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NILUTAMIDE RESPONSE AFTER FLUTAMIDE FAILURE IN POST-ORCHIECTOMY PROGRESSIVE PROSTATE CANCER
Vol. 159,990, March 1998 Printed in USA.
NILUTAMIDE RESPONSE AFTER FLUTAMIDE FAILURE IN POSTORCHIECTOMY PROGRESSIVE PROSTATE CANCER JAMES A. EASTHAM AND OLIVER SARTOR From the Departments of Urology and Medicine, Louisiana State University Medical Center, Shreveport, Louisiana
KEYWORDS:orchiectomy, prostatic neoplasms, androgen antagonists, prostate-specificantigen, flutamide
remains controversial. Flutamide withdrawal failed in our patient but he responded to the addition of the antiandrogen nilutamide. PSA decreased approximately 80% with the response lasting at least 4 months. Although our patient responded to nilutamide, addition of an alternative antiandrogen may have produced similar results. This case suggests that interactions between antiandrogens and prostate cancer growth are more complex than previously believed. Antiandrogens and their interaction with wild type and select mutant androgen receptors have been studied in detail. In prostate cells expressing wild type androgen receptors all antiandrogens inhibit cellular growth. In the LNCaP cell line, which expresses a point mutated androgen receptor, physiological concentrations of hydroxyflutamide and nilutamide stimulate cellular growth, whereas bicalutamide is inhibitory.2.3 LNCaP type mutant androgen receptors have been isolated in patients on multiple occasions. Furthermore, PSA changes consistent with the expression of LNCaP type mutant cells in patients have been reported (bicalutamide responses aRer progression on flutamide).* However, our case suggests that in select patients antiandrogens can regulate PSA production in a manner distinct from that predicted in either of the currently used models. The frequency and duration of nilutamide induced responses in this setting as well as the molecular pathophysiology of the response deserve additional study.
Despite the functional similarities, different antiandrogens can interact in a unique way with the androgen receptor. We describe a patient with post-orchiectomy progressive prostate cancer in whom flutamide and flutamide withdrawal failed but who subsequently responded to nilutamide therapy. CASE REPORT
A 79-year-old black man had been evaluated initially for lower tract obstructive symptoms in February 1989. At that time he had a markedly enlarged and hard prostate gland. Serum prostate specific antigen (PSA) was elevated at 44.5 ngJml. (normal less than 4). Prostate biopsy revealed a Gleason score of 3 + 4 = 7 in all 4 prostate cores. Bone scan showed no evidence of metastatic disease. The patient was diagnosed with locally advanced T3NxMx prostate cancer and underwent bilateral scrotal orchiectomy in March. Serum PSA subsequently decreased to less than 10 ngJml. and the lower tract obstructive symptoms resolved. The patient remained asymptomatic but was noted to have slowly increasing serum PSA, which reached 11.4 ngJml. in Odober 1993. Bone scan remained negative and 250 mg. flutamide 3 times daily were prescribed. Serum FSA promptly decreased and remained less than 1ngJml. for the next 15 months, at which time it began to increase slowly. The patient remained asymptomatic. In October 1996 PSA had increased to 14.3 ngJml. Flutamide was discontinued to elicit an antiandrogen withdrawal response. However, PSA continued to increase and reached 40.4 ngJml. in December. At this time 300 mg. nilutamide daily for 30 days, then 150 mg. nilutamide daily thereafter were prescribed. FSA promptly decreased to 7.7 nglml. and remained less than 10 ngJml. for 4 months.
REFERENCES
DISCUSSION
Standard treatment for patients with risiig serum PSA despite combined androgen blockade is discontinuation of the antiandrogen. Approximately 20% of patients will respond, as measured by a greater than 50% decrease in serum PSA.1 In those cases which respond the median duration of PSA decrease is between 3.5 and 5 months.' Treatment of the 80% of patienta who do not respond to antiandrogen withdrawal Accepted for publication August 22,1997.
1. Small, E. J. and Vogelzang,N. J.: Second-linehormonal therapy for advanced prostate cancer: a shaing paradigm. J. Clin. Oncol., 15:382, 1997. 2. Olea, N.,Sakabe, IS., Soto, M. and Sonnenschein, C.: The proliferative effects of "anti-androgens"on the androgen-sensitive human prostate cancer cell line LNCaP. Endocrinology, 126 1457, 1990. 3. Figg, W.D.,McCall, N. A. and Sartor, 0.:The in vitro response to four antisteroidreceptor agents on the hormone-responsive prostate cancer cell line LNCaP. Oncol. Rep., 2 295, 1995. 4. Fenton, M. A.,Rode, P., Constantine, M., Balk, S., Gaynes, L., DeWolf, W., Taplin, M-E. and Bubley, G.: Bicalutamide for androgen-independent (AI)prostate cancer. Proc. Amer. SOC. Clin. Oncol.,suppl., 15: 262, 1996.
990
NILUTAMIDE RESPONSE AFTER FLUTAMIDE FAILURE IN POSTORCHIECTOMY PROGRESSIVE PROSTATE CANCER JAMES A. EASTHAM AND OLIVER SARTOR From the Departments of Urology and Medicine, Louisiana State University Medical Center, Shreveport, Louisiana
KEYWORDS:orchiectomy, prostatic neoplasms, androgen antagonists, prostate-specificantigen, flutamide
remains controversial. Flutamide withdrawal failed in our patient but he responded to the addition of the antiandrogen nilutamide. PSA decreased approximately 80% with the response lasting at least 4 months. Although our patient responded to nilutamide, addition of an alternative antiandrogen may have produced similar results. This case suggests that interactions between antiandrogens and prostate cancer growth are more complex than previously believed. Antiandrogens and their interaction with wild type and select mutant androgen receptors have been studied in detail. In prostate cells expressing wild type androgen receptors all antiandrogens inhibit cellular growth. In the LNCaP cell line, which expresses a point mutated androgen receptor, physiological concentrations of hydroxyflutamide and nilutamide stimulate cellular growth, whereas bicalutamide is inhibitory.2.3 LNCaP type mutant androgen receptors have been isolated in patients on multiple occasions. Furthermore, PSA changes consistent with the expression of LNCaP type mutant cells in patients have been reported (bicalutamide responses aRer progression on flutamide).* However, our case suggests that in select patients antiandrogens can regulate PSA production in a manner distinct from that predicted in either of the currently used models. The frequency and duration of nilutamide induced responses in this setting as well as the molecular pathophysiology of the response deserve additional study.
Despite the functional similarities, different antiandrogens can interact in a unique way with the androgen receptor. We describe a patient with post-orchiectomy progressive prostate cancer in whom flutamide and flutamide withdrawal failed but who subsequently responded to nilutamide therapy. CASE REPORT
A 79-year-old black man had been evaluated initially for lower tract obstructive symptoms in February 1989. At that time he had a markedly enlarged and hard prostate gland. Serum prostate specific antigen (PSA) was elevated at 44.5 ngJml. (normal less than 4). Prostate biopsy revealed a Gleason score of 3 + 4 = 7 in all 4 prostate cores. Bone scan showed no evidence of metastatic disease. The patient was diagnosed with locally advanced T3NxMx prostate cancer and underwent bilateral scrotal orchiectomy in March. Serum PSA subsequently decreased to less than 10 ngJml. and the lower tract obstructive symptoms resolved. The patient remained asymptomatic but was noted to have slowly increasing serum PSA, which reached 11.4 ngJml. in Odober 1993. Bone scan remained negative and 250 mg. flutamide 3 times daily were prescribed. Serum FSA promptly decreased and remained less than 1ngJml. for the next 15 months, at which time it began to increase slowly. The patient remained asymptomatic. In October 1996 PSA had increased to 14.3 ngJml. Flutamide was discontinued to elicit an antiandrogen withdrawal response. However, PSA continued to increase and reached 40.4 ngJml. in December. At this time 300 mg. nilutamide daily for 30 days, then 150 mg. nilutamide daily thereafter were prescribed. FSA promptly decreased to 7.7 nglml. and remained less than 10 ngJml. for 4 months.
REFERENCES
DISCUSSION
Standard treatment for patients with risiig serum PSA despite combined androgen blockade is discontinuation of the antiandrogen. Approximately 20% of patients will respond, as measured by a greater than 50% decrease in serum PSA.1 In those cases which respond the median duration of PSA decrease is between 3.5 and 5 months.' Treatment of the 80% of patienta who do not respond to antiandrogen withdrawal Accepted for publication August 22,1997.
1. Small, E. J. and Vogelzang,N. J.: Second-linehormonal therapy for advanced prostate cancer: a shaing paradigm. J. Clin. Oncol., 15:382, 1997. 2. Olea, N.,Sakabe, IS., Soto, M. and Sonnenschein, C.: The proliferative effects of "anti-androgens"on the androgen-sensitive human prostate cancer cell line LNCaP. Endocrinology, 126 1457, 1990. 3. Figg, W.D.,McCall, N. A. and Sartor, 0.:The in vitro response to four antisteroidreceptor agents on the hormone-responsive prostate cancer cell line LNCaP. Oncol. Rep., 2 295, 1995. 4. Fenton, M. A.,Rode, P., Constantine, M., Balk, S., Gaynes, L., DeWolf, W., Taplin, M-E. and Bubley, G.: Bicalutamide for androgen-independent (AI)prostate cancer. Proc. Amer. SOC. Clin. Oncol.,suppl., 15: 262, 1996.
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