w/ TESTOSTERONE INACTIVATING PHRMCTICLS (TIP)

LECTURE BY DR. MARK SCHOLTZ

PROSTATE ONCOLOGY SPECIALISTS MARINA DEL REY, CALIFORNIA

PRIMARY THERAPY WITH TESTOSTERONE INACTIVATING PHARMACEUTICALS (TIP)

Dr. Scholtz joined Dr. Stephen Strum in his LA practice some years ago. When Dr. Strum moved to Oregon, his practice was continued by Dr. Scholtz and Dr. Richard Lam who have continued working out of the Marina del Rey offices.

To set the backdrop for his lecture, Dr. Scholtz showed a slide with average years of survival following cancer relapses for several major cancers. For example, typical survival after pancreatic cancer relapse was listed at 4 months. Lung cancer was listed at 12 months, breast cancer at 36 months and prostate cancer at 160 months.

He emphasized that the wide variety of characteristics found in PCa makes it necessary to stratify it into three broad categories: low risk, or “good” cancers, bad or high risk ones, and the intermediate variety that fill the gap between the other two.

He quoted a statement by Dr. Thomas Stamey, one of the pioneers of PSA usage and a pre-eminent urologist at Stamford Univ. in California:

“I believe that when the final chapter of this disease is written, which is unlikely to be in my lifetime, never in the history of oncology will so many men have been so over-treated for one disease.” (Stamey, Urology 58, 2001)

Scholtz pointed out the dilemma facing the physician: to risk missing an opportunity to cure a dangerous disease on the one hand, or to administer a toxic treatment to a non-threatening condition thus ruining the quality of life.

He referred to the common use of radical surgery to remove the gland, but with its attendant side effects of incontinence and impotence has been a less than desirable procedure. He said that “40 years ago surgeons were the only “cancer specialists” who treated all cancers with surgery. Today he claimed that prostate cancer is the only remaining cancer that surgeons still manage.

[Ed. Note: The radiation oncologists would argue against this claim].

Surgery would be totally successful, if there weren’t significant side effects and IF no further treatment would be needed! He identified the major side effects (SEs) as: impotence 72%, incontinence 13%, scarring and blockage of the urethra 5%, and penile shrinkage with dry orgasms. With radiation he reported that impotence runs as high as 50%, life-long rectal damage in 5-20%, and rectal and bladder cancers in 1%. He classified these as the consequences of “over-treatment”.

[Ed. Note: Radiation oncologists would argue these statistics but Dr. Sholtz was building his case for TIP]

For the Under-treatment part of his argument he reported that “surgery often leads to more treatment.” Positive surgical margins were reported in 10-50% of prostate surgeries. The “standard” follow up treatment for these cases is radiation to the fossa. He reported that of these, an additional 10-50% will experience PSA relapses that will require some kind of TIP (and perhaps more radiation).

He cited another study (Messing, AUA #1480, 2003 that showed the effect on death rates after 10 years between a group that had TIP within 12 weeks of surgery vs. a similar group that didn’t have TIP until a + positive scan was obtained. After 10 years the former group had 6/47 (13%) deaths due to PCa while the latter had 22/51 (>40%) deaths.

Strong argument in favor of early TIP when PSA relapse first occurs following primary therapy. He also showed a slide in which hormonal resistance didn’t occur for an average of 11 years following failure within three years after surgery. During this portion of the lecture, Dr. Scholtz made the comment that the QOL of the intermittent therapy men was better than that of the continuous blockade group.

He then discussed some results from their own clinic. In these results, he discussed groups of men who had undergone TIP as their primary treatment vs a comparable group of men who had undergone 10 years of continuous TIP and then stopped. Within this group, a sub-group of 22 men were identified. They had a mean age of 74.

Eleven were still alive “with low and stable PSA” after the ten year period. That was 50%. Another sub-group of 28 men (age 66) who had had TIP repeated, 20 were still alive. Three had died of PC and 2 had developed TIP resistance.

Dr. Scholtz summarized their clinical results with a table showing the 10 year outcome of men with “intermediate risk disease”. Among the TIP group, mortality was 4% with 0% showing bone mets. In the surgery cohort with “intermediate risk” disease, mortality was 10% with 15% developing bone mets.

He also showed data on the effect of treatment with Proscar as part of the TIP protocol vs no Proscar. These were cases in which no primary treatment other than TIP w/wo Proscar was given to the men. A significant increase in the TOP (Time Off Period) occurred supporting the hypothesis that Proscar was an effective addition to the TIP therapy the men received.

The time it took for these men to reach T independence (essentially to become hormone refractory) was increased by the use of Proscar as part of the tx regimen. The increase, according to the data shown by Dr. Scholtz, ranged between 20 and 40 months. This was a very significant improvement in time to hormone blockade resistance.

Dr. Scholz put up a slide showing how the length of TIP effected the TOP. The longer periods of TIP tended to reduce the relative risk of biochemical failure. The effect was most dramatic with the data for TIP periods greater than 13 months.

After that, the effects were not nearly as dramatic. The difference (approximate) between the 13-17 months data and the longest, >21 months, was about (0.35 – 0.27 = .08). So by lengthening the TIP period to greater than 21 months, there was only about an 8% gain achieved.

He then showed data describing the effect of clinical tumor stage on time to T independence, or hormone refractoriness: as might be expected, the higher the stage of the PCa, the greater the relative risk of the tumor becoming refractory.

He put up a slide showing differences that have occurred in the field of TIP between 1995 and the present. In ’95 most men diagnosed already had palpable disease. There was no color Doppler ultrasound for better staging and there were no peri-prostatic biopsies.

Also re-staging biopsies after TIP were not performed and lastly, the significance of the PSA nadir (minimum point reached by TIP) was not known. Today, PSA velocity has become of greater diagnostic significance than the absolute level itself. He cited some 2004 data published by Dr. D’Amico of Boston’s Brigham and Women’s Hospital that was very significant: D’amico showed that the death rate was 0% for men whose PSA was rising at a rate of <2.0 ng/ml./year vs a 7% death rate after 7 years for that group whose PSAV was increasing at a rate > 2.0 ng/ml/year!

Taken along with other recently published data regarding the importance of the rate of change of PSA means that men should make this parameter an important part of their medical history when tracking prostate cancer or suspecting the possibility of PCa.

Dr. Scholz then showed some data that demonstrated the significance of PSA NADIR after TIP in predicting early progression to bone metastasis. He reported that a “PSA Nadir of > 0.05 was 90% accurate in predicting early progression to bone mets within 6 years of starting therapy.” So again, another sometimes-overlooked parameter was shown to be highly useful for men undergoing TIP therapy.

Dr. Scholz then summarized the protocol used in his office for PCa classified as “Intermediate Risk:” Staging is done with high resolution color Doppler ultra-sound. This technique allows for the detection of extra-capsular disease as well as disease in the gland. They then administer TIP for 12 months.

Assuming that the PSA nadir reaches < 0.05 they wait for 12 months and repeat the ultra-sound scan and biopsy. At this point they open the possibility for next stage treatment with either radiation or cryosurgery IF the dx procedures show persistent disease or if the PSA Nadir > 0.05. If the BX is favorable, they discontinue the TIP and initiate “active surveillance”.

He then discussed cancers that might be treated by “active surveillance”. Some data by J. Epstein of Johns Hopkins in 1994 showed that for prostate cancers with the following characteristics:

PSA density <0.15 ng/ml

Gleason < or = 6.0

Fewer than 3 bx cores being +

Less than 50% PCa in any bx core

Some 92% had organ-confined disease confirmed after RP (sample size was 237). Scholz concluded that these Epstein criteria “remain a useful tool for making treatment decisions.

Another strong proponent of “active surveillance” is Dr. J. Klotz of Toronto, CA. Scholz reported on some of Klotz’s results published in JCO 2005 (exact ref. as given by Scholz). Some 299 men starting in 1995 were followed by “AS” (active surveillance) by Dr. Klotz. The group was stratified as follows:

Age < 70, PSA < 10, GS 6

Age >70, PSA < 15, GS 3+4 = 7

Biopsy results were “OK”

Taken off AS if:

PSA doubling time < 3 years

GS increased to > 3+4= 7

After 5.5 years Klotz reported the following results:

34% have had treatment

15% for rapid PSA increase

3% for change in DRE

4% because of results of repeat BX

12% because patient wanted treatment Mortality @ 8 years was < 1%

These results support the idea that too many men are over-treated for PCa and could well enjoy a longer time free of treatment with its attendant side effects if they more carefully determine their disease parameters at the time of diagnosis and opt to practice “AS”.

Dr. Scholz then described his clinic’s Active Surveillance Protocol: Low risk disease: PSA < 8, GS =6

1-2 BX cores < 50% cancer

PSA density <0.15

Slow PSA velocity [Ed. Not specified]

Measure PSA Quarteryly, same lab

Color Ultrasound, HiRes, Q 6 mos.

MRI S, annually

Low Fat, low sugar diet

Use Proscar or Avodart

He reported that single agent Proscar® (or Avodart® )can effectively suppress low grade disease. He further reported that these agents “make PSA testing more accurate”. [Ed. Note: this claim is worth researching separately]

Sholz concluded his lecture by making these points:

Prostate cancer is very common but few die from it

A step-wise approach to treating it, escalating treatment only when indicated is a sensible approach When treatment is required, start with TIP first -It has reversible side effects

_ it is effective for occult disease outside the prostate

-Response to TIP yields further information about the nature of the disease

Avoid surgery with its attendant side effects which become even worse when more advanced disease is uncovered

MORE RESEARCH IS NEEDED TO FIND LESS TOXIC TX FOR EARLY-STAGE PCa.

Intl Prostate Conference October 2006

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