Research at the PCRI

BY MARK SCHOLZ

As Executive Director for the Prostate Cancer Research Institute, I am often asked about our research focus. The PCRI has given unrestricted grants to various institutions over the years. These institutions are listed on the website at www.PCRI.org.   In addition, since the inception of the PCRI, Dr. Lam, Dr. Strum and I have published at least ten scientific articles relevant to prostate cancer in peer-reviewed journals This blog very briefly summarizes the most useful conclusions that can be drawn from this body of work (the article titles are in italics).

1. Anemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade:  We were the first to report that blocking testosterone can result in anemia, i.e. a drop in red blood cell (RBC) counts. The anemia caused by low testosterone resolves spontaneously when testosterone levels are restored to the normal range. Doctors need to be aware of the cause of this phenomenon or else men are unnecessarily subjected to treatment with iron (which may stimulate prostate cancer growth) or to uncomfortable diagnostic studies such as bone marrow biopsy.

2. Low-Dose Weekly Docetaxel (Taxotere) in Elderly Men with Prostate Cancer:  Rather than giving a standard dose of Taxotere every three weeks, which can be associated with low white blood cell counts, infection and excess fatigue, we evaluated 20 elderly men (average age 78) with a 1/3 dose of Taxotere administered weekly.  We found the anticancer effect to be maintained (twelve of the twenty men in the study had more than a 50% decline in PSA).  However, side effects were reduced: Only three of the patients stopped treatment for reasons of fatigue.  No patients experienced low blood counts or infections.

3. Using Splines* to Detect Changes in PSA Doubling Times: We collaborated with two mathematicians from UCLA, Robert Jennrich and Ray Redheffer, to develop a mathematical model for measuring the change in the rate of PSA rise after starting a new therapy.

4. Modified Citrus Pectin (MCP) Increases the Prostate-Specific Antigen Doubling Time in Men with Prostate Cancer: A Phase II Pilot Study:  This study used the statistical methods developed in the previous study to measure PSA doubling times before and after starting MCP. We showed a significant slowing in the rate of PSA rise in seven of the ten men who were administered MCP in the study.

5.  Long-Term Outcome for Men with Androgen Independent Prostate Cancer Treated with Ketoconazole and Hydrocortisone: Ketoconazole was the best treatment for men resistant to Casodex and Lupron before FDA approval of Zytiga and Xtandi. In 2005 we published a report of 78 patients showing PSA suppression for an average of 14.5 months.  Even longer responses occurred when treatment was initiated when men were in the earlier stages of androgen independence.

6. Intermittent Use of Testosterone Inactivating Pharmaceuticals (TIP) Using Finasteride Prolongs the Time Off Period: This study of 101 men treated with intermittent TIP reported a number of interesting findings: The “Holiday Period” after TIP is stopped is doubled [twice as prolonged] when finasteride (Proscar) is employed. Longer holiday periods were also associated with advanced age and lower Gleason score.

7.  Preventing and Treating the Side Effects of Testosterone Inactivating Pharmaceuticals in Men with Prostate Cancer: This article reviewed effective methods to reduce or eliminate common side effects of TIP such as fatigue, weakness, anemia, muscle loss, weight gain, penile atrophy, dry skin, breast enlargement, blood pressure changes, hot flashes, osteoporosis, joint aches and urinary symptoms.

8. Prostate Cancer-Specific Survival and Clinical Progression-Free Survival in Men with Prostate Cancer Treated Intermittently with Testosterone Inactivating Pharmaceuticals: 160 men were treated with TIP and monitored for survival over 10 years. We found that the single most powerful factor for predicting extended survival was to have attained a PSA less than 0.05 within eight months of starting TIP.

9. Primary Intermittent Androgen Deprivation as Initial Therapy for Men with Newly Diagnosed Prostate Cancer: This study was an observational report on 73 men who were eligible to have surgery or radiation but instead elected to initiate TIP. After an average observation period of 12 years, three men died of prostate cancer. Of the remaining 70 men, none developed metastasis. 28 men underwent delayed surgery or radiation. On average, the delayed surgery or radiation occurred 5.5 years after TIP was first initiated.

10. Primary Androgen Deprivation (AD) Followed by Active Surveillance (AS) for Newly Diagnosed Prostate Cancer (PC): A Retrospective Study:   This study evaluated 102 men treated with initial TIP to determine how often a single course of TIP for 12 months resulted in durable remission (defined as more than 7 years).  Durable remission occurred in 94% of men in the Low-Risk category, 47% of men with Intermediate-Risk prostate cancer and only 29% of men with High-Risk disease. There were no prostate cancer deaths.

Conclusion

One consistent theme in our published research is that stand-alone hormonal therapy is a reasonable option for men with Intermediate-Risk category prostate cancer. Men with Low-Risk disease are best managed with initial observation, i.e., without any initial therapy at all.  Men with High-Risk disease should be treated with a combination of TIP plus radiation.

Another important conclusion is that while the side effects of TIP can be managed, they tend to be more notable than the side effects of other popular treatments for Intermediate-Risk prostate cancer such as radioactive seed implants or intensity modulated radiation therapy (IMRT). The main exception being a somewhat lower risk of permanent erectile dysfunction with TIP compared to radiation.

Lastly, the overriding theme of all modern prostate cancer research is that over-enthusiasm for curative treatments that extend life must be tempered by the potential negative impact that treatment can have on quality of life.

* A “spline” is a bent line, i.e. a line with an angle. When rising PSA levels are represented graphically the dots can be connected creating a line.  If there is a change in the rate of rise, an angle in the line occurs.