British Journal of Uro/ogy (1992),70, Suppl 1,33-38
01992 British Journal of Urology
Challenges in the Management of Prostate Cancer E. D. CHAWFORD Division of Urology, University of Colorado Health Sciences Center, Denver, Colorado, USA
Summary-An estimated 32,000 American men will die of prostate cancer this year. Local prostate cancer may be successfully treated by radical prostatectomy or radiotherapy. Advanced cases may necessitate the use of hormonal ablation with bilateral orchiectomy, an approach that is regarded as the gold standard of therapy but not always the preferred treatment of patients. Oestrogen therapy is an alternative but is associated with side effects, such as hot flushes and gynaecomastia, which frequently lead to treatment cessation. Luteinising hormone-releasinghormone (LH RH) analogues work by initially producing a surge of androgen, followed by a down-regulation in hormone production to effect a medical castration. Various groups have studied the effects of androgen blockade administered as monotherapy and as combination therapy (LH RH analogue plus antiandrogen). The National Cancer Institute intergroup protocol 0036, which is the largest cooperative study to date of patients with advanced prostatic cancer, showed that combination therapy with leuprolide and flutamide offered greater benefit in both time to disease progression and median survival while circumventing tumour flare and its associated symptoms. Thus, combination therapy for total androgen ablation may become the new treatment standard for advanced prostatic cancer, pending further studies in the efficacy and cost-effectiveness of all available treatments.
or by bilateral orchiectomy. Huggins was awarded a Nobel Prize for this work in 1953; bilateral orchiectomy has since become the gold standard treatment for this condition. While surgical castration would be accepted by most patients, it may not be their treatment preference, all things being equal. Cassileth et al. (1989) reported in their multicentre study in the United States that patients offered a choice between orchiectomy or current hormonal therapy chose the non-surgical modality more than 78% of the time. In reality, all things are not equal between the various treatments. Bilateral orchiectomy has few associated complications, can be performed easily under local anaesthesia if necessary, and is relatively low in cost. Side effects include impotence Overview of Treatment Methods (which is common to most current theraties) and As early as 1941, Huggins and Hodges demon- hot flushes. The effectiveness of this therapy is strated that progression of prostatic cancer could based on the fact that the testes produce approxibe slowed by hormonal intervention. Because mately 95% of the circulating androgens. prostatic cancer cell growth generally correlates Historically, oestrogen therapy as a non-invasive with androgen levels, Huggins and Hodges reduced alternative to orchiectomy has also been shown patient androgen levels by injection of oestrogens effectively to reduce testosterone to castrate levels
The National Cancer Institute estimates that 132,000 new cases of prostate cancer will be diagnosed this year in the United States alone (Boring et al., 1992). Furthermore, an estimated 34,000 American men will die of prostate cancer. Although radical prostatectomy or radiotherapy is frequently successful in treating carcinoma that is confined to the prostate, only 60% of all patients with prostatic cancer initially present with carcinoma that is still localised (Boring et al., 1992). Treatment beyond radiotherapy or localised surgery is therefore required for a substantial number of patients with advanced prostatic cancer.
33
34 within 7-21 days. This reduction occurs as oestrogens suppress the secretion from the hypothalamus of luteinising hormone-releasing hormone (LHRH). Without this suppression, LHRH would act on the pituitary to cause secretion of LH. LH would then stimulate the testes to produce testosterone. However, although oestrogen has been shown to effectively reduce the level of circulating androgens, its effectiveness must be weighed against any associated cardiovascular risk. A study by Henriksson and Edhag (1986) found that 25% of patients experienced a serious cardiovascular event necessitating hospitalisation within a mean of 5 months after initiation of oestrogen therapy. In contrast, no such events were associated with orchiectomy. Recent work in titrating the maintenance dose of oestrogen to a more tolerable level has revealed, for example, that diethylstilboestrol (DES) administered daily as a 3 mg dose was safer than the traditional 5 mg dose, while still reasonably effective in reducing the serum testosterone to anorchid levels (Prout et al., 1976; Resnick, 1984; Stege et al., 1989). Other side effects of this treatment include nausea and vomiting, gynaecomastia, breast tenderness and hot flushes. Other works examining the role of oestrogen in male development have shown that oestrogens may actually act in synergy with androgens or possibly even act alone to stimulate prostate cell growth (Mawhinney and Neubauer, 1979; Thompson et al., 1979). Additionally, tissue concentrations of oestrogens have been found to be higher in prostates with neoplasms than in those with benign prostatic hyperplasia (Ghanadian and Puah, 1981). These findings may indicate that oestrogen therapy for prostatic cancer may need to be re-examined. A newer hormonal method of reducing the level of testosterone uses LHRH analogues, which have been shown to be approximately 100 times more potent than natural LHRH. Long-term use of these potent hormones eventually desensitises the pituitary to hormonal stimulation, paradoxically but effectively down-regulating the production of testicular testosterone. Numerous studies have shown therapy with LHRH analogues such as leuprolide (Lupron, TAP Pharmaceuticals, Bannockburn, USA) or goserelin (Zoladex, ICI Pharma, Wilmington, USA) to be as effective as orchiectomy or oestrogen therapy in reducing testosterone levels (Warner et al., 1983; Sharifi, 1985; Ahmann et al., 1987; Murphy et al., 1987; Seely, 1987; Beacock, 1988; Borgmann et al., 1988; Debruyne et al., 1988; Kotake et al., 1988; Solowayet al., 1988; Waxman,
BRITISH JOURNAL OF UROLOGY
1988; Peeling, 1989). Surgery is avoided, and many of the serious side effects of oestrogen therapy, including cardiovascular effects, are significantly reduced. A randomised, multicentre study compared the effects of leuprolide versus DES and found no significant difference between treatment groups in time to disease progression (Leuprolide Study Group, 1984). However, a significantly higher incidence of side effects such as peripheral oedema, nausea and vomiting, gynaecomastia and hot flushes was experienced by the oestrogen group. This group also had a greater trend toward deep venous thrombosis, phlebitis and pulmonary embolus. Mean survival time was not established at the time of publication of the study. A similar study with goserelin also showed minimal side effects, with efficacy equivalent to that of oestrogen therapy. Other studies indicate that LHRH may decrease testosterone through more than one route. Although the primary site of action for LHRH is the pituitary gland, some evidence indicates that secondary LHRH receptors in the testes and the prostate may also help to decrease testosterone levels.
Aetiology and Management of Metastatic Disease Although there have been significant advances in the management of prostate cancer, patient mortality due to metastatic disease is still high 5 years after diagnosis. Two theories have been advanced to explain the metastasis of prostate cancer, which develops despite the low circulating levels of testosterone. Both theories are based on the idea that tumour cells are heterogenous in the amount of androgen that they require for growth. The first theory states that surgical or chemical castration inhibits “androgen-dependent’’ cells, or cells that cannot grow without normal levels of testosterone. However, this theory postulates that some cells in the tumour population will, by chance, require a very low level of androgen for growth; such cells are considered to be “androgen-sensitive”. Since traditional treatments for prostatic cancer inhibit production of androgens by the testes without inhibiting hormonal production by the adrenal gland, androgen-sensitive tumour cells might be able to thrive on the low levels of androgens produced by this alternate pathway. Androstenedione, dihydroepiandrostene, and the sulphate derivative of dihydroepiandrostene are the primary adrenal androgens (Labrie et al., 1983). Although these androgens are only 5-10% as potent as testosterone, they normally compose
35
CHALLENGES IN THE MANAGEMENT OF PROSTATE CANCER
approximately 15-20% of the total dihydrotestosterone (DHT) present in the prostate (Harper et al., 1974). In fact, these hormones may be metabolised to testosterone or to DHT either in the plasma or in the prostate itself. Labrie et al. (1987~) reported that after traditional treatment such as orchiectomy or LHRH agonists, as much as 50% of the intraprostatic DHT remained. Furthermore, these adrenal androgens have been shown to aid in the growth of prostatic cells in animal models. Research by Tullner (1963), whose studies involved castrated rats, showed that supplemental adrenocorticotropic hormone (ACTH) promoted growth of the ventral prostate, although no such prostatic growth occurred in adrenalectomised animals. If prostatic cancer progresses as a result of the postulated androgen-sensitive cells, then elimination of the adrenal androgens may slow or halt disease progression. As early as 1945, Huggins and Scott attempted such treatment by performing bilateral adrenalectomy in 4 patients. However, the procedure did not improve patient mortality in this group, probably because of inadequate adrenal hormone replacement therapy at that time. Miller and Hinman first attempted “medical adrenalectomy” through the administration of cortisone treatment in 1954 but the idea of total androgen ablation with the use of anti-androgens was re-popularised by Labrie et al. in the 1980s (Labrie et al., 1983; 1985; 1986b; 1987a; 1987b). A series of studies in the early 1980s showed excellent treatment results, but there were no placebomatched controls (Labrie et al., 1982; Belanger et al., 1984; Labrie and Veilleux, 1986; Labrie et al., 1986a; Labrie et al., 1987b). Opponents of combined androgen ablation propose an alternate hypothesis which states that some prostatic cancer cells are not androgen-sensitive but rather androgen-independent. These cells are believed to require essentially no androgen for growth. In experiments with an androgen-sensitive rat model displaying a tumour classified by the Dunning system, it was found that lowering the testosterone level below 0.25 ng/ml gave no further benefit in tumour growth retardation (Isaacs, 1982; Ellis and Isaacs, 1985). In other words, cells that could proliferate with a minimal level of testosterone also seemed to be capable of proliferating without the presence of testosterone. Furthermore, rat survival rates were no better with combined orchiectomy and anti-androgens than with orchiectomy alone. Various groups trying to reproduce this experiment or similar ones saw different results. Some
found that combination therapy offered no benefit beyond that of monotherapy (Fox and Hammonds, 1980; Brisset et al., 1987; Robinson, 1987); other groups found that combination therapy was advantageous (Trachtenberg et al., 1983; Crawford et al., 1987,1990; Debruyne et af.,1987; Murray and Pitt, 1987; Navratil, 1987; Smith, 1987). The NCI study The National Cancer Institute (NCI) investigated the disparity of opinion regarding combination therapy by setting up the largest co-operative study to date of patients with advanced prostate cancer. Referred to as protocol 0036, it randomised half of the patients to a treatment of leuprolide plus flutamide, a synthetic non-steroidal anti-androgen, and the other half to leuprolide plus placebo. Leuprolide was administered orally on a daily basis, as the depot formulation was not available when the study was initiated. A total of 603 patients were evaluable. The results of this study were published in 1989 (Crawford et al., 1989). Fig. 1 shows the time from study entry to disease progression. Median time to prostatic cancer progession was 3.1 months longer in the group receiving flutamide. Median survival time was 5.8 months longer in this same group (Fig. 2). The results showed obvious benefit with total androgen ablation. Two findings were significant but unexpected in the NCI study. The first finding was the strong correlation of good performance scores upon initial examination, with increased benefit seen after the administration of flutamide. For those patients with poor initial performance scores, there was no benefit to anti-androgen therapy. In fact, those patients given placebo actually had a median time Progression-Free Survival February 1992 0
*OX 60%
Flutarnide
I Placebo
h
\
20%
~
1
0%
’
1
0
I 24
Flutamide Placebo
I
I
I
I
I
I
”
48 Months After Registration
At Risk 303 300
Events 245 247
I 72
1
1
I 96
Median In Months 16.9 13.8
Fig. 1 Time from study entry to progressionof prostatic cancer.
36
BRITISH JOURNAL OF UROLOGY Overall Survival February 1 9 9 2
-
:::I
0 Flutamide
Placebo
20% 0%
i
i
I
I
I
0
I
24
I
I
I
I
I
48 Months After Registration
At Risk
Flutamide Placebo
I
Events 230 238
303 300
I
I I
20%
I
72
I
-
-
96
Median in Months 35.1 29.3
Fig. 2 Survival time for patients with prostatic cancer
to disease progression that was 0.5 months longer than that of patients given flutamide, as well as median survival time that was 2.6 months longer. Among those patients with good initial performance scores and severe disease, however, leuprolide plus flutamide added 3.2 months to the median time to disease progression and 6.9 months to the median survival time. For those patients with good performance scores and minimal disease, the addition of the anti-androgen added 39.2 months to the time to disease progression, making the median time to progression 58.3 months (Fig. 3). The median survival time for this group was 61.0 months, an increase of 19.5 months over that of the placebo group (Fig. 4). The second surprising finding was that race also seemed to be associated with survival. The median survival time for blacks with prostate cancer was Progression- Free Survival Good-Prognosis Patients
February 1992 0 Good I Good
I
60%E
PS, Min. Dls., Flutamide PS, Min. Dis., Placebo
-
100%
0
80%
,
Black Nonbiack
60%
40%
40%
20% 20% 24
48 Months After Registration
Good PS, Min. Dis., Flutamide Good PS, Mln. Dis., Placebo
At Risk 41 41
Events 23 32
72
96
I-
0% 0
Median in Months 58.3 19.1
Fig.3 Progression of prostatic cancer in relation to initial performance scores (PS) and extent of disease (min. dis., minimal disease).
&
12
24 36 Months After Randomisation
Events Black Nonblack
107 454
89 340
48
60
Median in Months 27.7 33.8
Fig.5 Survival time in black and non-black patients with prostatic cancer.
CHALLENGESIN THE MANAGEMENT OF PROSTATE CANCER
Another advantage of combined androgen blockade therapy is the prevention of the tumour flare that is sometimes associated with LHRH agonists administered alone. Although long-term doses of these hormones eventually desensitise the pituitary, initial doses merely stimulate overproduction of androgen, which can exacerbate hormone-dependent disease. LHRH agonists cause testosterone levels to peak approximately 74 h after initiation of therapy and then to gradually decrease to castrate levels. Although there is no evidence that tumour flare affects the survival rate, combined androgen blockade can alleviate symptoms associated with the phenomenon. These include increased bone pain, increased outlet obstruction, increased serum creatinine concentrations and spinal cord compression. Various other drugs can block and/or alter adrenal androgens. These drugs include anandron, cyproterone acetate, ketoconazole, spironolactone, glucocorticoids and aminoglutethimide. Non-steroidal anti-androgens such as flutamide and anandron exert their effect at the target androgen receptor, regardless of serum levels of testosterone. Thus, they have the potential to inhibit both testicular and adrenal androgens. However, these agents have not been studied as extensively as monotherapy. LHRH therapy with anti-androgens is a controversial treatment for advanced or metastatic prostatic cancer. Previous studies have shown leuprolide and goserelin to be equivalent to bilateral orchiectomy or oestrogen therapy, with fewer side effects than oestrogen therapy. The NCI study confirms the findingsof Labrie and numerous other researchers (Trachtenberg et al., 1983; Crawford et al., 1987;Debruyne etal., 1987; Murrayand Pitt, 1987; Navratil, 1987;Smith, 1987),in whichcombination androgen blockade was found to be more beneficial than monotherapy in terms of median time to disease progression and median survival time. Other studies are needed to address the difference in treatment efficacy between subsets of patients, as well as the cost-effectiveness of the various therapeutic modalities. In the meantime, total androgen ablation may attain status as the new standard of treatment for advanced prostatic cancer. References Ahmann, F. R., Citrin, D. L., deHaan, H. A. e t d . (1987).Zoladex: a sustained-release, monthly luteinizing hormone-releasing hormone analogue for the treatment of advanced prostate cancer. J . Clin. Oncol., 5,912-917.
37
Beacock,C. J. M. (1988). Long-term results of treating advanced prostatic cancer with the LH-RH analogue Zoladex. Am. J . Clin. Oncol., 11(Suppl2), S115-Sl16. Belanger, A., DuPont, A. and Lahrie, F. (1984). Inhibition of basal and adrenocorticotropin-stimulated plasma levels of adrenal androgens after treatment with an antiandrogen in castrated patients with prostatic cancer. J . Endocrinol. Metab., 59,422426. Borgmann, V., Al-Abadi, H. and Nagel, R. (1988). Treatment of locally advanced prostatic carcinoma with LHRH analogues : cytological, DNA-cytophotometrical, and clincal results. Am. J . Clin. Oncol., ll(Supp1 1). S19-S28. Boring, C. C., Squires,T.S. and Tong, T. (1992). Cancer statistics, 1991. Ca-A Cancer J . Clinicians, 41, 19-37. Brisset, J.-M., Boccon-Gibod, L., Botto, H. et al. (1987). Anandron (RU 23908) associated to surgical castration in previously untreated stage D prostate cancer: a multicenter comparative study of two doses of the drug and of a placebo. In Prostate Cancer, Part A : Research, Endocrine Treatment, and Histopathology, ed. Murphy, G . P., Kiiss, R., Khoury, S. et al. Pp. 41 1422. New York: Alan R. Liss. Cassileth, B. R., Soloway, M. S., Vogelzang, N. J. et d.(1989). Patients’ choice of treatment in stage D prostate cancer. Urology, 33(Suppl5), 57-62. Crawford, E. D., Ahmann, F. R., Davis, M. A. et d. (1987). Aminoglutethimide in metastatic adenocarcinoma of the prostate. In Prostate Cancer, Part A : Research, Endocrine Treatment, and Histopathology, ed. Murphy, G . P., Kiiss, R., Khoury, S . e t a [ . Pp. 283-289. New York: Alan R. Liss. Crawford, E. D., Eisenberger, M. A., McLeod, D. G. e t d . (1989). A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N . Engl. J . Med., 321,419424. Crawford, E. D., Goodman, P. and Blumenstein, B. (1990). Combined androgen blockade : leuprolide and flutamide versus leuprolide and placebo. Semin. Urol., 8, 154-158. Debruyne, F. M. J., Denis, L., Lunglmayer, G. etal. (1988). Longterm therapy with a depot luteinizing hormone-releasing hormone analogue (Zoladex) in patients with advanced prostatic carcinoma. J . Urol., 140, 775-777. Debruyne, F. M. J., Witjes, F. A. and the Dutch South-Eastem Urological Cooperative Group. (1987). Ketoconazole high dose (H.D.) in the management of hormonally pretreated patients with progressive metastatic prostate cancer. In Prostate Cancer, Part A :Research, Endocrine Treatment,and Histopathology, ed. Murphy, G . P., Kiiss, R., Khoury, S. etal. Pp. 301313. New York: Alan R. Liss. Ellis, W. and Isaan, J. T. (1985). Effectiveness of complete versus partial androgen withdrawal therapy for the treatment of prostatic cancer as studied in the Dunning R-3327 system of rat prostatic adenocarcinomas. Cancer Res., 45,6041-6050. Fox, M. and Hammonds, J. C. (1980). Palliative effect of cyproterone acetate in carcinoma of the prostate with widespread metastatic bone disease. Br. J . Urol., 52,402. Ghanadian, R. and Puah, C. M. (1981). Relationships between oestradiol-I7beta, testosterone, dihydrotestosterone and 5alpha-androstane-3aIpha, 17beta-diol in human benign hypertrophy and carcinoma of the prostate. J . Endocrinol., 88, 255-262. Harper, M. E., Pike, A., Peeling, W. B. et al. (1974). Steroids of adrenal origin metabolized by human prostate tissue both in vivo and in vitro. J . Endocrinol., 60,117--125. Henriksson, P. and Edhag, 0. (1986). Orchiectomy versus oestrogen for prostatic cancer: cardiovascular effects. Br. Med. J . , 293,413-415. Huggins, C. and Hodges, C. V. (1941). Studies on prostatic cancer. I. The effect of castration, of estrogen, and of androgen
38
BRITISH JOURNAL OF UROLOGY
injection on serum phosphatases in metastatic carcinoma of Navratil, H. (1987). Double-blind study of anandron versus the prostate. Cancer Res., 1,293-297. placebo in stage Dz prostate cancer patients receiving buserelin: results on 49 cases from a multicentre study. In Huggins, C . and Scott, W. W. (1945). Bilateral adrenalectomy in Prostate Cancer, Part A :Research, Endocrine Treatment, and prostatic cancer. Ann. Surg., 122, 1031-1041. Isaacs, J. 'T.(1982). Hormonally responsive versus unresponsive Histopathology, ed. Murphy, G . P., Kiiss, R., Khoury, S . et al. Pp. 401-410. New York: Alan R. Liss. progression of prostatic cancer to antiandrogen therapy as studied with the Dunning R-3327-AT and -G rate adenocar- Peeling, W. B. (1989). Phase 111 studies to compare goserelin cinomas. Cancer Res., 42,5010-5014. (Zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma. Urology, 33(Suppl), 45-52. Kotake, T., Usami, M., Sonoda, T. e t d . (1988). LH-RH agonist, Zoladex (goserelin), depot formulation in the treatment of Prout, G. R., Jr., K h a n , B., Daly, J. J. et al. (1976). Endocrine changes after diethylstilbestrol therapy: effect on prostatic prostatic cancer: randomized dose-finding trial in Japan. Am. neoplasm and pituitary-gonadal axis. Urology, 7, 148-155. J . Clin. Oncol., 11(Suppl2), S108-Slll. Labrie, F., Dupont, A., Belanger, A. el d. (1985). Combination Resnick, M. I. (1984). Hormonal therapy in prostatic carcinoma. therapy with flutamide and castration (LHRH agonist or Urology, 24(Suppl), 18-23. orchiectomy) in advanced prostate cancer: a marked improve- Robinson, M. R. G. (1987). Complete androgen blockade: the ment in response and survival. J . Steroid Biochem. Mol. Biol., EORTC experience comparing orchidectomy versus orchidec23, 833--841. tomy plus cyproterone acetate versus low-dose stilboestrol in the treatment of metastatic carcinoma of the prostate. In Labrie, F., Dupont, A., Belanger. A. et d. (l987a). Flutamide Prostate Cancer, Part A : Research, Endocrine Treatment, and eliminates the risk of disease flare in prostatic cancer patients Histopathology, ed. Murphy, G. P., Kuss, R., Khoury, S. et al. treated with a luteinizing hormone-releasing hormone agonist. Pp. 383-390. New York: Alan R. Liss. J . Urol., 138,804806. Labrie, F., Dupont, A., Belanger. A. e t d . (1983). New approach Seely, J. H. (1987). Phase I11 studies in prostatic cancer with in the treatment of prostate cancer: complete instead of partial leuprolide acetate. Radiology, 8, 5. withdrawal of androgens. Prostate, 4, 579-594. Sharifi, R., Lee, M., Ojeda, L. et d. (1985). Comparison of Labrie, F., Dupont, A., Belanger. A. e t d . (1982). New hormonal leuprolide and diethylstilbestrol for stage D Zadenocarcinoma therapy in prostatic carcinoma: combined treatment with an of the prostate. Urology, 26, 117-124. LHRH agonist and an antiandrogen. Clin. Invest. Med., 5 , Smith, J. A. (1987). New methods of endocrine management of prostatic cancer. J . Urol.,137, 1-9. 267-215. Labrie, F., Dupont, A., Belanger. A. et d. (1986a). Treatment of Soloway, M. S. and the Busereli Protocol 301 Study Group. prostate cancer with gonadotropin-releasing hormone ago(1988). Efficacy of buserelin in advanced prostate cancer and nists. Endocr. Rev., 7,67-74. comparison with historical controls. Am. J . Clin. Oncol., Labrie, F., Dupont, A., Giguere, M. e t d . (1986b). Advantages of 11(Suppl), S29-S32. Stege, R., Carlstrom, K., Collste, L. et d. (1989). Single-drug the combination therapy in previously untreated and treated parenteral estrogen treatment in prostatic cancer: a study of patients with advanced prostate cancer. J . Steroid Biochem two maintenance-dose regimens. Prostate, 14, 183-1 88. Mol. Biol., 25, 877-883. Labrie, F., Dupont, A., Giguere, M. e t d . (1987b). Combination Thompson, S. A., Rowley, D. R. and Heidger, P. M. (1979). therapy with flutamide and castration (orchiectomyor LHRH Effects of estrogen upon the fine structure of epithelium and agonist): the minimal endocrine therapy in both untreated stroma in the rat ventral prostate gland. Invest. Urol., 17, and previously treated patients. J . Steroid Biochem Mol. Biol., 83-89. 27, 525--532. Trachtenberg,J., Halpern, N. and Pont, A. (1983). Ketoconazole: Labrie, F., Luthy, I., Veilleux, R. et d. (1987~).New concepts on a novel and rapid treatment for advanced prostatic cancer. J . the androgen sensitivity of prostate cancer. In Prostate Cancer, Urol., 130, 152-153. Tullner, W. W. (1963). Hormonal factors in the adrenalPart A . Research, Endocrine Treatment, and Histopathology, dependent growth of the rat ventral prostate. NCI Monogr., ed. Murphy, G. P., Kuss, R., Khoury, S. et al. Pp. 145-172. New York: Alan R. Liss. 12,211-223. Labrie, F. and Veilleux, R. (1986). A wide range of sensitivities Warner, B., Worgul, T. J., Drago, J. e t d . (1983). Effect of very to androgens develops in cloned Shionogi mouse mammary high dose d-leucine6-gonadotropin-releasinghormone protumor cells. Prostate, 8, 293-300. ethylamide on the hypothalamic-pituitary testicular axis in Leuprolide Study Group. (1984). Leuprolide versus diethylstilpatients with prostatic cancer. J . Clin. Invest., 71, 1842-1853. bestrol for metastatic prostate cancer. N . Engl. J . Med., 311, Waxman, J. (1988). A review of the Hammersmith Hospital, St. 1281-1286. Bartholomew's Hospital and Institute of Urology studies of Mawhinney, M. G. and Neubauer, B. L. (1979). Actions of buserelin in advanced prostatic cancer. Am. J . Clin. Oncol., estrogen in the male. Invest. Urol., 16,409-420. ll(Supp1 l), S16-Sl8. Miller, G. M. and Hinman, F., Jr. (1954). Cortisone treatment in advanced carcinoma of the prostate. J . Urol.,72,485495. Murphy, G . P., Greco, J. M., Chin, J. L. et d. (1987). Zoladex (ICI 1 18,630): clinical trial of new luteinizing hormone- The Author releasing hormone analog in metastatic prostatic carcinoma. E. D. Crawford, MD, Professor and Chairman, Division of Urologj, 29, 185-190. Urology. Murray, B. and Pitt, P. (1987). Aminoglutethimide in the treatment of advanced prostatic cancer. In Prostate Cancer, Part A . Research, Endocrine Treatment, and Histopathology, Requests for reprints to: E. D. Crawford, Division of Urology, University of Colorado Health Sciences Center, Campus Box ed. Murphy, G . P., Kuss, R., Khoury, S . et al. Pp. 275-282. C-319,4200 East Ninth Avenue, Denver, CO 80262, USA. New York: Alan R. Liss.
01992 British Journal of Urology
Challenges in the Management of Prostate Cancer E. D. CHAWFORD Division of Urology, University of Colorado Health Sciences Center, Denver, Colorado, USA
Summary-An estimated 32,000 American men will die of prostate cancer this year. Local prostate cancer may be successfully treated by radical prostatectomy or radiotherapy. Advanced cases may necessitate the use of hormonal ablation with bilateral orchiectomy, an approach that is regarded as the gold standard of therapy but not always the preferred treatment of patients. Oestrogen therapy is an alternative but is associated with side effects, such as hot flushes and gynaecomastia, which frequently lead to treatment cessation. Luteinising hormone-releasinghormone (LH RH) analogues work by initially producing a surge of androgen, followed by a down-regulation in hormone production to effect a medical castration. Various groups have studied the effects of androgen blockade administered as monotherapy and as combination therapy (LH RH analogue plus antiandrogen). The National Cancer Institute intergroup protocol 0036, which is the largest cooperative study to date of patients with advanced prostatic cancer, showed that combination therapy with leuprolide and flutamide offered greater benefit in both time to disease progression and median survival while circumventing tumour flare and its associated symptoms. Thus, combination therapy for total androgen ablation may become the new treatment standard for advanced prostatic cancer, pending further studies in the efficacy and cost-effectiveness of all available treatments.
or by bilateral orchiectomy. Huggins was awarded a Nobel Prize for this work in 1953; bilateral orchiectomy has since become the gold standard treatment for this condition. While surgical castration would be accepted by most patients, it may not be their treatment preference, all things being equal. Cassileth et al. (1989) reported in their multicentre study in the United States that patients offered a choice between orchiectomy or current hormonal therapy chose the non-surgical modality more than 78% of the time. In reality, all things are not equal between the various treatments. Bilateral orchiectomy has few associated complications, can be performed easily under local anaesthesia if necessary, and is relatively low in cost. Side effects include impotence Overview of Treatment Methods (which is common to most current theraties) and As early as 1941, Huggins and Hodges demon- hot flushes. The effectiveness of this therapy is strated that progression of prostatic cancer could based on the fact that the testes produce approxibe slowed by hormonal intervention. Because mately 95% of the circulating androgens. prostatic cancer cell growth generally correlates Historically, oestrogen therapy as a non-invasive with androgen levels, Huggins and Hodges reduced alternative to orchiectomy has also been shown patient androgen levels by injection of oestrogens effectively to reduce testosterone to castrate levels
The National Cancer Institute estimates that 132,000 new cases of prostate cancer will be diagnosed this year in the United States alone (Boring et al., 1992). Furthermore, an estimated 34,000 American men will die of prostate cancer. Although radical prostatectomy or radiotherapy is frequently successful in treating carcinoma that is confined to the prostate, only 60% of all patients with prostatic cancer initially present with carcinoma that is still localised (Boring et al., 1992). Treatment beyond radiotherapy or localised surgery is therefore required for a substantial number of patients with advanced prostatic cancer.
33
34 within 7-21 days. This reduction occurs as oestrogens suppress the secretion from the hypothalamus of luteinising hormone-releasing hormone (LHRH). Without this suppression, LHRH would act on the pituitary to cause secretion of LH. LH would then stimulate the testes to produce testosterone. However, although oestrogen has been shown to effectively reduce the level of circulating androgens, its effectiveness must be weighed against any associated cardiovascular risk. A study by Henriksson and Edhag (1986) found that 25% of patients experienced a serious cardiovascular event necessitating hospitalisation within a mean of 5 months after initiation of oestrogen therapy. In contrast, no such events were associated with orchiectomy. Recent work in titrating the maintenance dose of oestrogen to a more tolerable level has revealed, for example, that diethylstilboestrol (DES) administered daily as a 3 mg dose was safer than the traditional 5 mg dose, while still reasonably effective in reducing the serum testosterone to anorchid levels (Prout et al., 1976; Resnick, 1984; Stege et al., 1989). Other side effects of this treatment include nausea and vomiting, gynaecomastia, breast tenderness and hot flushes. Other works examining the role of oestrogen in male development have shown that oestrogens may actually act in synergy with androgens or possibly even act alone to stimulate prostate cell growth (Mawhinney and Neubauer, 1979; Thompson et al., 1979). Additionally, tissue concentrations of oestrogens have been found to be higher in prostates with neoplasms than in those with benign prostatic hyperplasia (Ghanadian and Puah, 1981). These findings may indicate that oestrogen therapy for prostatic cancer may need to be re-examined. A newer hormonal method of reducing the level of testosterone uses LHRH analogues, which have been shown to be approximately 100 times more potent than natural LHRH. Long-term use of these potent hormones eventually desensitises the pituitary to hormonal stimulation, paradoxically but effectively down-regulating the production of testicular testosterone. Numerous studies have shown therapy with LHRH analogues such as leuprolide (Lupron, TAP Pharmaceuticals, Bannockburn, USA) or goserelin (Zoladex, ICI Pharma, Wilmington, USA) to be as effective as orchiectomy or oestrogen therapy in reducing testosterone levels (Warner et al., 1983; Sharifi, 1985; Ahmann et al., 1987; Murphy et al., 1987; Seely, 1987; Beacock, 1988; Borgmann et al., 1988; Debruyne et al., 1988; Kotake et al., 1988; Solowayet al., 1988; Waxman,
BRITISH JOURNAL OF UROLOGY
1988; Peeling, 1989). Surgery is avoided, and many of the serious side effects of oestrogen therapy, including cardiovascular effects, are significantly reduced. A randomised, multicentre study compared the effects of leuprolide versus DES and found no significant difference between treatment groups in time to disease progression (Leuprolide Study Group, 1984). However, a significantly higher incidence of side effects such as peripheral oedema, nausea and vomiting, gynaecomastia and hot flushes was experienced by the oestrogen group. This group also had a greater trend toward deep venous thrombosis, phlebitis and pulmonary embolus. Mean survival time was not established at the time of publication of the study. A similar study with goserelin also showed minimal side effects, with efficacy equivalent to that of oestrogen therapy. Other studies indicate that LHRH may decrease testosterone through more than one route. Although the primary site of action for LHRH is the pituitary gland, some evidence indicates that secondary LHRH receptors in the testes and the prostate may also help to decrease testosterone levels.
Aetiology and Management of Metastatic Disease Although there have been significant advances in the management of prostate cancer, patient mortality due to metastatic disease is still high 5 years after diagnosis. Two theories have been advanced to explain the metastasis of prostate cancer, which develops despite the low circulating levels of testosterone. Both theories are based on the idea that tumour cells are heterogenous in the amount of androgen that they require for growth. The first theory states that surgical or chemical castration inhibits “androgen-dependent’’ cells, or cells that cannot grow without normal levels of testosterone. However, this theory postulates that some cells in the tumour population will, by chance, require a very low level of androgen for growth; such cells are considered to be “androgen-sensitive”. Since traditional treatments for prostatic cancer inhibit production of androgens by the testes without inhibiting hormonal production by the adrenal gland, androgen-sensitive tumour cells might be able to thrive on the low levels of androgens produced by this alternate pathway. Androstenedione, dihydroepiandrostene, and the sulphate derivative of dihydroepiandrostene are the primary adrenal androgens (Labrie et al., 1983). Although these androgens are only 5-10% as potent as testosterone, they normally compose
35
CHALLENGES IN THE MANAGEMENT OF PROSTATE CANCER
approximately 15-20% of the total dihydrotestosterone (DHT) present in the prostate (Harper et al., 1974). In fact, these hormones may be metabolised to testosterone or to DHT either in the plasma or in the prostate itself. Labrie et al. (1987~) reported that after traditional treatment such as orchiectomy or LHRH agonists, as much as 50% of the intraprostatic DHT remained. Furthermore, these adrenal androgens have been shown to aid in the growth of prostatic cells in animal models. Research by Tullner (1963), whose studies involved castrated rats, showed that supplemental adrenocorticotropic hormone (ACTH) promoted growth of the ventral prostate, although no such prostatic growth occurred in adrenalectomised animals. If prostatic cancer progresses as a result of the postulated androgen-sensitive cells, then elimination of the adrenal androgens may slow or halt disease progression. As early as 1945, Huggins and Scott attempted such treatment by performing bilateral adrenalectomy in 4 patients. However, the procedure did not improve patient mortality in this group, probably because of inadequate adrenal hormone replacement therapy at that time. Miller and Hinman first attempted “medical adrenalectomy” through the administration of cortisone treatment in 1954 but the idea of total androgen ablation with the use of anti-androgens was re-popularised by Labrie et al. in the 1980s (Labrie et al., 1983; 1985; 1986b; 1987a; 1987b). A series of studies in the early 1980s showed excellent treatment results, but there were no placebomatched controls (Labrie et al., 1982; Belanger et al., 1984; Labrie and Veilleux, 1986; Labrie et al., 1986a; Labrie et al., 1987b). Opponents of combined androgen ablation propose an alternate hypothesis which states that some prostatic cancer cells are not androgen-sensitive but rather androgen-independent. These cells are believed to require essentially no androgen for growth. In experiments with an androgen-sensitive rat model displaying a tumour classified by the Dunning system, it was found that lowering the testosterone level below 0.25 ng/ml gave no further benefit in tumour growth retardation (Isaacs, 1982; Ellis and Isaacs, 1985). In other words, cells that could proliferate with a minimal level of testosterone also seemed to be capable of proliferating without the presence of testosterone. Furthermore, rat survival rates were no better with combined orchiectomy and anti-androgens than with orchiectomy alone. Various groups trying to reproduce this experiment or similar ones saw different results. Some
found that combination therapy offered no benefit beyond that of monotherapy (Fox and Hammonds, 1980; Brisset et al., 1987; Robinson, 1987); other groups found that combination therapy was advantageous (Trachtenberg et al., 1983; Crawford et al., 1987,1990; Debruyne et af.,1987; Murray and Pitt, 1987; Navratil, 1987; Smith, 1987). The NCI study The National Cancer Institute (NCI) investigated the disparity of opinion regarding combination therapy by setting up the largest co-operative study to date of patients with advanced prostate cancer. Referred to as protocol 0036, it randomised half of the patients to a treatment of leuprolide plus flutamide, a synthetic non-steroidal anti-androgen, and the other half to leuprolide plus placebo. Leuprolide was administered orally on a daily basis, as the depot formulation was not available when the study was initiated. A total of 603 patients were evaluable. The results of this study were published in 1989 (Crawford et al., 1989). Fig. 1 shows the time from study entry to disease progression. Median time to prostatic cancer progession was 3.1 months longer in the group receiving flutamide. Median survival time was 5.8 months longer in this same group (Fig. 2). The results showed obvious benefit with total androgen ablation. Two findings were significant but unexpected in the NCI study. The first finding was the strong correlation of good performance scores upon initial examination, with increased benefit seen after the administration of flutamide. For those patients with poor initial performance scores, there was no benefit to anti-androgen therapy. In fact, those patients given placebo actually had a median time Progression-Free Survival February 1992 0
*OX 60%
Flutarnide
I Placebo
h
\
20%
~
1
0%
’
1
0
I 24
Flutamide Placebo
I
I
I
I
I
I
”
48 Months After Registration
At Risk 303 300
Events 245 247
I 72
1
1
I 96
Median In Months 16.9 13.8
Fig. 1 Time from study entry to progressionof prostatic cancer.
36
BRITISH JOURNAL OF UROLOGY Overall Survival February 1 9 9 2
-
:::I
0 Flutamide
Placebo
20% 0%
i
i
I
I
I
0
I
24
I
I
I
I
I
48 Months After Registration
At Risk
Flutamide Placebo
I
Events 230 238
303 300
I
I I
20%
I
72
I
-
-
96
Median in Months 35.1 29.3
Fig. 2 Survival time for patients with prostatic cancer
to disease progression that was 0.5 months longer than that of patients given flutamide, as well as median survival time that was 2.6 months longer. Among those patients with good initial performance scores and severe disease, however, leuprolide plus flutamide added 3.2 months to the median time to disease progression and 6.9 months to the median survival time. For those patients with good performance scores and minimal disease, the addition of the anti-androgen added 39.2 months to the time to disease progression, making the median time to progression 58.3 months (Fig. 3). The median survival time for this group was 61.0 months, an increase of 19.5 months over that of the placebo group (Fig. 4). The second surprising finding was that race also seemed to be associated with survival. The median survival time for blacks with prostate cancer was Progression- Free Survival Good-Prognosis Patients
February 1992 0 Good I Good
I
60%E
PS, Min. Dls., Flutamide PS, Min. Dis., Placebo
-
100%
0
80%
,
Black Nonbiack
60%
40%
40%
20% 20% 24
48 Months After Registration
Good PS, Min. Dis., Flutamide Good PS, Mln. Dis., Placebo
At Risk 41 41
Events 23 32
72
96
I-
0% 0
Median in Months 58.3 19.1
Fig.3 Progression of prostatic cancer in relation to initial performance scores (PS) and extent of disease (min. dis., minimal disease).
&
12
24 36 Months After Randomisation
Events Black Nonblack
107 454
89 340
48
60
Median in Months 27.7 33.8
Fig.5 Survival time in black and non-black patients with prostatic cancer.
CHALLENGESIN THE MANAGEMENT OF PROSTATE CANCER
Another advantage of combined androgen blockade therapy is the prevention of the tumour flare that is sometimes associated with LHRH agonists administered alone. Although long-term doses of these hormones eventually desensitise the pituitary, initial doses merely stimulate overproduction of androgen, which can exacerbate hormone-dependent disease. LHRH agonists cause testosterone levels to peak approximately 74 h after initiation of therapy and then to gradually decrease to castrate levels. Although there is no evidence that tumour flare affects the survival rate, combined androgen blockade can alleviate symptoms associated with the phenomenon. These include increased bone pain, increased outlet obstruction, increased serum creatinine concentrations and spinal cord compression. Various other drugs can block and/or alter adrenal androgens. These drugs include anandron, cyproterone acetate, ketoconazole, spironolactone, glucocorticoids and aminoglutethimide. Non-steroidal anti-androgens such as flutamide and anandron exert their effect at the target androgen receptor, regardless of serum levels of testosterone. Thus, they have the potential to inhibit both testicular and adrenal androgens. However, these agents have not been studied as extensively as monotherapy. LHRH therapy with anti-androgens is a controversial treatment for advanced or metastatic prostatic cancer. Previous studies have shown leuprolide and goserelin to be equivalent to bilateral orchiectomy or oestrogen therapy, with fewer side effects than oestrogen therapy. The NCI study confirms the findingsof Labrie and numerous other researchers (Trachtenberg et al., 1983; Crawford et al., 1987;Debruyne etal., 1987; Murrayand Pitt, 1987; Navratil, 1987;Smith, 1987),in whichcombination androgen blockade was found to be more beneficial than monotherapy in terms of median time to disease progression and median survival time. Other studies are needed to address the difference in treatment efficacy between subsets of patients, as well as the cost-effectiveness of the various therapeutic modalities. In the meantime, total androgen ablation may attain status as the new standard of treatment for advanced prostatic cancer. References Ahmann, F. R., Citrin, D. L., deHaan, H. A. e t d . (1987).Zoladex: a sustained-release, monthly luteinizing hormone-releasing hormone analogue for the treatment of advanced prostate cancer. J . Clin. Oncol., 5,912-917.
37
Beacock,C. J. M. (1988). Long-term results of treating advanced prostatic cancer with the LH-RH analogue Zoladex. Am. J . Clin. Oncol., 11(Suppl2), S115-Sl16. Belanger, A., DuPont, A. and Lahrie, F. (1984). Inhibition of basal and adrenocorticotropin-stimulated plasma levels of adrenal androgens after treatment with an antiandrogen in castrated patients with prostatic cancer. J . Endocrinol. Metab., 59,422426. Borgmann, V., Al-Abadi, H. and Nagel, R. (1988). Treatment of locally advanced prostatic carcinoma with LHRH analogues : cytological, DNA-cytophotometrical, and clincal results. Am. J . Clin. Oncol., ll(Supp1 1). S19-S28. Boring, C. C., Squires,T.S. and Tong, T. (1992). Cancer statistics, 1991. Ca-A Cancer J . Clinicians, 41, 19-37. Brisset, J.-M., Boccon-Gibod, L., Botto, H. et al. (1987). Anandron (RU 23908) associated to surgical castration in previously untreated stage D prostate cancer: a multicenter comparative study of two doses of the drug and of a placebo. In Prostate Cancer, Part A : Research, Endocrine Treatment, and Histopathology, ed. Murphy, G . P., Kiiss, R., Khoury, S. et al. Pp. 41 1422. New York: Alan R. Liss. Cassileth, B. R., Soloway, M. S., Vogelzang, N. J. et d.(1989). Patients’ choice of treatment in stage D prostate cancer. Urology, 33(Suppl5), 57-62. Crawford, E. D., Ahmann, F. R., Davis, M. A. et d. (1987). Aminoglutethimide in metastatic adenocarcinoma of the prostate. In Prostate Cancer, Part A : Research, Endocrine Treatment, and Histopathology, ed. Murphy, G . P., Kiiss, R., Khoury, S . e t a [ . Pp. 283-289. New York: Alan R. Liss. Crawford, E. D., Eisenberger, M. A., McLeod, D. G. e t d . (1989). A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N . Engl. J . Med., 321,419424. Crawford, E. D., Goodman, P. and Blumenstein, B. (1990). Combined androgen blockade : leuprolide and flutamide versus leuprolide and placebo. Semin. Urol., 8, 154-158. Debruyne, F. M. J., Denis, L., Lunglmayer, G. etal. (1988). Longterm therapy with a depot luteinizing hormone-releasing hormone analogue (Zoladex) in patients with advanced prostatic carcinoma. J . Urol., 140, 775-777. Debruyne, F. M. J., Witjes, F. A. and the Dutch South-Eastem Urological Cooperative Group. (1987). Ketoconazole high dose (H.D.) in the management of hormonally pretreated patients with progressive metastatic prostate cancer. In Prostate Cancer, Part A :Research, Endocrine Treatment,and Histopathology, ed. Murphy, G . P., Kiiss, R., Khoury, S. etal. Pp. 301313. New York: Alan R. Liss. Ellis, W. and Isaan, J. T. (1985). Effectiveness of complete versus partial androgen withdrawal therapy for the treatment of prostatic cancer as studied in the Dunning R-3327 system of rat prostatic adenocarcinomas. Cancer Res., 45,6041-6050. Fox, M. and Hammonds, J. C. (1980). Palliative effect of cyproterone acetate in carcinoma of the prostate with widespread metastatic bone disease. Br. J . Urol., 52,402. Ghanadian, R. and Puah, C. M. (1981). Relationships between oestradiol-I7beta, testosterone, dihydrotestosterone and 5alpha-androstane-3aIpha, 17beta-diol in human benign hypertrophy and carcinoma of the prostate. J . Endocrinol., 88, 255-262. Harper, M. E., Pike, A., Peeling, W. B. et al. (1974). Steroids of adrenal origin metabolized by human prostate tissue both in vivo and in vitro. J . Endocrinol., 60,117--125. Henriksson, P. and Edhag, 0. (1986). Orchiectomy versus oestrogen for prostatic cancer: cardiovascular effects. Br. Med. J . , 293,413-415. Huggins, C. and Hodges, C. V. (1941). Studies on prostatic cancer. I. The effect of castration, of estrogen, and of androgen
38
BRITISH JOURNAL OF UROLOGY
injection on serum phosphatases in metastatic carcinoma of Navratil, H. (1987). Double-blind study of anandron versus the prostate. Cancer Res., 1,293-297. placebo in stage Dz prostate cancer patients receiving buserelin: results on 49 cases from a multicentre study. In Huggins, C . and Scott, W. W. (1945). Bilateral adrenalectomy in Prostate Cancer, Part A :Research, Endocrine Treatment, and prostatic cancer. Ann. Surg., 122, 1031-1041. Isaacs, J. 'T.(1982). Hormonally responsive versus unresponsive Histopathology, ed. Murphy, G . P., Kiiss, R., Khoury, S . et al. Pp. 401-410. New York: Alan R. Liss. progression of prostatic cancer to antiandrogen therapy as studied with the Dunning R-3327-AT and -G rate adenocar- Peeling, W. B. (1989). Phase 111 studies to compare goserelin cinomas. Cancer Res., 42,5010-5014. (Zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma. Urology, 33(Suppl), 45-52. Kotake, T., Usami, M., Sonoda, T. e t d . (1988). LH-RH agonist, Zoladex (goserelin), depot formulation in the treatment of Prout, G. R., Jr., K h a n , B., Daly, J. J. et al. (1976). Endocrine changes after diethylstilbestrol therapy: effect on prostatic prostatic cancer: randomized dose-finding trial in Japan. Am. neoplasm and pituitary-gonadal axis. Urology, 7, 148-155. J . Clin. Oncol., 11(Suppl2), S108-Slll. Labrie, F., Dupont, A., Belanger, A. el d. (1985). Combination Resnick, M. I. (1984). Hormonal therapy in prostatic carcinoma. therapy with flutamide and castration (LHRH agonist or Urology, 24(Suppl), 18-23. orchiectomy) in advanced prostate cancer: a marked improve- Robinson, M. R. G. (1987). Complete androgen blockade: the ment in response and survival. J . Steroid Biochem. Mol. Biol., EORTC experience comparing orchidectomy versus orchidec23, 833--841. tomy plus cyproterone acetate versus low-dose stilboestrol in the treatment of metastatic carcinoma of the prostate. In Labrie, F., Dupont, A., Belanger. A. et d. (l987a). Flutamide Prostate Cancer, Part A : Research, Endocrine Treatment, and eliminates the risk of disease flare in prostatic cancer patients Histopathology, ed. Murphy, G. P., Kuss, R., Khoury, S. et al. treated with a luteinizing hormone-releasing hormone agonist. Pp. 383-390. New York: Alan R. Liss. J . Urol., 138,804806. Labrie, F., Dupont, A., Belanger. A. e t d . (1983). New approach Seely, J. H. (1987). Phase I11 studies in prostatic cancer with in the treatment of prostate cancer: complete instead of partial leuprolide acetate. Radiology, 8, 5. withdrawal of androgens. Prostate, 4, 579-594. Sharifi, R., Lee, M., Ojeda, L. et d. (1985). Comparison of Labrie, F., Dupont, A., Belanger. A. e t d . (1982). New hormonal leuprolide and diethylstilbestrol for stage D Zadenocarcinoma therapy in prostatic carcinoma: combined treatment with an of the prostate. Urology, 26, 117-124. LHRH agonist and an antiandrogen. Clin. Invest. Med., 5 , Smith, J. A. (1987). New methods of endocrine management of prostatic cancer. J . Urol.,137, 1-9. 267-215. Labrie, F., Dupont, A., Belanger. A. et d. (1986a). Treatment of Soloway, M. S. and the Busereli Protocol 301 Study Group. prostate cancer with gonadotropin-releasing hormone ago(1988). Efficacy of buserelin in advanced prostate cancer and nists. Endocr. Rev., 7,67-74. comparison with historical controls. Am. J . Clin. Oncol., Labrie, F., Dupont, A., Giguere, M. e t d . (1986b). Advantages of 11(Suppl), S29-S32. Stege, R., Carlstrom, K., Collste, L. et d. (1989). Single-drug the combination therapy in previously untreated and treated parenteral estrogen treatment in prostatic cancer: a study of patients with advanced prostate cancer. J . Steroid Biochem two maintenance-dose regimens. Prostate, 14, 183-1 88. Mol. Biol., 25, 877-883. Labrie, F., Dupont, A., Giguere, M. e t d . (1987b). Combination Thompson, S. A., Rowley, D. R. and Heidger, P. M. (1979). therapy with flutamide and castration (orchiectomyor LHRH Effects of estrogen upon the fine structure of epithelium and agonist): the minimal endocrine therapy in both untreated stroma in the rat ventral prostate gland. Invest. Urol., 17, and previously treated patients. J . Steroid Biochem Mol. Biol., 83-89. 27, 525--532. Trachtenberg,J., Halpern, N. and Pont, A. (1983). Ketoconazole: Labrie, F., Luthy, I., Veilleux, R. et d. (1987~).New concepts on a novel and rapid treatment for advanced prostatic cancer. J . the androgen sensitivity of prostate cancer. In Prostate Cancer, Urol., 130, 152-153. Tullner, W. W. (1963). Hormonal factors in the adrenalPart A . Research, Endocrine Treatment, and Histopathology, dependent growth of the rat ventral prostate. NCI Monogr., ed. Murphy, G. P., Kuss, R., Khoury, S. et al. Pp. 145-172. New York: Alan R. Liss. 12,211-223. Labrie, F. and Veilleux, R. (1986). A wide range of sensitivities Warner, B., Worgul, T. J., Drago, J. e t d . (1983). Effect of very to androgens develops in cloned Shionogi mouse mammary high dose d-leucine6-gonadotropin-releasinghormone protumor cells. Prostate, 8, 293-300. ethylamide on the hypothalamic-pituitary testicular axis in Leuprolide Study Group. (1984). Leuprolide versus diethylstilpatients with prostatic cancer. J . Clin. Invest., 71, 1842-1853. bestrol for metastatic prostate cancer. N . Engl. J . Med., 311, Waxman, J. (1988). A review of the Hammersmith Hospital, St. 1281-1286. Bartholomew's Hospital and Institute of Urology studies of Mawhinney, M. G. and Neubauer, B. L. (1979). Actions of buserelin in advanced prostatic cancer. Am. J . Clin. Oncol., estrogen in the male. Invest. Urol., 16,409-420. ll(Supp1 l), S16-Sl8. Miller, G. M. and Hinman, F., Jr. (1954). Cortisone treatment in advanced carcinoma of the prostate. J . Urol.,72,485495. Murphy, G . P., Greco, J. M., Chin, J. L. et d. (1987). Zoladex (ICI 1 18,630): clinical trial of new luteinizing hormone- The Author releasing hormone analog in metastatic prostatic carcinoma. E. D. Crawford, MD, Professor and Chairman, Division of Urologj, 29, 185-190. Urology. Murray, B. and Pitt, P. (1987). Aminoglutethimide in the treatment of advanced prostatic cancer. In Prostate Cancer, Part A . Research, Endocrine Treatment, and Histopathology, Requests for reprints to: E. D. Crawford, Division of Urology, University of Colorado Health Sciences Center, Campus Box ed. Murphy, G . P., Kuss, R., Khoury, S . et al. Pp. 275-282. C-319,4200 East Ninth Avenue, Denver, CO 80262, USA. New York: Alan R. Liss.
