Synopsis of the 2007 Prostate Cancer Symposium
by Mark Scholz, M.D.

See also: PCRI Attends 3rd PC Symposium in Orlando

Two years ago ASCO inaugurated the annual prostate cancer symposium. The symposium aims at uniting all the various disciplines involved in delivering prostate cancer care — urology, medical oncology, radiation therapy, radiology and basic science — at one meeting. To this end, the symposium has been moderately successful.

Unfortunately, perhaps because its occurrence in February steals the thunder of the traditional venue for the presentation of new prostate cancer research — the annual meeting of the American Urological Association (AUA) — the AUA has declined to be fully involved (however, a subgroup of the AUA, the Society of Urologic Oncology, has been supporting the symposium). This synopsis provides highlights of the presentations I was able to cover in the three-day meeting. The talks and abstracts referenced are available on the ASCO website.

Screening

The symposium began by addressing the topic of screening. The initial studies that were presented, while of interest, were basically further refinements of previous studies on the topics of PSA velocity, Free PSA, and PSA density. The data presented indicated that, in men with PSA levels less than 4.0 ng/ml, a PSA velocity of more than 0.4 points per year is sufficient justification to consider a prostate biopsy even if the PSA is still in the normal range (Abstract #2). A second study showed that a low Free PSA to total PSA ratio in men with PSA levels less than 2.5 was also a valid indication for doing a prostate biopsy (Abstract #3). A third study showed that a high PSA density, that is the sum of the total PSA divided by the prostate volume, is an indication that Gleason 7 (or higher) disease is more likely to be diagnosed if a prostate biopsy is performed (Abstract #361).

What came next (in a podium session by Robert Getzenberg) was nothing short of revolutionary. Previous research has shown that certain nuclear matrix proteins are specifically associated with prostate cancer. One such protein is called EPCA-2 (early prostate cancer antigen-2). In a study of more than 400 individuals, EPCA-2 was found in the serum of men with prostate cancer but not in disease free individuals. Testing for the presence or absence of this protein accurately correlated with the presence or absence of prostate cancer 95% of the time. EPCA-2 accurately detected prostate cancer even when PSA levels were in the normal range. Even more amazing, EPCA-2 could also predict prior to surgery which men would have cancer confined within the prostate gland and which men would have prostate cancer that extended through the capsule. Apparently the commercialization of this new test is actively proceeding and may be on the market within a couple years.

Using PSA Response To Predict Survival

The degree of PSA decline that is needed to predict increased survival after intervention with effective therapy (such as chemotherapy) has been debated for years. Various cut points such as 50% or 75% have been utilized in various published studies in the past. Reanalysis of the 1000-patient trial that led to the approval of Taxotere indicates that a cut point using a threshold of a 30% decline is the most accurate way to determine if a treatment is going to result in longer survival (Abstract #148).

Active Surveillance

There was broad consensus that many men with early-stage prostate cancer are receiving unnecessary surgery or radiation, especially in the United States. Four talks were presented on Active Surveillance that is, deferring immediate radical therapy in men with good risk disease (PSA < 10, Gleason < 7, less than a third of cores positive on biopsy, and no core more than 50% replaced by cancer). The early results of an ongoing study at the Royal Marsden in Sutton, England were presented. They looked at 273 patients with an average PSA of 6.4. Treatment with surgery or radiation was recommended if the PSA rose at a doubling rate of faster than four years or if a repeat prostate biopsy resulted in an upgrade of the Gleason score. Twenty percent of the men have undergone treatment in the first two years of observation. No one has developed metastases, and there have been no deaths from prostate cancer (Abstract #319).

Dr. Niel Fleshner from Toronto presented some fascinating data that builds on previous studies showing anti-cancer benefits in men receiving selenium, lycopene or vitamin E. Dr. Fleshner looked at the combination of all three agents administered to men who were scheduled to undergo radical prostatectomy. When all three agents were administered, uniformly favorable pathologic changes indicating slower growth (decreased KI-67) and reduced metastatic potential (increased P-27) were seen. These changes occurred within a matter of weeks of starting these common supplements. When men were treated with only one or two of these agents, the results were not nearly as good.

Salvage Radiation for Men with PSA Relapse after Surgery

The results of two large trials for salvage radiation initiated in the 1990s and involving close to 1500 men were presented in another podium session. These trials were designed to answer one fairly simple question: If, after surgery, a man finds that the cancer has spread outside the gland, is he better off having immediate radiation to the prostate fossa, or should he wait and have radiation when the PSA starts to rise. The radiation consisted of about a 6000-rad dose over six weeks.

The men who had immediate radiation had an improved chance for a better outcome: Five years down the line, the PSA relapse was reduced from one out of two to one out of four. Ten years after radiation the relapse rate was one out of two in the treated men and three out of four in the untreated men. The incidence of bone metastasis 10 years later was reduced from 17% in the untreated group down to 8% in the treated group. Overall survival at 10 years was also improved from 66% to 74%. However, the risk of side effects such as incontinence was twice as high in the men receiving radiation.

Hormone Blockade

There has been increasing discussion about the side effects of hormone blockade. Testosterone deprivation can cause weight gain, blood sugar problems, and even the rare possibility of a heart attack. All of this data was retrospectively derived from insurance databases, not from medical studies (Abstract #298). However, few experts deny that testosterone deprivation leads to weight gain and to blood sugar problems. Therefore, it was rather surprising that a large prospective randomized trial (1000 men) comparing survival between men treated with immediate testosterone blockade to those treated with delayed testosterone blockade showed a reduction in the incidence of cardiac mortality.

My theory to explain this increased survival (even in the face of weight gain and sugar problems) is that the shorter life expectancies of men (as compared to women) result from the effects of testosterone in the blood — it makes it thicker. Thicker blood puts more strain on the heart and on the blood vessels leading to a higher incidence of heart attacks and strokes. However, when a man’s testosterone is eliminated, his blood thins down to the some degree that is normally present in women (Dr. Stephen Strum and I first reported this phenomenon back in 1994 in the British Journal of Urology). Hence, it appears that the impact of low testosterone on heart disease is a mixed bag. Having a low testosterone may even be beneficial if side effects like weight gain and increased blood sugar are kept in check with proper medication and diet.

Another study that looked at the anti-cancer effectiveness of hormone blockade examined the important and unanswered question — what is the optimum duration of treatment? Testosterone deprivation is often administered in combination with radiation to improve cure rates. Dr. D’Amico released the results of a study several years ago showing a survival advantage with just six months of testosterone blockade. Re-analysis of the data revealed that the biggest survival advantage was seen in the men who had the slowest testosterone recovery after the testosterone blockade was stopped (the average time to recovery ranged between 13 and 19 months. These findings would seem to imply that six months of adjuvant testosterone deprivation is insufficient in younger men who have faster rates of testosterone recovery (Abstract #190).

I had led a team that did a retrospective chart review of 154 prostate cancer patients with negative bone scans and PSAs < 100 who had started on ADT before January 2000. The study team measured the predictive value of Gleason score, initial PSA, PSA doubling time, clinical stage, and ultra-sensitive PSA nadir for their ability to predict early progression to bone metastases within 72 months of starting an anti-androgen and an LHRH agonist. The report described the finding that “Ultra-sensitive PSA nadir is a more accurate indicator of early progression to bone metastases (90%) than [the second-best] marker, Gleason score (75%), as well as being more sensitive and specific (72% vs. 37% and 95% vs. 86%, respectively.” Moreover, the report concluded, this prognostic information provided by PSA nadir is obtainable within the first eight months of starting ADT in 97% of the patients.

New Drugs

Satraplatin is a chemotherapy drug derived from the element platinum. The drug is administered orally for a five-day period followed by a 30-day holiday. A study of men with advanced disease compared this drug with a steroid called prednisone (which also has some mild anticancer activity) and showed that Satraplatin did a better job of delaying cancer growth in the bones. The side effects of the drug seemed to be manageable. However, the development of progressive anemia occurred about 15% of the time. This problem, however, can probably be prevented with the use of common bone marrow-supporting drugs like Aranesp that can reverse anemia (Abstract #145).

CTLA-4 (ipilimumab) is a new drug that works by stimulating the immune system to attack the cancer. It actually functions by reducing the activity of the cells in the immune system that suppress the immune system. In other words, this drug suppresses the suppressor cells. The results of this preliminary trial were presented by Dr. Eric Small from UCSF. CTLA-4 was administered once a month for four consecutive months. The treatment was combined with another drug called Leukine (GM-CSF) that has been previously shown to stimulate the immune system. Three out of six men who received full dose CTLA-2 therapy with Leukine responded with greater than a 50% decline in PSA levels. These results are impressive considering that all three men had advanced disease. As might be expected, immune related side effects such as colitis and endocrine changes were common. However, I spoke to Dr. Small after the presentation, and he expressed hope that these immune-related side effects will be manageable with standard therapies already on the market (Abstract #49).

Results of another new drug, Abiraterone acetate (which works by blocking testosterone synthesis rather than by blocking the androgen receptor directly) were presented. One might think that this drug is just a rehash of ketoconazole (Nizoral) a drug already on the market that works by a similar mechanism. Not so. Five out of six patients with advanced prostate cancer who had already failed ketoconazole benefited with a greater than 50% decline in PSA. Side effects were limited to mild fatigue and dizziness in one patient (Abstract #278).

New Uses of Drugs Already on The Market

Avodart® (dutasteride), a cousin to Proscar (finasteride) was evaluated for its ability to reduce PSA levels in men with hormone refractory disease who were failing treatment with ketoconazole. Dr. Oliver Sartor evaluated the impact of starting Avodart in 10 men with rising PSA levels. In this study, eight of the 10 men had some degree of PSA decline that lasted for a median of five months. As would be expected from a drug that the FDA has already approved for treating a benign condition — to reverse benign swelling of the prostate — no side effects were encountered (Abstract #257).

Follow up from the spectacular results with Avastin® (bevacizumab) reported by the National Cancer Institute by Dr Figg at this meeting last year were updated. The Institute now has 33 patients with advanced metastatic prostate cancer on trial using Avastin, Taxotere, and Thalidomide in combination. Twenty-eight patients have had a greater than 50% decline in PSA. Not only is a high percentage of men responding to treatment, there is a low incidence of treatment resistance developing. So far most of the men who have started the study still remain on therapy. The median response time is greater than a year. (Abstract #228)

Celebrex - Forty-five patients with newly diagnosed prostate cancer volunteered to either take Celebrex or a placebo starting prior to surgery. After the prostates were removed, the men who were taking Celebrex showed a reduction in tumor growth as measured by MIB-1, a pathologic index that measures the rate of tumor proliferation. Another study looked at Celebrex in combination with an older form of oral chemotherapy called Cyclophosphamide. Seventy percent of men (17 of 24) either had PSA stabilization or decline. Eight (33%) had a greater than 50% decline in PSA. No unusual side effects were encountered (Abstract #215).

Samarium is an intravenous drug that the FDA has approved for the palliation of painful bone metastasis. This “drug” is a form of radioactive calcium that is injected into the blood stream. Once there, it seeks out areas of the bone that are hyperactive due to irritation from the presence of cancer. As a result, when Samarium is brought in close proximity to the cancer cells, the cancer cells receive a lethal dose of radiation. Samarium has been used sparingly in the past because it was believed that the effects of the drug were too mild to impact survival. Several preliminary studies indicate that when Samarium is combined with Taxotere, the combination appears to be better than either drug alone. Abstract # 231 presented preliminary findings of a dose finding study indicating that this combination is indeed workable

Revlimid® (lenalidomide) is an oral antiangiogensis inhibitor (it blocks blood vessel growth) that the FDA has approved to treat another cancer called multiple myeloma. Revlimid is closely related to Thalidomide, which has known activity in prostate cancer. In many cases, however, the intolerable side effects of Thalidomide (constipation, fatigue and nerve damage) have precluded its widespread use. Revlimid appears to be much better tolerated, and in a small study by the Cleveland Clinic, it appears to be active when used in combination with Leukine. Sixteen patients were treated with a large dose: 25 mg a day. Nine of the men had some degree of PSA decline. Side effects included low blood counts, diarrhea and fatigue. I believe this drug will be effective in prostate cancer but I expect it will be better tolerated in smaller doses (Abstract #229)

The Androgen Receptor

Much more attention is being paid to this “nuclear switch” that is turned off and on by testosterone (or by dihydrotestosterone). Even though testosterone levels in the blood can be suppressed with medicines like Lupron, Trelstar, or Zoladex, it appears that testosterone and DHT remain in the cancer cells. Cancer cells that keep growing, even when testosterone levels in the blood are low, are called androgen independent. However, it appears that in many cases, “androgen independence” is really nothing more than androgen hypersensitivity. The cancer cells simply increase their sensitivity to the smaller amount of residual testosterone by increasing the number of androgen receptors.

One company called Aureon has developed technology to measure the amount of androgen receptor present in the cancer cells. They studied whether higher levels of androgen receptor can predict which men will be more likely to relapse after surgery. In the study they presented, the presence of a high androgen receptor level predicted an 85% chance for subsequent PSA relapse of the cancer (Abstract #296).

Drugs to block the androgen receptor, like Casodex and Eulexin, are already on the market and have been shown to be clinically beneficial. However, at some point they stop working. One possible explanation is that they simply are not potent enough to overcome the increased numbers of androgen receptors that are present when hormone resistance develops. Favorable results from preclinical studies in animals were presented on a new drug, MDV-3100, which is estimated to be 10 times more potent than Casodex. The researchers were able to show cancer responses in cancer cell lines that were resistant to Casodex. Studies of this new drug in humans are just getting started. (Abstract 48)

To have so many new drugs coming is very exciting. The work that is being done with the immune system is especially promising. Dendreon is seeking FDA approval for its immune enhancing treatment called Provenge. The FDA has just requested more clinical data on Provenge, thereby delaying the drug’s approval for an indeterminate period. (See “A Voice Raised for Prostate Cancer” new webpage.) We hope we will have good news to report concerning the FDA’s final decision later this year.

 

Prostate Cancer Research Institute (PCRI)
 

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