An LHRH agonist was first administered to a prostate cancer patient 16 years ago in 1980 while combination therapy with an LHRH agonist and a pure antiandrogen was first administered 14 years ago in 1982. We take this opportunity to review briefly the events which, in our opinion, led to such fundamental changes in the endocrine therapy of prostate cancer. Following the observations of Huggins and his colleagues in 1941, orchiectomy and treatment with high doses of estrogens remained the standard therapy of prostate cancer for 50 years. Discovery of the structure of LHRH in 1971 by Schally and his colleagues stimulated the synthesis of highly potent analogs of LHRH with the objective of treating infertility. However, difficulties were met in finding the proper schedule of administration as well as the dose of LHRH agonists which could maintain stimulatory effects upon repeated administration. In fact, contrary to the expectations of a stimulatory effect, we found in 1977 that treatment of adult male rats with an LHRH agonist for a few days caused some inhibition of ventral prostate and seminal vesicle weight, although the inhibitory effects achieved were small compared with those of castration. It was then believed that the high serum LH levels induced by LHRH agonist treatment caused desensitization of the steroidogenic response in the testes. Even more unexpected was the finding that of all the species studied, man was the most sensitive to the inhibitory action of LHRH agonists on testicular androgen biosynthesis and that medical castration could be easily achieved with LHRH agonists in adult men. In fact, a single intranasal administration of an LHRH agonist to healthy men in 1979 caused the expected acute rise in serum levels of testosterone and its precursors. This increase, however, was followed by a loss of diurnal cyclicity and lowered serum androgen levels which lasted for 3 to 4 days, thus suggesting that man is exquisitely sensitive to the inhibitory action of LHRH agonists. When, in 1980, the first prostate cancer patient received an LHRH agonist at the Laval University Medical Center, it was found that treatment with a high dose of the peptide caused a dramatic reduction in serum testosterone and dihydrotestosterone (DHT) after 2 weeks of administration. Contrary to the usual pattern in medical discoveries, the castration effect of LHRH agonists was first observed in men and not in experimental animals where castration is difficult or sometimes impossible to achieve with daily administration of LHRH agonists. A limitation to the use of LHRH agonists to achieve castration in prostate cancer patients was the temporary rise in serum testosterone and DHT at the start of treatment: such an elevation of serum androgens could cause an exacerbation of the symptoms or flare of prostate cancer. It was then decided to combine a pure antiandrogen with the LHRH agonist. In 1978, we found that the inhibitory effects observed in the rat with the combination of an LHRH agonist associated with a pure antiandrogen were more than additive, especially on seminal vesicle weight. These promising results suggested the use of a pure antiandrogen, not only to avoid the risk of disease flare during the first days of treatment with an LHRH agonist but also to offer the possibility of potentiating the inhibitory effects of the LHRH agonist on androgen-sensitive parameters. Combination therapy with an LHRH agonist and a pure antiandrogen was first administered to a prostate cancer patient in March 1982, also at the Laval University Medical Center. The first patients with advanced prostate cancer treated with combination therapy in a non-randomized study showed a rapid fall in serum prostatic acid phosphatase and a marked improvement of the signs and symptoms of prostate cancer which were highly suggestive of the advantage of combination therapy compared with previous treatments. In fact, the first 58 stage D2 prostate cancer patients showed a positive objective response to combination therapy while a 94% rate of positive response was achieved in the total group of 260 patients entered in this first study. The highly promising results obtained in this initial study provided the stimulus for large-scale randomized and placebo-controlled clinical trials which confirmed the unique benefits of combination therapy on both duration of response and, most importantly, on survival. In fact, combination therapy became the first treatment shown to prolong life in prostate cancer and it has been the gold standard for the endocrine therapy of prostate cancer since 1989. Since localized disease provides the only opportunity for cure of prostate cancer, the same combination therapy was next administered to patients at earlier stages of the disease. Randomized studies performed in patients with localized disease have recently demonstrated that combination therapy administered for 3 months before radical prostatectomy increases the proportion of patients having organ-confined disease by about 50% while the same approach associated with radiotherapy has been shown to delay the time to progression. Although the impact on survival of this neoadjuvant and adjuvant use of combination therapy, in association with radical prostatectomy or radiotherapy, remains to be assessed by long-term follow-up of the patients, it certainly raises the hope of a further significant improvement in the therapy of prostate cancer. Since screening for prostate cancer with serum prostatic specific antigen is gaining wide acceptance, the diagnosis of prostate cancer is made at earlier stages of the disease where the reversibility of medical castration with LHRH agonists is the only acceptable approach. It has thus become clear that LHRH agonists should almost completely replace orchiectomy in the near future while there is no more valid reason to use treatment with estrogens because of their serious and life-threatening cardiovascular side-effects. Knowledge of the structure of the genes responsible for the formation of DHT in the human prostate provides the scientific basis for the observation that about 50% of total androgens responsible for the growth of prostate cancer are synthesized in the prostatic tissue itself. Fortunately, prostate cancer is exquisitively sensitive to androgen deprivation, thus providing a powerful tool to control this cancer. The data summarized above indicate that the use of a pure antiandrogen in association with chemical castration represents the most acceptable approach to block androgen action maximally and thus cause maximal induction of cell cycle arrest and apoptosis in prostate cancer. Since the available antiandrogens still leave some free DHT in the prostatic tissue, research efforts should be directed to improving androgen blockade further with the development of more potent antiandrogens as well as efficient inhibitors of androgen formation. Simultaneously, efforts should be made to detect and treat prostate cancer at an earlier stage, when endocrine therapy alone or combined with radical prostatectomy or radiotherapy is clearly most efficient.
