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Finding the Key to Dihydrotestosterone Control in Prostate Cancer Prevention

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

21st Annual Congress of the European Association of Urology

Paris, France / April 5-8, 2006

According to Dr. Jack Schalken, University Medical Centre, Nijmegen, The Netherlands, endocrinotherapy has become a therapeutic mainstay in prostate cancer. Unfortunately, dihydrotestosterone (DHT) synthesis continues despite endocrinotherapy, coinciding with the increased expression of 5 alpha-reductase (5AR) type 1 in prostate cancer. As a result, DHT still triggers androgen receptor activity, which in turn stimulates prostate cancer growth and progression.

“The most marked change [associated with prostate cancer progression] is the induction of the expression of 5AR type 1,” noted Dr. Schalken. “That by itself can explain, to a degree, why the cancer cell has its own factory to synthesize DHT, which drives the process.”

Lowering DHT still remains the prime goal of endocrine therapy. However, maximum androgen blockade (MAB), as currently practiced, does not prevent DHT synthesis by prostate cancer cells. Adding a 5AR inhibitor (5ARI) to MAB theoretically would achieve total suppression of testosterone and DHT, thereby inactivating the androgen receptor, Dr. Schalken told delegates.

Dual Inhibition

As explained by Dr. Ian M. Thompson, University of Texas Health Sciences Center, San Antonio, the chemopreventive potential of the 5ARI dutasteride has attracted considerable interest because of its potent inhibition of DHT. The agent appears to achieve significantly greater inhibition of DHT compared to finasteride (Clark RV. J Clin Endocrinol Metab 2004;89:2179-84).

Indirect evidence of its potential to prevent prostate cancer has already emerged from evaluation of the 5ARI in BPH patients. In phase III clinical trials, it was associated with a significantly lower incidence of prostate cancer detection compared to placebo (Andriole G. Urology 2004;64:537-41). Upcoming results of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial (Gomella LG. Curr Opin Urol 2005;15:29-32) should help clarify the role of dutasteride in chemoprevention of prostate cancer. However, the evidence accumulated to date for use of 5ARIs to prevent prostate cancer has already given clinicians ample reason to broach the issue with patients.

As noted by Dr. Thompson, principal investigator in the PCPT (Prostate Cancer Prevention Trial) (Thomson IM. N Engl J Med 2003;349:215-24) , “We can now prevent prostate cancer. We must understand this opportunity and be able to offer it to our patients. The level of evidence of a benefit in prostate cancer’s prevention is much greater than that for early diagnosis and treatment.”

Statistical Data

Dr. Fritz Schroder, Erasmus University Medical Centre, Rotterdam, The Netherlands, used statistical modelling based on results of the PCPT. It has provided a hint of the potential effects of prostate cancer prevention with 5ARI use. In a meta-analysis comprising several recent publications, investigators have estimated that chemoprevention with a 5ARI could save 316,760 person-years over five years in the US (Unger JM. Cancer 2005;103:1375-8); add 140 life-years to 1000 men aged 62 years (Grover S. J Urol 2006;175:934-8); add six life-years per 1000 men treated, regardless of age (Zeliadt SB. Am J Med 2005;118:850-7); and prolong 15-year survival by as much as 1.7 months (Lotan Y. J Clin Oncol 2005;23:1911-20).

However, the cost-effectiveness of chemoprevention with a 5ARI remains to be determined, Dr. Schroder continued. If chemoprevention were applied to all men aged 55 years, the cost per life-year gained would be $1.6 million. If 46 quality-adjusted life-years (QALYs) were gained in 1000 men, he explained, the incremental cost per QALY would be $200,000. Chemoprevention with a 5ARI might be cost-effective if the price per QALY could be cut in half (Zeliadt SB. Am J Med 2005;118:850-7).

According to Dr. Neil Fleshner, Chief of Urology, University of Toronto, Ontario, “Application of chemoprevention principles in clinical practice requires careful consideration of each patient’s risk factors and clinical characteristics.” The consideration begins with the issue of what type of prostate cancer risk warrants prevention, i.e. if prevention should apply to all prostate cancers or be limited to clinically significant disease.

One of the concerns about the PCPT is that some of the cancers detected by the end-of-study biopsies were perhaps not the same type of cancers typically seen in patients, indicated Dr. Fleshner. “My belief is that we should be focusing on clinically significant prostate cancers. Those are cancers that, if they are not prevented, would lead to more serious disease or treatment-related morbidity or mortality.”

Assessing Cancer Risk Factors

Prostate cancer risk assessment should weigh a patient’s current risk vs. future risk. Such an assessment involves consideration of factors such as patient age, family history, biopsy status, race, lifestyle issues, and prostate-specific antigen (PSA) level. In the PCPT, increased cancer risk was associated with older age, black race, and positive family history, although 5ARI treatment reduced the risk by a similar magnitude across all major subgroups.

Dr. Fleshner cited recent study findings which showed that a positive family history of prostate cancer was associated with an increased risk for biochemical failure after treatment and more adverse histopathology at radical prostatectomy (Spangler E. Int J Cancer 2005;113:471-4).

“It is definitely food for thought that men with a positive family history are likely to have clinically significant prostate cancer in their life,” he declared.

A variety of lifestyle issues also may influence prostate cancer risk. With respect to diet, vitamins A, D, E and selenium may decrease the risk, and dietary fat may increase prostate cancer risk. Smoking is unlikely to increase prostate cancer risk but is probably associated with a worse outcome, noted Dr. Fleshner. Obesity may have a marginal impact on prostate cancer risk but is probably associated with worse outcomes.

The PCPT data reaffirmed PSA level as a major factor in prostate cancer risk. End-of-study biopsy results showed that higher PSA levels increased the risk of prostate cancer per se and the risk of high-grade disease (Thompson IM. N Engl J Med 2004;350:2239-46).

“Even though PSA has taken somewhat of a hit over the past few years, it still provides very valuable information as a marker for prostate cancer,” confirmed Dr. Fleshner.

It was stressed that a negative prostate biopsy does not mean that a man need no longer worry, as far as prostate cancer risk is concerned. Between 10 and 15% of men whose initial prostate biopsy is negative will subsequently develop prostate cancer that is detected on repeat biopsy (Djavan B. J Urol 2000;163:1144-9, Remzi M. J Urol 2005;174:1256-60).

The data are mixed regarding the cancer risk conferred by a finding of high-grade prostatic intraepithelial neoplasia (PIN). Dr. Fleshner and colleagues found a 42.5% prostate cancer detection rate in men who had high-grade PIN and were followed with serial biopsies over three years. In contrast, a retrospective comparison of 190 patients with high-grade PIN and 1677 men with benign prostate tissue revealed no difference in prostate cancer detection rates during follow-up (Gokden N. Urology 2005;65:538-42).

Summarizing the evidence on patient selection for prostate cancer prevention, Dr. Fleshner stated, “When we see a patient in our office, we have to think in terms of a multivariable approach, taking in a variety of risk factors.”


Findings from the ongoing REDUCE trial are expected to be promising. It is hoped that the results will yield to a better understanding of prostate cancer’s development and growth, thereby placing physicians in a better position to offer a more individualized approach to endocrinotherapy for their patients.

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