Clinical outcome of maximum androgen blockade using flutamide as second-line hormonal therapy for hormone-refractory prostate cancer

Abstract

OBJECTIVES

To investigate the efficacy of maximum androgen blockade (MAB) using flutamide as second-line hormonal therapy for advanced hormone-refractory prostate cancer (HRPC).

PATIENTS AND METHODS

The study included 55 patients with HRPC who were treated with MAB using flutamide (375 mg daily) as second-line hormonal therapy. All patients had previously received bicalutamide combined with either surgical or medical castration as first-line hormonal therapy, which failed. The effect of the second-line therapy was evaluated by serum prostate-specific antigen (PSA) level alone, and the response defined as a decrease of >50% from the baseline PSA at the start of second-line therapy.

RESULTS

On initiating second-line hormonal therapy there was a reduction in the PSA level in 25 of the 55 patients (45%), among whom 12 (22%) were regarded as responders, while the PSA level continued to increase in the remaining 30 (55%). The median (range) duration of the PSA response was 6 (1–13) months. During the observation period there were no severe side-effects from the second-line MAB therapy. Patients without bone metastases or whose disease progressed >1 year after first-line therapy had a significantly higher incidence of PSA response to second-line therapy, despite no significant effect of other factors examined on the PSA response to second-line therapy. Furthermore, the cause-specific survival in responders to second-line therapy was significantly better than that in nonresponders; however, multivariate analysis showed that no factors, including response to second-line therapy, could be used as independent predictors of cause-specific survival.

CONCLUSIONS

MAB using flutamide as second-line hormonal therapy can give a comparatively favourable PSA response with no severe side-effects; therefore, this therapy may be suitable for patients with HRPC after primary MAB using bicalutamide has failed, particularly in those with no bone metastases or whose disease has progressed for >1 year after first-line therapy.

Abbreviations

MAB

maximum androgen blockade

HRPC

hormone refractory prostate cancer

AW

androgen withdrawal.

INTRODUCTION

Hormonal therapy remains the best first choice for men with advanced prostate cancer, producing symptomatic and/or objective responses in >80% of patients [1,2]. To date, maximum androgen blockade (MAB) in a combined regimen with either a LHRH agonist or bilateral orchidectomy plus an antiandrogen has become the most widely used hormonal therapy for advanced prostate cancer [1,3]. The rational for MAB is as follows: castration effectively prevents testicular androgen synthesis, without affecting androgens of adrenal origin, while additional administration of an antiandrogen can block the action of adrenal androgens at the receptor level. Several recent studies showed that MAB for advanced prostate cancer gave significantly better patient survival than castration alone [3–5].

Unfortunately, progression to androgen-independence ultimately occurs within a few years after first-line hormonal therapy in most patients with advanced prostate cancer, and represents the major obstacle to improving the survival and quality of life in men with this disease [2]. Therefore, it is important to establish an effective strategy for hormone-refractory prostate cancer (HRPC); however, despite recent promising outcomes of a docetaxel-based regimen showing significant effects on the survival of patients with HRPC [6,7], conventional cytotoxic chemotherapy has limited effects against prostate cancer for several reasons, e.g. the inherent chemoresistant phenotype and the inability of elderly patients to tolerate its toxicity [8,9]. Collectively, these findings suggest that after first-line therapy fails, it would be suitable to use different types of hormonal therapy rather than conventional cytotoxic chemotherapy, by combining multiple agents with dose escalation.

Recent findings investigating the mechanism of antiandrogen-withdrawal (AW) syndrome suggest one possibility for treating patients after androgen-independent progression, i.e. mutations of the androgen receptor gene and/or its amplification might cause an altered response to antiandrogens [10,11], indicating that androgen independence after first-line therapy does not always mean that such tumours are resistant to further hormonal therapy. Indeed, several investigators reported the usefulness of second-line hormonal therapy for HRPC after primary MAB [12–16], and experimental studies also support the concept of this approach [17–19]. However, to our knowledge, it remains controversial whether second-line hormonal therapy could provide a survival benefit for men with HRPC; therefore, we analysed the clinical outcomes of patients with HRPC who were treated with MAB, using flutamide as second-line hormonal therapy.

PATIENTS AND METHODS

This study included 55 patients who were histologically diagnosed as having prostate cancer between April 2000 and May 2004. They subsequently received MAB with bicalutamide and had disease progression afterward. Serum PSA levels were measured using the automated assay system (Roche Diagnostics, Mannheim, Germany) at least every 2 months. Clinical variables were evaluated based on the findings of TRUS, systematic TRUS-guided needle biopsy, pelvic CT and bone scan, and were determined according to the TNM classification system [20]. The characteristics of the 55 patients are shown in Table 1.

Table 1.  Patient characteristics and treatment outcomes

Variable	Value
Median (range):
age, years	71 (55–87)
observation period, months	34 (6–55)
pretreatment PSA, ng/mL	89.3 (4.4–925.5)
n (%)
Biopsy Gleason score
<6	8 (15)
7	21 (38)
≥8	26 (47)
Lymph node metastasis
N0	34 (62)
N1	21 (38)
Bone metastasis
M0	17 (31)
M1	38 (69)
Median (range); after first-line MAB:
nadir PSA, ng/mL	0.72 (0.01–142.3)
time to progression, months	14 (4–47)
AW response, n (%):
Yes	7 (13)
No	48 (87)
Median (range):
interval of AW response, months	4.5 (1–10)
PSA at start of second-line MAB, ng/mL	2.13 (0.10–395.6)
Response to second-line MAB, n (%):
Yes	12 (22)
No	43 (78)
Median (range) interval of response to  second-line MAB, months	6 (1–13)

All patients were initially treated with MAB consisting of either bilateral orchidectomy or medical castration using LHRH agonist (3.6 mg goserelin acetate or 3.75 mg leuprorelin acetate every 4 weeks) plus antiandrogen (80 mg bicalutamide daily) as first-line hormonal therapy. When first-line therapy was judged to fail, bicalutamide was discontinued to determine whether there was AW syndrome (defined as the PSA level being <50% of that when first-line therapy failed). Subsequent second-line hormonal therapy using 375 mg flutamide daily combined with either surgical or medical castration was started after evaluating the AW response. In this series, clinical progression was not considered, and treatment failure was defined as increased serum PSA levels on three successive occasions, with the response duration regarded as the time from the start of each treatment until failure. For second-line hormonal therapy, the response was defined as a decrease of >50% from the baseline serum PSA level at the start of second-line therapy.

Several factors associated with the PSA response were analysed using the chi-square test. The patients’ cause-specific survival rates were determined by the Kaplan-Meier method, and the difference determined using the log-rank test, with P < 0.05 considered to indicate significance in all tests.

RESULTS

In the 55 patients the median serum PSA level was ≈ 90 ng/mL (Table 1) and after first-line MAB using bicalutamide the median nadir serum PSA was 0.72 ng/mL, and the median time to treatment failure 14.0 months. The incidence of AW syndrome was analysed after first-line MAB failed; the serum PSA level decreased in 15 of the 55 patients (27%) by the time bicalutamide was stopped, but there was an AW response in only seven (13%), and the median interval of this response was 4.5 months (Table 1).

Before starting second-line MAB using flutamide, the median serum PSA level was 2.1 ng/mL. Second-line hormonal therapy resulted in a reduction of the PSA level in 25 of the 55 patients (45%), among whom 12 (22%) were regarded as responders, while the PSA level continued to increase in the remaining 30 (55%). The median duration of the PSA response was 6 months after the start of second-line therapy. There were no severe side-effects associated with second-line MAB using flutamide.

We subsequently analysed several factors associated with PSA response after second-line MAB. As shown in Table 2, patients with no bone metastases or whose disease progressed for >1 year after the start of first-line therapy had a significantly higher incidence of PSA response to the second-line therapy than those with bone metastases or whose progression occurred within a year after the start of first-line therapy, respectively; however, age, serum PSA level at the start of first-line therapy, biopsy Gleason score, lymph node metastasis, nadir level of serum PSA after first-line therapy, AW response and serum PSA level at the start of second-line therapy had no significant effect on the PSA response to second-line therapy.

Table 2.  Associations between several factors and response to second-line MAB therapy

Variable	Responders (12)	Nonresponders (43)	P
Age, years			0.99
<70	7	25
≥70	5	18
Pretreatment PSA level, ng/mL			0.34
<100	8	22
≥100	4	21
Biopsy Gleason score			0.91
<6	2	6
7	5	16
≥8	5	21
Lymph node metastasis			0.70
N0	8	26
N1	4	17
Bone metastasis			0.020
M0	7	10
M1	5	33
Nadir PSA after first-line MAB, ng/mL			0.42
<1	8	23
≥1	4	20
Time to progression after first-line MAB, months			0.030
<12	3	26
≥12	9	17
Antiandrogen withdrawal response			0.64
Yes	2	5
No	10	38
PSA at start of second-line MAB, ng/mL			0.66
<2.0	5	21
≥2.0	7	22

During the study 11 patients died from prostate cancer, i.e. 10 of the 11 who did not respond to second-line MAB and one who responded. As shown in Fig. 1, cause-specific survival in responders to second-line therapy was significantly better than that in nonresponders. Furthermore, to evaluate the predictive value of several factors for cause-specific survival, we used multivariate analysis with the Cox regression model; however, no factors, including response to second-line therapy, could be used as independent predictors of cause-specific survival (data not shown).

Figure 1. Cause-specific survival according to the response to second-line hormonal therapy. The cause-specific survival rate in responders was significantly higher than that in nonresponders.

DISCUSSION

To date there has been no standard approach for patients with advanced prostate cancer when first-line hormonal therapy fails, as established data are not available for therapeutic strategies that might improve the survival and quality of life for such patients [16]. Despite recent promising outcomes of cytotoxic chemotherapy using docetaxel for HRPC, the prognostic impact of this therapy remains limited, i.e. docetaxel-based therapies achieved a PSA response in about half the patients, but the median survival was <2 years [6,7]. Collectively, these findings indicate that a useful treatment option incorporating second-line hormonal therapy would be beneficial for these patients. Recently, several experimental and clinical studies have reported data supporting the use of second-line MAB after first-line MAB failed, including the secondary use of antiandrogens, therapies targeting adrenal steroid synthesis (i.e. ketoconazole, aminoglutethimide and corticosteroids) and oestrogenic therapies (i.e. diethylstilbestrol) [12–19]. Even so, the position of second-line hormonal therapy in the strategy for HRPC remains controversial. We therefore retrospectively analysed the clinical outcomes of second-line MAB with flutamide in 55 patients with HRPC who were initially treated by MAB with bicalutamide, as a phase III trial showed advantages of bicalutamide over flutamide as a component of MAB [21]. Although 93% of the patients had a complete or partial response to first-line MAB (data not shown), progression to androgen-independence ultimately occurred in all patients. There was a subsequent AW response in 13% of the patients, despite a relatively lower incidence of AW syndrome than that in previous studies after bicalutamide withdrawal [13,22]. Unfortunately, the precise mechanism underlying AW syndrome remains largely unknown, but some recent studies have shown the potential role of mutations of the androgen receptor gene in an altered response to antiandrogen [10,11,19]. Considering these findings, it is important to elucidate the effects of primary hormonal therapy at both the molecular and clinical levels, to significantly delay the emergence of hormone-refractory disease.

In the present series MAB using flutamide was given to all patients as second-line hormonal therapy, and there was a reduction in PSA level in 45% of the patients. When the response was defined as a decrease of >50% in PSA level, 22% could be regarded as responders. Furthermore, the cause-specific survival in responders to second-line MAB was significantly better than that in nonresponders. The outcomes of similar approaches to HRPC were recently reported [12–16]; for example, Kassouf et al.[12] noted a PSA response in 29% of patients after second-line hormonal therapy with nilutamide. Scher et al.[15] reported that 38% of patients with progressive disease initially treated with flutamide responded to an additional high dose of bicalutamide. To our knowledge, there has been only one study describing the efficacy of MAB with flutamide after first-line MAB with bicalutamide [13], which showed a response to second-line flutamide in half the patients after primary MAB using bicalutamide; however, this report was based on only 10 patients. Although it would be necessary to accumulate data for more patients over a longer period to draw definitive conclusions, we think that the present study is the first to include relatively many patients to show the clinical effects of second-line MAB using flutamide for HRPC.

It would be interesting to isolate factors identifying the subgroup of patients with HRPC who are likely to respond to second-line MAB with flutamide. In the present series, nonresponders to second-line MAB with flutamide tended to have a higher incidence of bone metastases and a shorter response period to first-line therapy than responders, although these two factors were not directly associated with survival (data not shown). Previous studies also detected some variables associated with the response to second-line therapy, e.g. serum PSA level before first-line therapy and the AW response [12,13]. These findings suggest that second-line hormonal therapy could be expected to have a favourable effect in patients with prostate cancer with comparatively indolent characteristics and limited disease extension. Moreover, Hara et al.[19] recently reported the possibility of predicting the response to second-line therapy based on the mutated patterns of the androgen receptor gene, suggesting the importance of investigating the molecular mechanism mediating the response of prostate cancer cells to hormonal therapy, focusing on the steroid nuclear receptor superfamily, including the androgen receptor and orphan receptor, and their mutations [17–19,23–25].

In conclusion, alternative MAB using flutamide can give a comparatively favourable PSA response with no severe side-effects in men with HRPC; therefore, this therapy may be worth considering for patients with hormone-refractory disease after primary MAB with bicalutamide has failed, particularly for those with no bone metastases or whose disease has progressed for >1 year after first-line therapy.

CONFLICT OF INTEREST

None declared.