1 Lank Center for Genitourinary Oncology, Division of Solid Tumor Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 2 Department of Medical Oncology, Massachusetts General Hospital, Boston, MA; 3 Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA; 4 Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA
Received 1 October 2003; revised 30 January 2004; accepted 3 February 2004
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ABSTRACT |
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Medical or surgical castration is effective in advanced prostate cancer but with profound side-effects, particularly on sexual function. Effective, less toxic therapies are needed. This study examined whether the addition of finasteride to high-dose bicalutamide enhanced disease control, as measured by additional decreases in serum prostate-specific antigen (PSA).
Patients and methods:
Forty-one patients with advanced prostate cancer received bicalutamide (150 mg/day). Finasteride (5 mg/day) was added at first PSA nadir. Serum PSA was measured every 2 weeks until disease progression. Questionnaires were administered to assess sexual function.
Results:
Median follow-up is 3.9 years. At the first PSA nadir, median decrease in PSA from baseline was 96.5%. Thirty of 41 patients (73%) achieved a second PSA nadir and median decrease of 98.5% from baseline. Median time to each nadir was 3.7 and 5.8 weeks, respectively. Median time to treatment failure was 21.3 months. Toxicities were minor, including gynecomastia. Seventeen of 29 (59%) and 12 of 24 (50%) men had normal sex drive at baseline and at second PSA nadir, respectively. One-third of men had spontaneous erection at both time points.
Conclusion:
Finasteride provides additional intracellular androgen blockade when added to bicalutamide. Duration of control is comparable to castration, with preserved sexual function in some patients.
Key words: bicalutamide, finasteride, prostate, potency
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Introduction |
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Intraprostatic dihydrotestosterone (DHT) levels remain high despite androgen deprivation therapy (ADT) and is presumably derived from adrenal steroids [5, 6]. Adding finasteride, a 5- reductase inhibitor, to antiandrogen monotherapy, may enhance intracellular androgen blockade and thus augment disease control.
We undertook a study to evaluate if the addition of finasteride to bicalutamide increased intracellular androgen blockade as measured by serum prostate-specific antigen (PSA) levels. We also assessed toxicity, including effects on sexual function.
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Patients and methods |
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Treatment plan
At study entry, baseline complete blood count, liver function tests, PSA, bone and CT scans were obtained. All except two patients were known to have undergone prophylactic breast irradiation prior to initiation of drug treatment. Pretreatment evaluation of sexual function was performed via a self-administered questionnaire, consisting of five questions derived from two previous quality-of-life studies and validated in a similar setting [79]. These questions addressed the quality and quantity of sexual functioning outcomes including erections, orgasms and libido over the last 4 weeks.
Bicalutamide (Casodex®, Astra-Zeneca) was administered at a dose of 150 mg orally once per day and serum PSA measured every 2 weeks. At the first PSA nadir (defined as two consecutive values with each value 90% of the other), finasteride (Proscar®, Merck) was added at a dose of 5 mg orally daily. At the second PSA nadir, the sexual function questionnaire was readministered. Bone and CT scans were repeated if baseline scans were positive. Patients had monthly visits with physical examination and blood tests for the first 3 months of study and then every 3 months until treatment failure. At treatment failure, all blood tests and appropriate scans were repeated.
Treatment failure and therapy at the time of failure
Treatment failure was defined as a PSA value 150% of the nadir value on two separate determinations spaced
2 weeks apart or progressive or new lesions on bone or CT scans. The first maneuver following failure was discontinuation of both drugs at a time left to the discretion of the treating physicians. Patients were taken off study and offered standard ADT: leuteinizing hormone-releasing hormone (LH-RH) agonist or orchiectomy.
Statistical considerations
Data are summarized as median and interquartile range (25th to 75th percentiles), or as number and per cent of patients; 95% exact binomial confidence intervals are reported for PSA response proportions and all patients who began study treatment were included in the denominators. Time-to-event variables were calculated from the date of treatment initiation and analyzed using the KaplanMeier method to account for censoring; Greenwood estimates of the standard errors were used to construct 95% confidence intervals (CI).
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Results |
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The median PSA level at baseline was 19.1 ng/ml. Among 34 patients who achieved a first PSA nadir on bicalutamide alone, the median PSA nadir was 0.75 ng/ml (median 96.5% decrease from baseline) and median time to first nadir was 3.7 weeks. The median PSA nadir for the 30 patients at second PSA nadir was 0.35 ng/ml (median 98.5% decrease from baseline) and median time taken was 5.8 weeks following initiation of bicalutamide. The median treatment failure-free survival (TFFS) was 21.3 months (95% CI 12.632.9 months) and estimated 2 and 4 years TFFS were 43.6% (95% CI 30.163%) and 29.9% (95% CI 17.650.9%), respectively.
Information on additional hormonal therapy was available for 17 of the 19 patients who failed treatment following the second PSA nadir. Fifteen patients received ADT, which included leuprolide acetate, one continued treatment with bicalutamide alone, and another patient remained on bicalutamide plus finasteride off protocol. Further information was available for 14 of the 15 patients treated with ADT. Twelve patients achieved third PSA nadir while two patients experienced PSA progression before reaching further nadir. The median time to PSA progression from initiation of leuprolide acetate was 9.8 months (range 322 months) with two patients censored at 5 and 10 months.
Common toxicities are outlined in Table 2. The most common side-effects were mild gynecomastia and breast tenderness, mild anemia and fatigue. Despite prior breast irradiation, 18 of 39 patients developed gynecomastia. Mild abdominal discomfort and diarrhea were seen, which resolved with supportive care. Transient mild transaminitis seen in four patients resolved spontaneously despite continuation of treatment. A patient developed grade 3 prolonged prothromin time while on warfarin. Secondary malignancies were reported in two patients (lymphoma; synchronous lymphoma and colon carcinoma) but were not thought to be treatment-related.
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Discussion |
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In this study, additional PSA suppression was seen following the addition of finasteride to bicalutamide. With bicalutamide alone, PSA fell to a nadir value that was 3.5% of the baseline value. After finasteride was added, the PSA nadir was 1.5% of the baseline value. This result provides indirect evidence of additive intracellular androgen suppression with the addition of finasteride to bicalutamide. It is possible that the additional PSA suppression may have come from the activity of finasteride on normal prostatic epithelium following recovery from RT. However, given that the response was also seen in 10 post-RP patients, we believe this was unlikely. In fact, a similar effect on PSA by finasteride was also seen after flutamide in another study [7]. One additional caveat is that the first PSA plateau achieved at the first nadir and confirmed with a second PSA reading is presumed to be the maximal response attainable with bicalutamide alone and the subsequent drop in PSA is due to finasteride.
Despite initial response rates of 8090% from LH-RH agonists, nearly all men develop progressive disease after an average of 1824 months. In this study, median duration of response (21.3 months) was comparable to LH-RH agonists although this requires confirmation in a prospective randomized trial. Furthermore, 12 of 14 (86%) patients in this study remained responsive to subsequent LH-RH agonists, although the duration of their efficacy appeared shorter had LH-RH agonists been used upfront. Nevertheless, this observation indicates that the combination of finasteride and bicalutamide as primary hormonal therapy for advanced prostate cancer probably may not compromise the overall duration of the androgen-responsive disease. Being a phase II study, no comparison can be made with other modalities such as LH-RH analog or bicalutamide monotherapy. However, in several studies, post-treatment PSA nadir is predictive of freedom from treatment failure and survival [16, 17]. Therefore, whether the lower PSA nadir achieved with bicalutamide and finasteride prolongs disease-free and overall survival can only be answered in a phase III study.
Many men with prostate cancer are concerned with loss of libido and erectile dysfunction with ADT. In a previous study on the quality of life outcome in men with advanced prostate cancer after primary ADT, only 5.6% of men retained sexual interest during ADT. Spontaneous erection was absent in 83% of men while only 8% had erection firm enough for sexual intercourse [18]. In this study, higher proportions of men had better sexual function: 50% with adequate sexual interest, 33% with spontaneous erection. In addition, 79% of men who completed the questionnaires at either time point indicated that an active sex life was at least of some concern. In fact, 50% and 46% of men who answered the sexual function questionnaire at the second PSA nadir did not complain of loss of sex drive or having difficulty in becoming sexually aroused, respectively; this was comparable to baseline (59% for both questions). Although most men were not sexually active during the study, spontaneous erections were reported in one-third of men who completed the questionnaires at both time points, an encouraging finding compared with ADT.
Finally, among the 18 men who answered both questionnaires at baseline and at second PSA nadir, two men had lowered sex drive as a result of treatment, but there were also two men with an increased sex drive. Although serum testosterone was not measured at either time, one possible reason for this phenomenon could be due to elevated serum testosterone as a result of the bicalutamide therapy.
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Conclusion |
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FOOTNOTES |
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