Effects of flutamide as a second-line agent for maximum androgen blockade of hormone refractory prostate cancer

Authors


Kenji Nishimura md, phd, Department of Urology, Hyogo Prefectural Nishinomiya Hospital, 13-9, Rokutanji-cho, Nishinomiya 662-0918, Japan. Email: nkenikeda@nifty.com

Abstract

Abstract:  We analyzed clinical effects of flutamide as a second-line agent for maximum androgen blockade (MAB) in patients with relapsing prostate cancer who received bicalutamide as the first-line MAB agent. This study included 13 patients with progressive prostate cancer who had relapsed after first-line MAB, with bicalutamide at 80 mg/day. After checking for antiandrogen withdrawal syndrome, they were given flutamide at 375 mg/day as second-line MAB. The effectiveness of that therapy was evaluated by changes in prostatic specific antigen (PSA) levels, with response defined as a decrease of greater than 50% from the start of therapy. We also compared several factors between responders and non-responders. Nine (69.2%) of the 13 patients showed a decrease in PSA levels, of whom five (38.5%) had a greater than 50% decrease and were defined as responders. The median duration of PSA response was 11.0 months (range 5–20 months). Patients who had a longer duration of response to first-line MAB had a significantly greater response to second-line MAB. For advanced prostate cancer patients who progressed on first-line MAB with bicalutamide, flutamide administration as a second-line antiandrogen was found to be relatively effective, especially for those who showed a longer duration of response to the first-line MAB. Our results confirm previous findings that MAB using flutamide is an effective second-line hormonal therapy.

Introduction

Secondary hormonal therapies are moderately effective for patients with advanced prostate cancer who relapse after first-line hormonal therapy, including maximum androgen blockade (MAB). For example, partial responses to hormonal therapy with glucocorticoids given to diminish adrenal androgen production have been reported.1 Scher et al. proposed the following classification of prostate cancer tumors based on hormone sensitivity: (i) hormone-naive; (ii) androgen-independent and hormone-sensitive; and (iii) androgen-independent and hormone-insensitive.2 For tumors in category (ii), those that proliferate in a castration environment may undergo programmed cell death in response to second-line hormonal manipulation. Steroidal antiandrogen chlormadinone acetate, as well as the non-steroidal antiandrogens bicalutamide and flutamide, available in Japan and covered by national health insurance, differ in several important functioning respects.3 Based on the classification of Scher, it is possible that a patient who has relapsed after first-line MAB therapy will respond to administration of another antiandrogen. In addition, it has recently been reported that certain patients with disease resistant to first-line MAB responded to alternative antiandrogens given as second- or third-line hormonal therapy.4,5 In the present study, we analyzed the clinical effects of flutamide as a second-line MAB agent in patients with relapsing prostate cancer who had received bicalutamide as first-line MAB therapy.

Methods

Patients and study design

A total of 13 patients with histologically confirmed prostate cancer treated at our hospital between 1999 and 2005 were enrolled. Histological findings were determined by systematic prostatic needle biopsy results and clinical staging was evaluated according to tumor node metastasis (TNM) classification using transrectal ultrasound, computed tomography, magnetic resonance intensity and bone scintigram examinations.

All patients received an luteinizing hormone releasing hormone (LHRH) agonist, either goserelin acetate at 3.6 mg or leuprorelin acetate at 3.75 mg, given by s.c. depot injection every 4 weeks, plus an additional antiandrogen (80 mg/day bicalutamide) as a first-line MAB agent. After first-line MAB was shown to have failed, bicalutamide administration was discontinued for 8 weeks to investigate the existence of antiandrogen withdrawal syndrome (AWS). All then received flutamide at 375 mg/day as a second-line agent. Prostatic specific antigen (PSA) levels were determined using a chemiluminescent enzyme immunoassay in most cases by our laboratory every 4 weeks. In all cases, LHRH agonist administration was continued to maintain medical castration after failure of first-line MAB.

Evaluation of response

The initial hormonal therapy was administration of LHRH agonist only or that plus bicalutamide. In the former group of patients treated by medical castration only at the start of hormonal therapy, first-line MAB was defined as treatment with LHRH agonist plus bicalutamide received after that monotherapy was resisted. We classified the patients according to PSA levels in response to hormonal therapy. With first-line MAB, a complete response (CR) was defined as a decrease in PSA levels to less than 4 ng/mL at 3 months after therapy, while a partial response (PR) was considered to be a decrease in PSA levels of greater than 50% with a concentration not less than 4 ng/mL. The existence of AWS was defined as a decrease in PSA levels of greater than 50% after the stoppage of bicalutamide. Second-line MAB therapy with flutamide was started after evaluation of AWS. Following second-line MAB, response was defined as a decrease in PSA level of greater than 50% from that at the start of therapy. Toxicity was evaluated by determination of liver function each month. In all cases that received first- and second-line MAB, we defined disease progression as increased PSA levels on three successive occasions, while response duration was considered to be the period from the start of either type of MAB until progression. Statistical analyses of differences in response to therapy were evaluated by a Mann–Whitney U-test or a χ2 test.

Results

Patient characteristics

Patient characteristics are shown in Table 1. The median age was 74.0 years old and all patients in clinical stage D had bone metastasis. Three were treated by medical castration only at the start of hormonal therapy and received bicalutamide as the first-line antiandrogen after that monotherapy was resisted, while the other 10 started with first-line MAB from the beginning. All patients responded to first-line MAB (CR = 10, PR = 3). The median duration of response to first-line MAB was 12 months and ranged 4–24 months. AWS was observed in two patients, and the duration was 3 and 10 months, respectively. None of the patients discontinued second-line MAB because of toxicity.

Table 1.  Patient characteristics
Median age, years (range)74.0 (58–80)
  1. AWS, antiandrogen withdrawal syndrome; CR, complete response; LHRH, luteinizing hormone releasing hormone; MAB, maximum androgen blockade; PR, partial response.

Clinical stage
 A1
 B2
 C3
 D7
Gleason score
 ≤ 63
 74
 8–106
Initial hormonal therapy
 LHRH agonist only3
 MAB10
Median PSA at initial hormonal therapy, ng/mL (range)110.0 (27–1834.8)
Response to first-line MAB
 CR10
 PR3
AWS
 Yes2
 No11

Effects of flutamide as a second-line agent

Five (38.5%) of the 13 patients had a greater than 50% decrease in PSA levels with second-line MAB with flutamide and were considered to be responders. The median duration of PSA response was 11 months (range, 5–20 months). In the patient with a 20-month duration of PSA response (Fig. 1), that response continues at the time of writing. In addition, four (30.8%) patients had brief and minor (less than 50% decrease) PSA responses after the start of flutamide administration.

Figure 1.

Changes in prostrate-specific antigen (PSA) levels in a patient who responded to second-line maximum androgen blockade (MAB) for a long period. The patient was a 74 years old at the time of first treatment for prostate cancer, and had histological findings that included a Gleason score of 3 + 3, and was classified as clinical stage T3bNoM1b. The initial PSA level of 47.08 ng/mL was decreased to a nadir of 0.03 ng/mL in response to first-line MAB with bicalutamide, and that response continued for 15 months. The patient was determined to have antiandrogen withdrawal syndrome (AWS) after relapse following first-line MAB and received second-line MAB with flutamide. The decline in PSA in response to second-line MAB was sustained for 20 months with a PSA nadir of 0.003 ng/mL.

Comparisons of different factors between responders and non-responders

We compared several factors in order to determine the differences between responders and non-responders (Table 2). Patients who had a longer duration of response to first-line MAB and initial hormonal therapy had a significantly greater response to second-line MAB. Among the 10 patients who received first-line MAB from the beginning, the three responders tended to have a longer duration of response to first-line MAB than the seven non-responders (median response duration: responders, 15 months [range, 12–20 months]; non-responders, 12 months [range, 4–18 months][= 0.1337]). There were no statistically significant differences found for median age, clinical stage, Gleason score, initial hormonal therapy, response to first-line MAB, and AWS, as well as for PSA values at the time of starting first- or second-line MAB, at the time of starting initial hormonal therapy, and at the nadir following first-line MAB.

Table 2.  Comparisons of clinical factors in responders and non-responders to second-line MAB
 RespondersNon-respondersP-value
  1. PSA, prostrate-specific antigen.

No. patients58 
Median age, years (range)74.0 (67–78)73.0 (58–80)0.5571
Clinical stage  0.7249
 A–C24 
 D34 
Gleason score  0.1654
 ≤ 612 
 731 
 8–1015 
Initial hormonal therapy  0.2522
 LHRH agonist only21 
 MAB37 
Median starting PSA at initial hormonal therapy, ng/mL (range)52.0 (27–1500)137.3 (42.58–1834.8)0.5582
Median starting PSA at first-line MAB, ng/mL (range)47.1 (15.15–1500)92.1 (12.34–1834.8)0.3055
Median nadir PSA after first-line MAB, ng/mL (range)0.29 (0.03–2.16)0.46 (0.026–164.16)0.5571
Response to first-line MAB  0.1185
 CR55 
 PR03 
Median response duration of initial hormonal therapy, months (range)20.0 (12–56)12.0 (4–18)0.0326
Median response duration of first-line MAB, months (range)19.0 (12–24)9.5 (4–18)0.0185
AWS  0.2242
 Yes02 
 No56 
Median starting PSA at second-line MAB, ng/mL (range)6.1 (2.202–48.910)7.2 (1.255–704.75)0.8836

Discussion

Since the early 1980s, numerous randomized clinical trials have been conducted to evaluate the efficacy of MAB as compared with surgical or medical castration.6,7 In Japanese patients with advanced prostate cancer, MAB has become an established first-line hormonal therapy with the steroidal antiandrogen chlormadinone acetate, and non-steroidal antiandrogens bicalutamide and flutamide available for use. In addition, other clinical trials have been conducted to determine which steroidal and non-steroidal antiandrogens are useful for combined therapy. A survival advantage for non-steroidal antiandrogen over steroidal antiandrogen MAB was demonstrated in a recent collaborative meta-analysis of 27 randomized trials.6 In a study of Japanese patients, there were no significant differences found between MAB with steroidal antiandrogen and LHRH agonist monotherapy with respect to objective progression, overall survival or disease-specific survival.8 As for non-steroidal antiandrogens, flutamide-related hepatotoxicity in Japanese patients receiving MAB has been reported to occur at a high rate and more frequently than in Caucasians.9 Further, diarrhea has been reported to occur more frequently with flutamide than bicalutamide.10 Therefore, bicalutamide has recently become the drug of choice for first-line MAB for Japanese patients, because of the disadvantages with flutamide in terms of tolerability. Taking into consideration that most advanced prostate cancer patients relapse following first-line MAB with bicalutamide, our clinical evidence for the effectiveness of second-line MAB with flutamide is very important in Japan.

To our knowledge, only two retrospective studies have reported responses to second-line MAB with flutamide in patients who progressed on first-line MAB with bicalutamide.4,5 In those studies, flutamide at 375 mg/day was reported to be effective in 50% (five of 10) and 21.8% (12 of 55) of the patients, while the median durations of PSA response were 4 and 6 months, respectively. In the present study, nine (69.2%) of 13 patients had a decrease in PSA levels and five (38.5%) were responders with a greater than 50% decrease, which are similar results to those reported in the previous two reports. In contrast, the median duration of PSA response (11 months; range, 5–20 months) in our patients was longer as compared with those reports, with one patient showing a very long response duration of 20 months (Fig. 1). Our results suggest that some patients who show a response to flutamide as a second-line MAB drug may continue as responders for an extended period. Thus, our retrospective analysis of 13 patients confirms the efficacy of treatment with flutamide in second-line MAB.

It is important to determine which of several factors are suitable for use as predictive factors for the response to second-line MAB. Miyake reported that patients without bone metastasis or whose disease progressed for more than 1 year after the start of first-line MAB had a significantly higher incidence of good PSA response to second-line MAB.4 Kojima found that though second-line responders tended to have lower PSA levels at the start of second-line MAB and a longer first-line therapy response than non-responders, there was no significant difference in those parameters to predict responders.5 In the present study, patients who demonstrated a longer duration of response to first-line MAB had a significantly greater response to second-line MAB. From these findings, the duration of PSA response to first-line MAB is considered to be an important factor for estimation of response to second-line MAB. In other words, careful follow-up examinations during second-line MAB and consideration of other therapies thereafter are important points to consider when treating patients whose duration of PSA response to first-line MAB is short.

Miyake reported that PSA levels at the start of second-line MAB had no significant effect on the response to second-line MAB in a comparison of patients with PSA levels at ≥ 2.0 ng/mL and those with levels < 2.0 ng/mL5 In our study, median PSA levels at the start of second-line MAB were not significantly different between responders and non-responders. Further, though the two non-responders had very different PSA levels (359.68 ng/mL and 704.75 ng/mL) as compared to the other eight, there was no significant difference between those with a level of ≥ 100 ng/mL and those < 100 ng/mL (= 0.2242; data not shown). Therefore, PSA levels at the start of second-line MAB may not be associated with response to second-line MAB.

In conclusion, among patients with advanced prostate cancer who progressed on first-line MAB with bicalutamide, flutamide administration as a second-line antiandrogen was effective in some cases, especially for those who demonstrated a longer duration of response to first-line MAB. Our results confirm that MAB with flutamide can be an effective second-line hormonal therapy. Accumulation of such evidence is important to extend the choice of therapies for treatment of patients suffering from androgen ablation-resistant prostate cancer.

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