PROSTATE CANCER – WHAT’S NEW. A Short Synopsis of Recent Developments of Clinical Interest. (November 2010)

Compiled by Edward L. Weber, MD, Medical Oncologist, Retired, Swedish Hospital Cancer Institute, Seattle, WA.

Author of PCa Commentary, an analysis of new information and management options in prostate cancer found at Seattleprostate.org, click on “News and Events.”

1) ASPIRIN: Studies show improvement in prostate cancer outcome, a significant decrease in risk for disease-specfic mortality in a 10-year analysis of users versus non-users. The absolute risk decrease for Aspirin users was 1% at 5 years; 2% at 10. This was seen particularly in men with high-risk prostate cancer. CapSure data on 5295 men with localized disease treated with radiation therapy (RT) had better biochemical control. The relative risk of recurrence at 5 years was 22% lower in the Aspirin users; and 33% lower at 10 years. Source: American Society of Therapeutic Radiologists (ASTRO) Abstract, 2010 #270.
Another study also showed that the risk of getting prostate cancer was reduced by 21% in Aspirin users. Long-term use of less than 5 years showed a 24% decrease while daily low-dose, “baby” aspirin lessened the risk by 29%. This data was based on a study from the Fred Hutchinson Cancer Research Center (FHCRC) of 1001 cases and 942 controls. (Published Sept 1, 2010)

2) STATINS (cholesterol lowering drugs such as Lipitor, Pravacol): (Reviewed in PCa Commentary, Jul/Aug 2010) Statin usage reduces risk of a diagnosis of advanced prostate cancer by 40% if used for less than 5 years; and by 74% for usage greater than 5 years. Also seen was a 30% reduction of recurrence. All-cause mortality decreased 65% after radical prostatectomy, and 41% after radiation therapy.

3) POLYUNSATURATED FATS: A FHCRC study on diet and supplement use based on data from the Prostate Cancer Prevention Trial showed that the risk of high-grade prostate cancer (Gleason 8-10) was increased 2.41 X in association with a high intake of polyunsaturated fats. No effect was seen in cancer prevention from lycopene, long-chain-3 fatty acids, Vit. D, Vit. E, and selenium. N-6 fatty acids (found in red meat) may increase prostate cancer risk. (Article: Sept 1, 2010 )

4) PSA SCREENING: Despite the brisk controversy on the benefits of PSA screening, an ASTRO report (Oct, 2010) found that routine screening improved quality of life and decreased the occurrence of metastatic disease at 10 years in all risk groups compared to men who were not screened. The analysis was based on 1700 prostate cancer patients.
(See PCa Commentary article, Sept/Oct 2010, reviewing the Swedish Goteberg study which showed a 20% decrease in prostate cancer-specific mortality (PCSM).
Dr. Crawford, a prominent urologic surgeon, Denver, CO, reported at the 2010 ASCO meeting that after 10-years of follow-up a “significant decrease in the risk of PCSM (22/164 v. 38/164) was “observed in men with no or minimal co-morbidity. This was based on analysis of prostate cancer deaths in the major screening study (the international Lung, Colon, Ovarian, Prostate study) wherein no overall benefit was seen for PSA screening. However, when results were analyzed in reference to co-morbidities of the prostate patients (mainly cardiovascular disease and diabetes), screening in these healthy men showed a benefit as regards the risk of a diagnosis of prostate cancer.

5) DIAGNOSIS: (PCa Commentary Nov/Dec, 2010 ) Five-year usage of a statin reduces PSA by 13% and thiazide diuretics ( e.g. hydrochorothiazide, Diuril, or Enduron) reduce PSA by 26%. Used together for five years, the reduction is 36%.

6) ANDROGEN DEPRIVATION THERAPY (ADT)

a) FDA asked manufacturers to add new label warnings for GnRH agonists
(i.e. Lupron and Zoladex) linking the drugs to increased
cardiovascular risks, i.e. myocardial infarction and cardiac deaths.

b) Bicalutamide (Casodex) 150 mg/qd monotherapy is an established
alternative to GnRH agonists in Europe and provides comparable
outcome in men with non-metastatic cancer, but preserves bone mineral
density, muscle strength, and other quality of life (QOL) aspects. An
American Society of Clinical Oncology 2010 reported that “Endurance,
upper extremity strength and physical components of QOL are affected
within 3 months of starting ADT [with GnRH agonists].” Exercise
programs should start with the onset of treatment and have been shown
to lessen the deterioration associated with long-term ADT (i.e.
especially for longer than 6 months). Of note: bicalutamide does not
lower serum testosterone.

c) ASCO guidelines (2007) for initial hormonal management for androgen-
sensitive, recurrent, or progressive PC states: “Nonnsteroidal
antiandrogen monotherapy merits discussion as an alternative [to, eg.
Lupron].

d) Combined androgen blockade (i.e Lupron plus 50 mg Casodex) overall
confers a less than 5% survival advantage over Lupron alone (but may
be more helpful than 5% in extensive disease). Dr. Labrie, a
Canadian expert in endocrine aspects of prostate cancer, argues for
always adding an antiandrogen (i.e. Casodex or Flutamide) since, “…
after castration [medical or surgical] the 95-97% fall in serum
testosterone does not reflect the 40-50% testosterone and
dihydrotestosterone made locally in the prostate from DHEA (an
important intermediate steroid) of adrenal origin.”
The minimal effectiveness of Casodex may result from its weak
biologic binding to the androgen receptor. Assessment may change with
the likely availability of MDV3100 (a drug under development), which
is 200 X more effective in blocking the access of testosterone to the
androgen receptor and initiating the cascade of stimulation leading to
prostate cancer growth.

e) There is no current consensus for the timing of ADT initiation in the
face of PSA progression after primary treatment.
Immediate ADT lessens prostate cancer-specific deaths by 17%, but is
associated with a 15% increase in non-cancer deaths.
Special case: ASCO 2009 report – “ADT may prolong survival in the
subgroup of men who experience biochemical recurrence
early after prostatectomy [within 2 years] if they exhibit a rapid
PSA Doubling Time of <6 months]." f) The use of an 5alpha-reductase inhibitor, e.g. dutasteride or finasteride, during the "holiday" period of Intermittent ADT can lengthen the duration of the "off" period. 7) RISK OF COLORECTAL CANCER is increased by 30 - 40% in men on ADT compared to men who did not receive androgen deprivation (Journal of the National Cancer Institute, Oct. 2010) based on national outcome data. In men treated with GnRH agonists the incidence of colon cancer was 4.4 cancers per 1000 person years compared with 3.7 for men not receiving ADT. For GnRH usage of less than 24 months the increase was 1.19 times; and for use for >25 months, the increase in risk was 1.31 X. Suggestion: regular colorectal screening and increased exercise.
[see PCa Commentary March/April 2010 showing that exercise decreased the
incidence of colon cancer in men by 22%].

8. CASTRATE RESISTANT PROSTATE CANCER:

Abiraterone, a promising drug under development, combined with prednisone in a Phase III trial (PCa Commentary,Nov/Dec 2010) found a 35% reduction in risk of death from cancer, and a 36% increase in median survival, 14.8 months v. 10.9 months. Thirty eight percent of men with metastatic, CRPC under study who had progressed despite chemotherapy showed a >50% decrease in PSA. Other data showed 75% of men with CRPC without heavy or any exposure to chemotherapy had a >50% PSA decline.

MCV3100, a “super antiandrogen” continued to block cancer growth in studies of cells not responsive to androgen deprivation where mutant variations of the androgen receptor had lost the receptor’s binding portion (the customary target for anti-androgens). this finding suggested that MDV3100 has additional means of blocking cancer growth compared to the currently standard antiandrogens ( i.e. Casodex).

9) BONE METASTASIS: Denosumab (Amgen’s new inhibitor of bone destruction),
given by subcutaneous injection monthly, was compared to Zometa, given intravenously every 4 weeks, in men with CRPC. Denosumab delayed evidence of bone metastases 5 months versus 3.6 months for Zometa.

10) CHEMOTHERAPY: A new drug, Cabazitaxel (Jevtana), improved survival in men with metastatic CRPC resistant to first-line docetaxel increasing median survival to 15.1 months v. 12.7 for current 2nd line treatment, Mitxanthrone/prednisone.

11) Proton Beam Radiotherapy for Prostate Cancer: Despite positive reports from Loma Linda University (A California provider of proton therapy), prostate cancer experts writing in peer reviewed journals have found no substantiated evidence of better outcome or fewer side effects for proton therapy as compared to conventional radiotherapy.
See discussion “Protons versus Photons” in Nov/Dec issue of PCa Commentary