Abstract
In 1941, Huggins and his colleagues discovered that testicular androgens exert a stimulatory effect on prostate cancer growth. Our group has made the key observations that the human adrenals, in addition to the tests, also secrete important amounts of androgens and cancer cells exhibit a marked heterogeneity of androgen sensitivity. In fact, human adrenals secrete large amounts of precursor steroids that are converted into active androgens in peripheral tissues (including the prostate), thus providing 40% to 50% of total androgens in adult men. The action of these androgens remaining after castration can be inhibited in prostatic cancer tissue by administering a pure antiandrogen that also decreases the local concentration of dihydrotestosterone (DHT). The castration levels of serum testosterone left in men after castration have an important stimulatory activity on the growth of androgen-sensitive normal as well as cancer tissues. Cancer cells have markedly different requirements for androgens. Some cell clones can grow in the presence of minimal amounts of androgens, requiring more complete androgen blockade and more potent antiandrogens for inhibiting growth. Among the compounds recommended as antiandrogens, the most unexpected finding is that many of them are devoid of any antiandrogenic activity. In fact, medroxyprogesterone acetate, chlormadinone acetate, and megestrol acetate have androgenic activity, but do not inhibit the peripheral action of DHT in prostatic tissue. These compounds should not be classified as antiandrogens. Cyproterone acetate, on the other hand, is a mixed agonist-antagonist. The only compounds showing pure antiandrogenic activity are Flutamide and its analogues.
There is thus a need for a more complete blockade of androgens of both testicular and adrenal origins in order to exert a maximal inhibitory effect on cancer growth. We have therefore performed clinical studies in previously untreated stage D2 and C prostate cancer patients with the combination therapy using the LHRH agonist [D-Trp6, des Gly NH2 10] LHRH ethylamide and the antiandrogen Flutamide. There was a significant increase in patients with a complete response, as compared with studies limited to the removal or blockade of testicular androgens. There was also a significant decrease in the number of non-responders, an increased duration of positive response, and a decrease in the death rate. This was achieved with minimal or no side effects, thus preserving a good quality of life.
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References
Silverberg E, Lubera JA: A review of American Cancer Society estimates of cancer cases and deaths. CA 33: 2–25, 1983
Labrie F: A new approach in the hormonal treatment of prostate cancer: complete instead of partial blockade of androgens. Int J Androl 7: 1–4, 1984
Williams G, Blooms SR: Treatment of advanced carcinoma of the prostate. Brit Med J 11: 572–572, 1984
Murphy GP, Beckley S, Brady MF, Chu M, DeKernion JB, Dhabuwala C, Gaeta JF, Gibbons RP, Loening S, McKiel CF, McLeod DG, Pontes JE, Prout Gr, Scardino PT, Schlegel JU, Schmidt JD, Scott WW, Slack NH, Soloway M: Treatment of newly diagnosed metastatic prostate cancer patients with chemotherapy agents in combination with hormones versus hormones alone. Cancer 51: 1264–1272, 1983
Huggins C, Hodges CV: Studies of prostatic cancer. I. Effect of castration, estrogen and androgen injections on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1: 293–297, 1941
Huggins C: Antiandrogenic treatment of prostatic carcinoma in man, approaches to tumor chemotherapy. Am Ass Adv Sci 379–383, 1947
Paulson DF: The role of endocrine therapy in the management of prostatic cancer. In: Skinner DG, De Kernion JB (eds) Genitourinary Cancer. W.B. Saunders, Philadelphia, 1978, pp 288–396
Nesbit RM, Baum W: Endocrine control of prostatic carcinoma: clinical and statistical survey of 1818 cases. JAMA 143: 1317–1320, 1950
Jordan WP Jr, Blackard CE, Byar DP: Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma. South Med J 70: 1411–1413, 1977
Mettlin C, Natarajan N, Murphy GP: Recent patterns of care of prostatic cancer patients in the United States: results from the surveys of the American College of Surgeons Commission on Cancer. Int Adv Surg Oncol 5: 277–321, 1982
Resnick MI, Grayhack JT: Treatment of stage IV carcinoma of the prostate. Urol Clin North Am 2: 141–161, 1975
Johnson DE, Scott WW, Gibbons RP, Prout GR, Schmidt JD, Chu JTM, Gaeta J, Sarott J, Murphy GP: National randomized study of chemotherapeutic agents in advanced prostatic carcinoma: progress report. Cancer Treat Rep 61: 317–323, 1977
Slack NH, Murphy GD, NPCP participants: Criteria for evaluating patient responses to treatment modalities for prostatic cancer. Urol Clin North Am 11: 337–342, 1984
Glashan RW, Robinson MRG: Cardiovascular complications in the treatment of prostatic carcinoma. Br J Urol 53: 624–626, 1981
Labrie F, Auclair C, Cusan L, Kelly PA, Pelletier G, Ferland L: Inhibitory effects of LHRH and its agonists on testicular gonadotropin receptors and spermatogenesis in the rat. In: Hansson V (ed) Endocrine Approach to Male Contraception. Int J Androl (suppl 2): 303–308, 1978
Labrie F, Bélanger A, Cusan L, Séguin C, Pelletier G, Kelly PA, Lefebvre FA, Lemay A, Raynaud JP: Antifertility effects of LHRH agonists in the male. J Androl 1: 209–228, 1980
Faure N, Labrie F, Lemay A, Bélanger A, Gourdeau Y, Laroche B, Robert G: Inhibition of serum androgen levels by chronic intranasal and subcutaneous administration of a potent luteinizing hormone-releasing hormone (GnRH) agonist in adult men. Fertil Steril 37: 416–424, 1982
Warner B, Worgul TJ, Drago J, Demers L, Dufau M, Max D, Santen RJ, Abbott Study Group: Effect of very high doses of D-Leucine6-gonadotropin-releasing hormone proethylamide on the hypothalamic-pituitary testicular axis in patients with prostatic cancer. J Clin Invest 72: 1842–1855, 1973
Waxman JH, Was JAH, Hendry WF, Whitfield NH, Besser GM, Malpas JS, Oliver RTD: Treatment with gonadotropin-releasing hormone analogue in advanced prostatic cancer. Brit Med J 286: 1309–1312, 1983
Labrie F, Dupont A, Bélanger A, Cusan L, Lacourcière Y, Monfette G, Laberge JG, Emond JP, Fazekas ATA, Raynaud JP, Husson JM: New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen. Clin Invest Med 5: 267–275, 1982
Labrie F, Dupont A, Bélanger A, Lachance R, Giguère M: Long-term treatment with luteinizing hormone-releasing hormone agonists and maintenance of serum testosterone to castration concentrations. Brit Med J 291: 369–370, 1985
Farnsworth WE, Brown JR: Androgen of the human prostate. Endocr Res Commun 3: 105–117, 1976
Geller J, Albert JD, Nachtsheim DA, Loza DC: Comparison of prostatic cancer tissue dehydrotestosterone levels at the time of relapse following orchiectomy or estrogen therapy. J Urol 132: 693–696, 1984
Bélanger A, Brochu M, Cliche J: Levels of plasma steroid glucuronides in intact and castrated men with prostatic cancer. J Clin Endocrinol Metab 62: 812–815, 1986
Moghissi E, Ablan F, Horton R: Origin of plasma androstanediol gucuronide in men. J Clin Endocrinol Metab 59: 417–421, 1984
Sogani PC, Ray B, Whitmore Jr WF: Advanced prostatic carcinoma: flutamide therapy after conventional endocrine treatment. Urology 6: 164–166, 1975
Stoliar B, Albert DJ: SCH 13521 in the treatment of advanced carcinoma of the prostate. J Urol 111: 803–807, 1974
Sanford EJ, Paulson DF, Rohner TJ, Drago JR, Santen RJ, Bardin CW: The effects of castration on adrenal testosterone secretion in men with prostatic carcinoma. J Urol 118: 1019–1021, 1977
Robinson MR, Shearer RJ, Fergusson JD: Adrenal suppression in the treatment of carcinoma of the prostate. Brit J Urol 46: 555–559, 1974
Huggins C, Scott WW: Bilateral adrenalectomy in prostatic cancer. Ann Surg 122: 1031–1041, 1945
Labrie F, Dupont A, Bélanger A. Complete androgen blockade for the treatment of prostate cancer. In: De Vita VT, Hellman S, Rosenberg SA (eds) Important Advances in Oncology. J. B. Lippincott, Philadelphia, 1985, pp 193–217
Labrie F, Veilleux R: A wide range of sensitivities to androgens develops in cloned Shionogi mouse mammary tumor cells. Prostate 8: 293–300, 1986
Fowler JE, Whitmore Jr WF: The response of metastatic adenocarcinoma of the prostate of exogenous testosterone. J Urol 126: 372–375, 1981
Bartsch W, Knabbe M, Voigt KD: Regulation and compartmentalization of androgens in rat prostate and muscle. J Steroid Biochem 19: 929–937, 1983
Marchetti B, Plante M, Poulin R, Labrie F: Dramatic response of prostate weight and ornithine decarboxylase to low levels of testosterone in castrated rats. J Steroid Biochem 36: 32S, 1985
Labrie F, Dupont A, Bélanger A, Giguère M, Lacorucière Y, Emond J, Monfette G, Bergeron V: Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in advanced prostate cancer: a marked improvement in response and survival. J Steroid Biochem 23: 833–841, 1985
Labrie F, Dupont A, Bélanger A, St-Arnaud R, Giguère M, Lacourcière Y, Emond J, Monfette G: Treatment of prostate cancer with gonadotropin-releasing hormone agonists. Endocr Rev 7: 67–74, 1986
Labrie F, Dupont A, Bélanger A, Giguère M, Borsanyi JP, Lacourcière Y, Emond J, Monfette G, Lachance R: The importance of combination therapy with Flutamide and castration (LHRH agonist or orchiectomy) in previously untreated as well as previously treated patients with advanced prostate cancer. In: Hormonal Manipulation of Cancer: Peptides, Growth Factors and (Anti)-steroidal Agents. Raven Press, New York, 1986, pp 291–300
Dexter DL, Calabresi P: Intraneoplastic diversity. Biochim Biophys Acta 694: 97–112, 1982
Hamada H, Neumann F, Junkmann K: Intrauterine antimaskuline beeinflussing von rattenfetendurch ein stark gestagen wirksames steroid. Steroid Acta Endocrinol 44: 330–388, 1963
Neri R, Monahan MD, Meyer JG, Afonso BA, Tabachnick IA: Biological studies on an antiandrogen (SH-714). Eur J Pharmacol 1: 438–444, 1967
Dorfmann RI: Antiandrogens. In: Jarnes V, Martini L (eds) Proc of the Third Int Congress on Hormonal Steroids. Excerpta Medica, Amsterdam, 1971, p 995
Johnson DE, Kaesler KE, Ayala AG: Megestrol acetate for treatment of prostatic carcinoma. Br J Urol 53: 624–630, 1981
Poyet P, Labrie F: Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate and megestrol acetate. Mol Cell Endocrinol 32: 283–288, 1985
Mowszowicz I, Bieber DE, Chung KW, Bullock LP, Bardin CW: Synandrogenic and antiandrogenic effect of progestins: comparison with nonprogestational antiandrogens. Endocrinology 95: 1589–1599, 1974
Graf KJ, Kleinechke RI, Neumann F: The stimulation of male duct derivatives in female guinea pigs with an antiandrogen cyproterone acetate. J Reprod Fertil 39: 311–317, 1974
Tisell LE, Salander H: Androgenic properties and adrenal depressant activity of megestrol acetate observed in castrated male rats. Acta Endocrinol 78: 316–324, 1975
Noguchi S, Nishizama Y, Uchida N, Yamaguchi K, Sato B, Kitamura Y, Matsumoto K: Stimulative effect of physiological doses of androgens or pharmacological doses of estrogen on growth of Shionogi carcinoma 115 in mice. Cancer Res 45: 5746–5750, 1985
Pavone-Maculuso M, De Voogt HJ, Viggiano G, Barasolo E, Hardennois B, De Pauw M, Silvester R: Comparison of diethylstilbestrol, cyproterone acetate and medroxyprogesterone acetate in the treatment of advanced prostatic cancer: final analysis of the randomized phase III trial of the European Organization for Research on Treatment of Cancer Urological Group. J Urol 1: 624–631, 1986
Labrie F, Dupont A, Bélanger A, Lacourcière Y, Raynaud JP, Husson JM, Gareau J, Fazekas ATA, Sandow J, Monfette G, Girard JG, Emond J, Houle JG: New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. Prostate 4: 579–584, 1983
Kramer CY: Extension of multiple-range tests to groups means with unique numbers of replications. Biometrics 12: 307–310, 1956
Armitage T: Statistical methods in Medical Research. Blackwell Scientific Publications, Oxford, 1971
Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. Am Stat Ass J 53: 457–481, 1958
Smith JA, Glode LM, Wettlaufer JN, Stein BS, Glass AG, Max TD, Enber D, Jagst CL, Murphy GT: Clinical effects of gonadotropin-releasing hormone analogue in metastatic carcinoma of the prostate. Urology 1985: 20: 106–112, 1985
The Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. New Engl J Med 311: 1281–1286, 1984
Brendler H, Prout GR Jr: A cooperative group study of prostatic cancer. Stilbestrol versus placebo in advanced progressive disease. Cancer Chemother Rep 16: 323–327, 1962
Labrie F, Luthy I, Veilleux R, Simard J, Bélanger A, Dupont A: New concepts on the androgen sensitivity of prostate cancer. In: Murphy G (ed.) Second Int Symposium on Prostate Cancer. Alan R. Liss, Inc., New York, 1987 (in press)
Luthy I, Labrie F: Development of androgen resistance in mouse mammary tumor cells can be prevented by the antiandrogen flutamide. Prostate 10: 89–94, 1987
Simard J, Luthy I, Guay J, Bélanger A, Labrie F: Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Mol Cell Endocrinol 44: 261–270, 1986
Asselin J, Mélançon R, Moachon G, Bélanger A: Characteristics of binding to estrogen, androgen, progestin and glucocorticoid receptors in 7,12-dimethylbenz(a)anthracene-induced mammary tumors and their hormonal control. Cancer Res 40: 1612–1622, 1980
Kahan A, Delrieu F, Amor B, Chiche R, Steg A: Disease flare induced by D-Trp6-GnRH analogue in patient with metastatic prostatic cancer. Lancet 1: 971, 1984
Bélanger A, Dupont A, Labrie F: Inhibition of basal and adrenocorticotropin-stimulated plasma levels of adrenal androgens after treatment with an antiandrogen in castrated patients with prostatic cancer. J Clin Endocrinol Metab 59: 422–426, 1984
Moore RJ, Gazak JM, Wilson JD: Regulation of cytoplasmic dihydrotestosterone binding in dog prostate by 17β-estradiol. J Clin Invest 63: 351–357, 1979
Mobbs BG, Johnson IE, Connolly JG, Thompson J: Concentration and cellular distribution of androgen receptor in human prostatic neopolasia: can estrogen treatment increase androgen receptor content? J Steroid Biochem 19: 1279–1290, 1983
Gibbons RP, Mason JT, Correa RJ Jr, Cummings KB, Taylor WJ, Hafermann N, Richardson RG: Carcinoma of the prostate: local control with external beam radiation therapy. J Urol 121: 310–312, 1979
Tomlinson RL, Currie DP, Boyce WH: Radical prostatectomy: palliation for stage C carcinoma of the prostate. J Urol 117: 85–87, 1977
Paulson DF: Treatment of locally confined prostaic cancer: radiotherapy versus surgery-limits of curability. In: Kurth KIH, Debryene FMJ, Schraeder FH, Splinter TAW, Wagener TDJ (eds) Progress and Controversies in Oncological Urology. Alan R. Liss, New York, 1984, pp 483–492
Cupps RE, Utz DC, Fleming TR, Carson CC, et al. Definitive radiation therapy for prostatic carcinoma: Mayo Clinic Experience. J Urol 124: 855–859, 1980
Smith PH, Suciu S, Robinson MRG, Richards B, Bestable JRG, Glashan RW, Boussioux C, Lardennois B, William RE, De Pauw M, Sylvester R: A comparison of the effect of diethylstilbestrol with low dose estramustine phosphate in the treatment of advanced prostatic cancer: final analysis of a phase III trial of the European Organization for Research on Treatment of Cancer. J Urol 136: 619–623, 1986
Grayhack JT, Kozlowski JM: Endocrine therapy in the management of advanced prostatic cancer: the case for early initiation of treatment. Urol Clin North Am 7: 639–643, 180
Veterans Administration Cooperative Urological Research Group (VACURG): Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 124: 1011–1017, 1967
Hedlund PO, Gustafsson H, Sjogren S: Cardiovascular complications to treatment of prostatic cancer with estramustine phosphate (Estracyt) or conventional oestrogen. A follow-up of 212 randomized patients. Scand J Urol Nephrol [Suppl] 55: 103–105, 1980
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Labrie, F., Dupont, A., Bélanger, A. et al. Combination therapy in stage C and D prostatic cancer: rationale and five-year clinical experience. Cancer Metast Rev 6, 615–636 (1987). https://doi.org/10.1007/BF00047470
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DOI: https://doi.org/10.1007/BF00047470