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Keywords:

  • nilutamide;
  • androgen-independent prostate cancer;
  • secondary hormonal therapy;
  • PSA response

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

OBJECTIVE

To evaluate the activity of nilutamide as secondary hormonal therapy in patients with androgen-independent prostate cancer (AIPC), as treatment options are limited for these patients and secondary hormonal therapy with antiandrogens has advantages, including low toxicity, oral administration and high patient acceptance.

PATIENTS AND METHODS

We retrospectively identified 45 patients with AIPC who were treated with nilutamide as secondary hormonal therapy in two institutions. The decrease in prostate-specific antigen (PSA) levels, side-effects of treatment, and the relationship between baseline characteristics, type and duration of previous therapy and response to nilutamide were assessed. Most patients received oral nilutamide at 150 mg/day.

RESULTS

Eighteen of 45 evaluable patients (40%) had a PSA level decrease of ≥ 50%. Responders (PSA decline ≥ 50%) had a median (range) time to progression of 4.4 (0.31–44.7) months. There were responses to nilutamide whether used as the second to fifth line of hormonal therapy. There were no differences in response to nilutamide based on clinical stage, type of local therapy, PSA level at diagnosis or initiation of nilutamide, or type of previous antiandrogen therapy. Responders were more likely to have received monotherapy with luteinizing hormone-releasing hormone analogues or orchidectomy as first-line hormonal treatment (P = 0.02). The most common reversible adverse effects were mild to moderate visual adaptation effects, reported in 20% of patients.

CONCLUSIONS

Nilutamide appears to be an effective secondary hormonal therapy in patients with AIPC and is associated with a mild toxicity profile.


Abbreviations
AR

androgen receptor

AIPC

androgen-independent prostate cancer

DFCI

Dana-Farber Cancer Institute

LSU

Louisiana State University.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Prostate cancer remains the second most common cause of cancer death in men in the USA; the standard initial management of metastatic prostate disease consists of androgen-deprivation therapy. While most patients will respond to hormonal therapy, some will progress to androgen-independent prostate cancer (AIPC), often manifested, at least initially, by an asymptomatic increase in PSA level, in the setting of castrate levels of testosterone [1]. When initial hormonal therapy fails options include secondary hormonal therapy and chemotherapy; the former may include steroidal or nonsteroidal antiandrogens, adrenal androgen inhibitors (e.g. ketoconazole) and oestrogenic therapies [2]. Nilutamide (Nilandron®, Aventis, Bridgewater, NJ) is one of the three nonsteroidal antiandrogens available in the USA [3–6]. Despite functional similarities, each antiandrogen appears to interact uniquely with the androgen receptor (AR) [7]; detailed mechanisms of interaction between antiandrogens and the AR are yet to be elucidated. Nilutamide combined with orchidectomy, compared to orchidectomy alone, prolongs the time to progression and survival as first-line hormonal therapy [8,9]. However, there is little experience with the use of nilutamide as secondary hormonal therapy [10–12]. Two recent reports evaluated the efficacy of nilutamide as secondary hormonal therapy in patients with AIPC. Desai et al.[10] reported PSA level decreases of ≥ 50% in seven of 14 patients with AIPC treated with one or two previous antiandrogens, with a median duration of response of 11 months. In a study of 28 patients with AIPC, Kassouf et al.[12] reported PSA level decreases of ≥ 50% in 43% after nilutamide; 29% had a sustained response with a median time to progression of 7 months. These small studies showed a significant PSA level decline with a modest toxicity profile. Light-dark adaptation disorders (30%), alcohol intolerance (5%) and interstitial pneumonitis (<2%) were reported as unique reversible side-effects of nilutamide [13]. Although nilutamide has been used infrequently compared with other antiandrogens, its utility as a secondary hormonal therapy represents an opportunity to enhance the available therapeutic options in this group of patients. We retrospectively analysed patients with AIPC to evaluate the efficacy and toxicity profile of nilutamide as secondary hormonal therapy, and further investigated the difference between those responding or not responding to nilutamide, to investigate predictors of response.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

The institutional review boards of Dana-Farber Cancer Institute (DFCI) and Stanley Scott Cancer Center at Louisiana State University (LSU) approved this retrospective study. Eligible patients with AIPC included those treated with LHRH analogues or bilateral orchidectomy, and with progressive disease, according the PSA Working Group Consensus Criteria [14]. Patients on LHRH analogue therapy were required to have continued this treatment during treatment with nilutamide. We used a modified version of the Consensus Criteria to evaluate the PSA level response and progression; PSA data were not routinely obtained every 4 weeks and patients were not required to have radiographic evidence of disease. Any number of previous secondary hormonal therapies was allowed. Patients with a history of previous chemotherapy were not excluded. Patients were excluded from the analysis if they received concurrent antiandrogens, oestrogens, adrenal steroid inhibitors, systemic steroids or chemotherapy. All patients who had received another antiandrogen treatment discontinued that antiandrogen at least 4 weeks before starting nilutamide, to exclude an antiandrogen withdrawal effect. Treatment consisted of once-daily nilutamide at 150–300 mg. All consecutive patients were assessed in this retrospective analysis.

The primary endpoint of the study was to define the percentage of evaluable patients who achieved a clinically significant decline in PSA levels after nilutamide, defined as a ≥ 50% decrease. Among nonresponders, the date of progression was defined as the date nilutamide was ended because of an increasing PSA level. The time to progression was calculated from the start of nilutamide until the date of progression. Patients were censored if they stopped treatment for toxicity before progression, or at the last known follow-up, if they were still responding. Routine radiographic imaging was not used.

Variables were summarized as the n (%) of patients or median (range). Exact binomial 95% CI were reported for the response rate. Categorical variables were compared between responders and nonresponders using Fisher's exact test and extensions. Continuous variables were compared using Wilcoxon rank-sum tests, with P < 0.05 taken to indicate statistical significance. The time to progression was calculated using the method of Kaplan and Meier, with the median (range) reported with + denoting a censored minimum or maximum time. Toxicities were summarized in tables.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

In all, 57 patients were identified at both institutions; 45 were evaluable for analysis, with eight ineligible because they had received nilutamide as first-line hormonal therapy (six) and were receiving concomitant oestrogen or steroid therapy (two). Four patients were not evaluable because they had insufficient PSA level response data. Of 45 evaluable patients, 33 (73%) were followed at DFCI and 12 (27%) at LSU.

The baseline patient characteristics are shown in Table 1; the median (range) follow-up from starting nilutamide therapy was 15.4 (1.1–59.2) months. At the start of nilutamide there was radiographic evidence of metastases in 15 patients (33%; Table 1). The dose of nilutamide was 150 mg/day in 38 of 45 patients (84%) while seven were treated with 300 mg/day.

Table 1.  Baseline characteristics of the 45 patients
CharacteristicValue
  1. RP, radical prostatectomy; EBRT, external beam radiation therapy.

Median (range):
Age, years64 (43–88)
PSA at diagnosis, ng/mL17.0 (2.5–2356)
Gleason scores, n (%)
 4–6 11 (24)
 7 6 (13)
 8–916 (36)
 Unknown12 (27)
Clinical stage, n (%)
 T113 (29)
 T210 (22)
 T3-4 5 (11)
 Unknown17 (38)
Local therapy, n (%)
 RP 4 (9)
 RP + EBRT 11 (24)
 EBRT15 (33)
 EBRT + brachytherapy 4 (9)
 Brachytherapy 1 (2)
 None10 (22)
Castration, n (%)
 Bilateral orchidectomy 7 (16)
 LHRH analogue38 (84)
At start of nilutamide:
Median (range) PSA level, ng/mL15.6 (0.08–1287)
Metastases, n (%)15 (33)
 Bone 11 (24)
 Lymph nodes 2 (4)
 Bone and lymph nodes 2 (4)

Eighteen of 45 patients (40%; 95% CI 25.7–55.7%) had a decrease in PSA level of ≥ 50%; the median (range) time to progression on nilutamide was 4.4 (0.31–44.7) months. Seven patients (16%) were still on nilutamide at the time of the present analysis. There were no differences in response to nilutamide based on hospital (DFCI vs LSU), clinical stage, type of local therapy, PSA level at diagnosis, or PSA level at the start of nilutamide therapy. No responders reported the development of pain or had a worsening bone scan during the response period on nilutamide.

Table 2 summarizes the characteristics of nilutamide responders vs nonresponders, based on previous hormonal therapy. The median (range) duration of primary hormonal therapy was 29 (1–133) months. Responders were significantly more likely to have a history of primary hormonal treatment with monotherapy (LHRH analogue or bilateral orchidectomy alone) than were nonresponders (72% vs 33%; P = 0.02). Furthermore, although not statistically significant, responders tended to have a longer median duration of primary hormonal therapy than nonresponders (44 vs 26 months; P = 0.18).

Table 2.  Characteristics of the responders and nonresponders based on previous hormonal therapy
VariableRespondersNonresponders
N (%) patients18 (40)27 (60)
Nilutamide as x-line hormone therapy, n:
 2nd 9 9
 3rd 4 8
 4th 2 5
 5th 3 5
Types of previous hormone therapy, n:
 Bilateral orchidectomy 4 3
 LHRH analogue1425
 Bicalutamide1223
 Flutamide 1 8
 Ketoconazole 4 8
 Oestrogen 3 0
 Prednisolone 1 2
 Finasteride 0 2
 PC-SPES 1 4

We also assessed the history of antiandrogen use before nilutamide; the median duration of any previous antiandrogen therapy was 15.8 (0–133) months. Twenty-six patients received previous bicalutamide (11 responders and 15 nonresponders), and nine received bicalutamide and flutamide (one responder and eight nonresponders). There were responses to nilutamide when used as the second to fifth line of therapy (Table 2).

Among 35 patients previously treated with antiandrogens, 24 had attempted antiandrogen withdrawal. Six (25%) experienced an antiandrogen withdrawal response; having a response did not correlate with a subsequent nilutamide response (P = 0.38), although there were too few patients to allow definitive conclusions. Four patients received chemotherapy before nilutamide therapy; two of these responded to nilutamide, while two who had received estramustine and docetaxel + estramustine for AIPC did not respond to nilutamide.

Table 3 summarizes the toxicities reported with nilutamide. Of 45 evaluable patients, the most common side-effect was visual light-to-dark adaptation difficulties in 20%. Fatigue and nausea were also reported in some patients. Seven patients had toxicity that required discontinuation of nilutamide (16%). Notably, some patients had syncope, shortness of breath and cough during therapy, although there was no clear evidence of pulmonary infiltrates. No deaths were reported during nilutamide therapy. All side-effects appeared to be reversible, and there was no grade 3 or 4 toxicity during nilutamide therapy.

Table 3.  Grade 1/2 toxicity
Adverse effectTotal (%)
Dark adaptation9 (20)
Fatigue6 (13)
Nausea3 (7)
Diarrhoea1 (2)
Decreased appetite1 (2)
Cough1 (2)
Shortness of breath1 (2)
Syncope1 (2)
Liver function test abnormalities1 (2)
Insomnia1 (2)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Although patients with advanced prostate cancer usually respond to primary hormonal therapy, most eventually progress to AIPC. Treatment options include additional hormonal manipulations, including the secondary use of antiandrogens. However, the timing of therapy, which particular drugs to use, and how to incorporate these agents into a long-term therapeutic strategy remain controversial. We attempted to retrospectively identify the patient characteristics associated with a response to nilutamide. Characterizing these patients is important because it allows the identification of patients who are more likely to benefit from additional antiandrogen therapy. Secondary hormonal therapy with antiandrogens has the advantage of low toxicity, easy oral administration and high patient acceptance. Disadvantages include their high cost, low but real risk of serious liver and pulmonary toxicity, and lack of randomized data showing efficacy on clinically relevant endpoints.

In this retrospective study, 40% of patients who progressed after at least one previous hormonal therapy subsequently responded to nilutamide, with a median time to progression of 4.4 months. Nilutamide responders (PSA level decline of ≥ 50%) had received a shorter duration of previous antiandrogen therapies and significantly more often had a history of primary hormonal treatment with monotherapy (LHRH analogue or surgical castration alone) than had nonresponders. Both of these factors suggest that a response to nilutamide is most likely in patients who have had the least previous exposure to other antiandrogens. However, notably, patients responded to nilutamide even when it was used as the third-, fourth-, or fifth-line hormonal therapy. Indeed, two-thirds of responders received either one or two antiandrogens before nilutamide. The duration of the primary hormonal therapy was also longer in responders than in nonresponders. This implies that responders may have more ‘hormone-sensitive’ disease than nonresponders.

These observations suggest that nonsteroidal antiandrogens have unique mechanisms of action, a finding which has been shown in vitro in androgen-dependent LNCaP cells [7]. Although antiandrogens share a common chemical structure required for interaction with the AR, nilutamide has a unique interaction with the ligand-binding domain of the AR compared with flutamide and bicalutamide when analysed by three-dimensional crystal structure [15]. An Asn705 residue in the ligand-binding domain of the AR is crucial in anchoring flutamide and bicalutamide, and in determining its antiandrogenic activity, but has no such role in the case of nilutamide. This is one possible explanation as to why nilutamide remains effective in some patients in whom previous antiandrogen therapy has failed.

AR signalling is pivotal in the initiation and growth of prostate cancer, and in its response to hormonal therapy [16]. In a low-androgen environment, prostate cancer cells develop adaptive mechanisms which may include mutations, gene amplification of and changes in co-regulators to ARs to sustain growth signalling [16]. AR mutations after initial antiandrogen therapy have been reported in ≈ 44% of cases [17–20]. An understanding of the molecular mechanisms of response to different antiandrogens would help to identify patients who might benefit from specific antiandrogens, and may result in the development of more targeted therapies in the future.

In the present retrospective study, nilutamide appeared to have activity as a secondary hormonal therapy in AIPC. Notably, some patients had benefit from nilutamide even when it was used as fifth-line hormonal therapy. We think that this study adds to the growing experience with nilutamide as secondary hormonal therapy and supports the expanding practice of using this agent in patients who have already received an antiandrogen such as bicalutamide. However, as this was a retrospective study, we cannot eliminate inherent biases, including patient selection and an incomplete dataset. Randomized clinical trials are necessary to assess whether such therapy confers any survival benefit. Although adverse events including visual changes (light-to-dark adaptation), fatigue and respiratory symptoms were mild and reversible, these need to be carefully monitored by physicians.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

We thank Carolyn P. Evan for her excellent administrative support.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES