Long-Term Follow-Up of Four Patients with Advanced Prostate Cancer Treated With Nilutamide After Failure of Other Antiandrogens

Bülent Akduman, MD; E. David Crawford, MD; Ali M. Ziada, MD

•     Androgen deprivation can be achieved through surgical castration (orchiectomy) or medical castration (LHRH agonists), antiandrogens or the combination of castration and antiandrogens.

•     The combination of nilutamide and castration has been shown to be more effective than orchiectomy alone in the treatment of metastatic prostate cancer.

•     Standard treatment of patients who have failed combined androgen blockade is discontinuation of the antiandrogen.  Treatment of patients who do not respond to antiandrogen withdrawal is controversial.

•     Further studies to clarify the interaction between antiandrogens and prostate cancer cells are warranted.

Introduction
Androgen deprivation has been the cornerstone  of treatment for advanced prostate cancer.  It can be achieved through surgical castration (orchiectomy), medical castration (LHRH [luteinizing hormone-releasing hormone] agonists), antiandrogens or the combination of castration and antiandrogens.

Nilutamide is a nonsteroidal antiandrogen that has a long half-life of 56 hours, allows for a convenient once-a-day dosage and ensures permanent saturation of androgen receptor sites.1  The combination of nilutamide and castration has been shown to be more effective than orchiectomy alone in treatment of metastatic prostate cancer.2,3  The use of nilutamide as monotherapy has not been well documented. 

Only one study in the literature showed nilutamide  as monotherapy to have progression-free survival between 9 and 23 months in 26 patients with previously untreated advanced prostate cancer.4

This reports reviews 4 patients with advanced prostate cancer treated with nilutamide following primary hormonal therapy.

Case History

Case 1

JD is a 71-year-old male.  He was diagnosed with prostate cancer in December 1991.  His preoperative PSA was 9.4 ng/mL, and clinical stage was T2A. Prostate needle biopsy showed moderate-to-poor grade adenocarcinoma (Grade III-IV of IV).  Computed tomography (CT) pelvis and bone scan showed no evidence of metastasis, and the patient underwent pelvic lymph node dissection, which revealed positive lymph nodes for metastasis on the right side.  The patient had been controlled on flutamide monotherapy for 5 years with a PSA ranging from 0.8 ng/mL to 1.3 ng/mL.  PSA rose   to 20.9 ng/mL in September 1997.  Flutamide was stopped at that time and the patient’s PSA was  stable for 1 month and then elevated to 90.2 ng/mL in October 1997.  Nilutamide was started at that time.  A dramatic response was seen as a result; his PSA had decreased to 14.2 ng/mL by December 1997.  His PSA increased over 27 months and was 23.3 ng/mL in February 2000.  The patient is still on nilutamide and refuses LHRH therapy and orchiectomy.      

Case 2

GH is a 72-year-old male.  He was diagnosed with prostate cancer in April 1992.  His preoperative PSA was 49 ng/mL.  Laparascopic pelvic lymph node dissection and perennial radical prostatectomy were performed in May 1992.  His lymph nodes were negative for metastasis, but there was positive margin on the right and posterior side of the prostate specimen.  His PSA nadir was <0.2 ng/mL in July 1992.  His PSA increased to 1.0 in March 1994 and elevated to a maximum of 2.9 ng/mL in April 1996.  The patient was placed on finasteride (bid) and flutamide (bid) as part of a protocol at the University of Colorado in which 40 patients with advanced prostate cancer have been treated.  His PSA had been 1.0 and 1.3 ng/mL.  Due to breast tenderness, radiation was discussed as an option.  The patient’s PSA began to rise again and he was placed on flutamide alone (tid).  His PSA rose to 2.4 ng/mL in February 1997 and then to 7.9 ng/mL in March 1997.  His liver function elevated and he experienced diarrhea and bloating.  He stopped flutamide and was started on nilutamide in April 1997 (300 mg qd for 1 month followed by 150 mg qd).  His PSA dropped to

0.4 ng/mL in June 1997 and 0.9 ng/mL in September 1997.  The patient was taken off nilutamide in September 1997 because of the appearance of possible interstitial pneumonitis on his routine follow-up chest x-ray.  He did not report any chest symptoms.  His PSA was elevated to 6.8 ng/mL in February 1998, and bicalutamide was started.  His PSA had decreased to 4.5 ng/mL by June 1998, but increased again to 14.5 ng/mL in March 1999.  His bone scan was negative for metastasis, and prostate bed biopsy showed poorly differentiated carcinoma.  Radiotherapy to prostate bed was performed (45 Gy with a 4-field technique, and a boost to 69 Gy for the recurrence).  Multiple painful bone metastases were detected in August 1999, and LHRH agonist therapy was instituted in addition to palliative radiotherapy (2 full courses to pelvic girdle and thoracic spine:  36 Gy in 20 fractions to a field that appears to have been from T10 to L5).  The patient’s PSA had increased to 184.6 ng/mL by October 1999, and was 512.7 ng/mL in December 1999.  He was hospitalized for anemia and upper extremity weakness and chemotherapy (decadron + ketacanozole) was administered.  Although his PSA decreased slightly, he died 3 months later.

Case 3

CW is a 78-year-old male.  He was diagnosed with prostate cancer in 1994 and received radiotherapy with curative intent.  Following radiotherapy, his PSA began to rise.  Lupron alone had been administered for 3 years.  His PSA in this time period was undetectable.  It was elevated to 1.3 ng/mL in March 1997 and bicalutamide was added to his therapy.    His PSA decreased slightly to 0.9 in April 1997, but increased to 3.9 in November 1997.  Bicalutamide was stopped and nilutamide was started.  His PSA was down to 2.9 in January 1998; however, it started rising again and was up to 7.4 ng/mL by late February 1998.  Nilutamide was stopped to allow for androgen withdrawal.  The patient’s PSA continued to increase and reached 26.0 ng/mL in April 1998.  Lupron was continued and flutamide was started, but by July 1998, the patient’s PSA was 38.2 ng/mL.  Flutamide was stopped and the combination of lupron, dexamethazone and cytoxan was administered.  This combination was ineffective.  The patient’s PSA was 121.4 ng/mL in September 1998 and  288.0 ng/mL in November 1998.  Palliative radiotherapy to cervical spine was performed for  bone metastasis in December 1998.  His PSA was 1042.0 ng/mL in January 1999.  The combination of lupron, dexamethazone and cytoxan was stopped, and gemcitabine was started.  However, his PSA had increased to 1842.0 ng/mL by February 1999.  Finally, the combination of adriamycin and ketacanozole was tried.  The patient’s PSA had risen to 4752.0 by July 1999, and he died  of prostate cancer 2 months later.

Case 4

FM is a 76-year-old male who had a radical prostatectomy for prostate cancer in 1992.  Prior to that, his PSA was 7.8 ng/mL.  Following a rise in  PSA to 1.4 ng/mL in October 1995, he was started on flutamide.  He responded to flutamide and flutamide withdrawal.  His PSA reached 15.1 ng/mL in June 1997, when he started on nilutamide.  The patient tolerated nilutamide well and his PSA remained stable until March 1998, when nilutamide was stopped due to reappearance of lung metastasis as well as a left supraclavicular lymph node enlargement.  The patient was taken off the medication based on these new findings. 

Discussion
Standard treatment of patients who have failed  combined androgen blockade is discontinuation of the antiandrogen.  This withdrawal response is seen in up to 20% of cases.5  Antiandrogens stimulate, rather than block, the development of mutant nuclear receptors in prostate cancer cells during hormonal treatment, effecting the withdrawal response. Treatment of patients who do not respond to antiandrogen withdrawal is controversial.  Due to different mechanisms of action, one antiandrogen may be effective in the treatment of patients in whom another antiandrogen or antiandrogen withdrawal has failed.  In a case report published in 1998, one patient with T3NXMX prostate cancer responded to nilutamide therapy 4 months after flutamide failure.6 

In the first case study reviewed here, JD, who  had flutamide failure, did not respond to flutamide withdrawal.   The efficacy of nilutamide was dramatic in that case.  His PSA decreased to

14.2 ng/mL in December 1997 from 90.2 ng/mL

in October 1997.  His PSA has remained stable for    27 months.  In Case 2, GH had responded to nilutamide for 6 months.  Nilutamide was discontinued because of possible interstitial pneumonitis.  This side effect was reversible, and it was resolved after discontinuation of nilutamide.  CW had a response to nilutamide for 3 months.  After failure of nilutamide, he did not respond to combined androgen blockade and chemotherapy.

Nilutamide was generally well tolerated.  Side effects such as visual disturbances (mainly dark adaptation), alcohol intolerance, hepatitis and elevated liver enzymes were not seen.  Mild antiandrogenic effects and nausea, reversible interstitial pneumonitis in one patient and supraclavicular lymph node enlargement in another patient were the only side effects.

In the case of failure of an antiandrogen or its withdrawal, a different antiandrogen can be tried. Further studies to clarify the interaction between antiandrogens and prostate cancer cells are warranted.

References

1.   Pendyala L, Creaven PJ, Huben R, Tremblay D, Mouren M, Bertagna C. Clinical pharmacokinetics of a new antiandrogen Anandron ( RU 23908 ). In: Prostate Cancer. Part A: Research, Endocrine Treatment, and Histopathology. Murphy G, Khoury S, Kuss A, Chatelain C, Denis L. New York, NY: Alan R Liss, Inc. 1987:351-363.

2.   Dijkman GA, Janknegt RA, de Rejke TM, Debruyne FM for the international anandron study group. Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. J Urol.  1997;158:160-163.

3.   Janknegt RA, Abbou CC, Bartoletti R, et al. Orchiectomy and nilutamide or placebo as treatment of metastatic prostate cancer in a multinational double blind randomized trial.     J Urol.  1993;149:77-83.

4.   Descani AU, Boccardo F, Guarneri D, et al. Monotherapy with nilutamide, a pure nonsteroidal antiandrogen, in untreated   patients with metastatic carcinoma of the prostate. The Italian Prostate Cancer Project.     J Urol.  1991;146:377-381.

5.   Small EJ, Vogelzang NJ. Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol.  1997;15:382-388.

6.   Eastham JA, Sartor O. Nilutamide response after flutamide failure in post-orchiectomy progressive prostate cancer. J Urol.  1998;159:990.