CASTRATION PLUS NILUTAMIDE VS CASTRATION PLUS PLACEBO IN ADVANCED PROSTATE CANCER A Review D I O N I S I U S J. D U PLESSIS, M . D . F r o m the D e p a r t m e n t of Urology, University of Pretoria, Pretoria, South Africa
ABSTRACT--Combination o] antiandrogen treatment with surgical or medical castz improve the efficacy of endocrine treatment of prostatic cancer by blocking the effec androgens. A nonsteroidal antiandrogen, nilutamide, has shown promising results in open studies. In a short-term (29 days) comparison of nilutamide plus buserelin and b placebo, nilutamide (300 mg/day), significantly reduced bone pain, and fewer patientt worsening pain than in the control group. The initial buserelin-induced increase in phosphatase was prevented by nilutamide, but there was a similar increase in tesh gonadotropin concentrations to that seen in the control group. Thus, nilutamide car, tumor flare-up associated with the start 0] luteinizing hormone-releasing hormone (L ment, even though the endocrine responses are not affected. In three multicenter, double-blind placebo-controlled trials of castration and nilutamide involving 248 patie bination of nilutamide and castration decreased bone pain, improved performanct increased the number of patients with objective regression, compared with patients ~c trated but did not receive nilutamide. Nilutamide was generally well tolerated, though ders, gastrointestinal disorders, and alcohol intolerance were reported in patients re tamide. The results suggest that nilutamide improves the efficacy of castration in ] prostatic cancer. Current studies are investigating the effects of this treatment on surl risk-benefit ratio.
Suppression of testicular androgens has positive effects on the course of metastatic prostatic cancer.l.2 Castration may be brought about either by surgery (orchiectomy) or medically by administration of estrogens or luteinizing hormone-releasing hormone (LH-RH) agonists. Such pharmacologic castration induces a subjective and/or objective improvement in prostatic cancer in 60 percent of cases. 3 After castration, a low level of adrenal androgens continues to circulate which may permit continued development of the prostatic cancer; therefore, combination of an antiandrogen with castration should increase the efficacy of treatment. Nilutamide (Anandron) is a specific nonsteroidal antiandrogen which blocks all androgenic activity at the level of the target cell receptors without possessing any other hormonal or antihormonal activity. 4 It therefore inhibits the trophic action of androgens on
20
the prostate2 The results of l ies combining nilutamide wit prostate cancer were promi double-blind studies have bo The results of four rand, placebo-controlled studies ar include one short-term trial o agonist-induced flare-up of tt long-term studies, which eva] safety of nilutamide accordin criteria. Short-term Trial The purpose of the short-1 firm that nilutamide can blc observed at the start of tre; agonist. These effects, due to in the testosterone levels, may o
SUPPLEMENT TO UROLOGY
/
FEBRUARY 1991
/ VOLUME XXXVII, NUMBE~i'!~
40
+15
•
~3_
-30 c-..o ~ - 4 0 ~.~ ~ .~ -5e o~
"
•
-60 -70
-80 -90
!inical examination (comprising an evaluation n using a visual analog scale and the consumpFanalgesics) and laboratory tests (comprising 0 f PAP, PSA, testosterone, luteinizing hor[~H], and follicle-stimulating hormone [FSH] iWere conducted before treatment, every day i ~ e first fourteen days and then on days 18, !d29 All assays were performed in the same
v
22
Day of t r e a t m e n t
Day of treatment
Changes in bone pain in patients su]: ! ~om pain at start o] short-term study. Each represents median value obtained on l O0-mm !:analog scale, expressed as percentage change ~parison with corresponding critical values. {:Kuhn ]M, et al. 8 with permission o] The New md Journal o] Medicine.)
18
2 3 4 5 6 7 8 9 1011121314
18
22
29
Day o f treatment
Median changes in prostatic speciJic antigen (PSA) levels in short-term study comparing nilutamide with placebo in presence o] LH-RH agonist. Each point represents median PSA concentration expressed as percentage change in comparison with corresponding initial values. (From Kuhn ]M, et al.8 with permission o] The New England Journal of Medicine.)
FIGURE 3.
lutamide group (5/17 cases) than in the control group (12/19 cases).
Change in PAP levels In Figure 2 a marked drop is seen to occur in PAP concentration from day 4 in the nilutamide group, while a slight increase is followed by a decrease from day 14 with LH-RH agonist alone.
Change in PSA level An immediate drop in PSA levels occurred in the nilutamide group, while in the control group it was delayed until day 13 (Fig. 3).
UROLOGY / FEBRUARY1991 / VOLUMEXXXVII, NUMBER2
21
Placebo Nilutamide, 1fi0 rag/day Nilutamide, 300 rng/day p
ABSTRACT--Combination o] antiandrogen treatment with surgical or medical castz improve the efficacy of endocrine treatment of prostatic cancer by blocking the effec androgens. A nonsteroidal antiandrogen, nilutamide, has shown promising results in open studies. In a short-term (29 days) comparison of nilutamide plus buserelin and b placebo, nilutamide (300 mg/day), significantly reduced bone pain, and fewer patientt worsening pain than in the control group. The initial buserelin-induced increase in phosphatase was prevented by nilutamide, but there was a similar increase in tesh gonadotropin concentrations to that seen in the control group. Thus, nilutamide car, tumor flare-up associated with the start 0] luteinizing hormone-releasing hormone (L ment, even though the endocrine responses are not affected. In three multicenter, double-blind placebo-controlled trials of castration and nilutamide involving 248 patie bination of nilutamide and castration decreased bone pain, improved performanct increased the number of patients with objective regression, compared with patients ~c trated but did not receive nilutamide. Nilutamide was generally well tolerated, though ders, gastrointestinal disorders, and alcohol intolerance were reported in patients re tamide. The results suggest that nilutamide improves the efficacy of castration in ] prostatic cancer. Current studies are investigating the effects of this treatment on surl risk-benefit ratio.
Suppression of testicular androgens has positive effects on the course of metastatic prostatic cancer.l.2 Castration may be brought about either by surgery (orchiectomy) or medically by administration of estrogens or luteinizing hormone-releasing hormone (LH-RH) agonists. Such pharmacologic castration induces a subjective and/or objective improvement in prostatic cancer in 60 percent of cases. 3 After castration, a low level of adrenal androgens continues to circulate which may permit continued development of the prostatic cancer; therefore, combination of an antiandrogen with castration should increase the efficacy of treatment. Nilutamide (Anandron) is a specific nonsteroidal antiandrogen which blocks all androgenic activity at the level of the target cell receptors without possessing any other hormonal or antihormonal activity. 4 It therefore inhibits the trophic action of androgens on
20
the prostate2 The results of l ies combining nilutamide wit prostate cancer were promi double-blind studies have bo The results of four rand, placebo-controlled studies ar include one short-term trial o agonist-induced flare-up of tt long-term studies, which eva] safety of nilutamide accordin criteria. Short-term Trial The purpose of the short-1 firm that nilutamide can blc observed at the start of tre; agonist. These effects, due to in the testosterone levels, may o
SUPPLEMENT TO UROLOGY
/
FEBRUARY 1991
/ VOLUME XXXVII, NUMBE~i'!~
40
+15
•
~3_
-30 c-..o ~ - 4 0 ~.~ ~ .~ -5e o~
"
•
-60 -70
-80 -90
!inical examination (comprising an evaluation n using a visual analog scale and the consumpFanalgesics) and laboratory tests (comprising 0 f PAP, PSA, testosterone, luteinizing hor[~H], and follicle-stimulating hormone [FSH] iWere conducted before treatment, every day i ~ e first fourteen days and then on days 18, !d29 All assays were performed in the same
v
22
Day of t r e a t m e n t
Day of treatment
Changes in bone pain in patients su]: ! ~om pain at start o] short-term study. Each represents median value obtained on l O0-mm !:analog scale, expressed as percentage change ~parison with corresponding critical values. {:Kuhn ]M, et al. 8 with permission o] The New md Journal o] Medicine.)
18
2 3 4 5 6 7 8 9 1011121314
18
22
29
Day o f treatment
Median changes in prostatic speciJic antigen (PSA) levels in short-term study comparing nilutamide with placebo in presence o] LH-RH agonist. Each point represents median PSA concentration expressed as percentage change in comparison with corresponding initial values. (From Kuhn ]M, et al.8 with permission o] The New England Journal of Medicine.)
FIGURE 3.
lutamide group (5/17 cases) than in the control group (12/19 cases).
Change in PAP levels In Figure 2 a marked drop is seen to occur in PAP concentration from day 4 in the nilutamide group, while a slight increase is followed by a decrease from day 14 with LH-RH agonist alone.
Change in PSA level An immediate drop in PSA levels occurred in the nilutamide group, while in the control group it was delayed until day 13 (Fig. 3).
UROLOGY / FEBRUARY1991 / VOLUMEXXXVII, NUMBER2
21
Placebo Nilutamide, 1fi0 rag/day Nilutamide, 300 rng/day p
