Gonadotropin-Releasing Hormone Agonists in the Treatment of Prostate Cancer
Fernand Labrie,
Alain Bélanger,
Van Luu-The,
Claude Labrie,
Jacques Simard,
Leonello Cusan,
José Gomez and
Bernard Candas
Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (Centre Hospitalier de l’Université Laval) and Laval University, Quebec City, Quebec, Canada G1V 4G2
Correspondence: Address all correspondence and requests for reprints to: Professor Fernand Labrie, Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (Centre Hospitalier de l’Université Laval), 2705 Laurier Boulevard, Quebec City, Quebec, Canada G1V 4G2. E-mail: fernand.labrie{at}crchul.ulaval.ca
In 1979, the first prostate cancer patient was treated witha GnRH agonist at the Laval University Medical Center in QuébecCity, Canada, thus rapidly leading to the worldwide replacementof surgical castration and high doses of estrogens. The discoveryof medical castration with GnRH agonists was soon followed byfundamental changes in the endocrine therapy of prostate cancer.Most importantly, the excellent tolerance accompanying the treatmentwith GnRH agonists has been a key factor that permitted a seriesof studies demonstrating a major reduction in the death ratefrom prostate cancer ranging from 31 to 87% at 5 yr of follow-upin patients with localized or locally advanced prostate cancer.In fact, a one third reduction in prostate cancer deaths hasbeen calculated in the metaanalysis of all available studies.The general acceptance of this discovery by patients and physiciansis illustrated by world sales above 3.0 billion U.S. dollarsin 2003.
Although extremely efficient in achieving complete medical castrationand well tolerated, with no other side effects than the expectedhypoandrogenicity, GnRH agonists should not be administeredalone. In fact, shortly after discovery of the castration effectsof GnRH agonists, we observed that approximately 50% of androgensremain in the prostate after castration, thus leading to therecognition of the role of adrenal dehydroepiandrosterone asan important source of the androgens synthesized locally inthe prostate and in many peripheral target tissues. We thereforedeveloped combined androgen blockade (CAB), whereby the androgensof both testicular and adrenal origins are blocked simultaneouslyat start of treatment with the combination of a GnRH agonistto block the testis and a pure antiandrogen to block the actionof the androgens produced locally. CAB, first used in advancedmetastatic disease, has been the first treatment shown to prolonglife in prostate cancer. Most interestingly, in 2002, we madethe observation that CAB alone given continuously for 6.5 yror more leads to cure of the disease in at least 90% of cases,thus suggesting that androgen blockade combining a GnRH agonistand a pure antiandrogen could well be the most efficient treatmentof localized prostate cancer, and thus offering the possibilityof practically eliminating death from prostate cancer.
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