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Ketoconazole in Taiwanese castration-resistant prostate cancer patients: Evaluation of response rates, durations, and predictors
Urological Science 23 (2012) 48e51
Contents lists available at SciVerse ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Original article
Ketoconazole in Taiwanese castration-resistant prostate cancer patients: Evaluation of response rates, durations, and predictors Bing-Juin Chiang, Yeong-Shiau Pu, Hong-Jeng Yu, Chao-Yuan Huang* Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 May 2011 Received in revised form 16 August 2011 Accepted 26 October 2011 Available online 11 May 2012
Background/purpose: To evaluate the efficacy of ketoconazole in castration-resistant prostate cancer. Materials and methods: We reviewed the medical records of consecutive patients with pathologically confirmed prostate cancer from May 2006 to December 2008. The inclusion criteria were: (1) receiving 200 or 400 mg ketoconazole three times daily and replacement doses of prednisolone; (2) antiandrogen withdrawal for at least 2 months before ketoconazole treatment; and (3) no prior cytotoxic agents or other CYP17 inhibitors. Treatment consisted of ketoconazole at 200 mg three times daily (Group A) and 400 mg three times daily (Group B). Patients’ characteristics, time to prostate-specific antigen (PSA) progression, duration of PSA response, and adverse events were evaluated. Results: Of the 37 patients in Group A, 14 (37.8%) experienced a PSA response. Of the seven patients in Group B, four (57.1%) experienced a PSA response. Median durations of time to progression in those who experienced a > 50% PSA decline were 7.5 and 11.5 months in Group A and Group B, respectively. Median duration of PSA response was 5.5 and 9.0 months in Group A and Group B, respectively. There was no difference in the PSA response or time to progression between the two groups. Orchiectomy had a borderline unfavorable effect on the PSA response rate (p ¼ 0.067). Conclusion: The present study demonstrated that ketoconazole contributed to the PSA response in patients with castration-resistant prostate cancer. The efficacy and toxicity profiles were comparable to those in previous studies. Orchiectomy had a borderline unfavorable effect on PSA response rate. Further studies are required to confirm the efficacy of ketoconazole therapy in surgically castrated patients. Copyright Ó 2012, Taiwan Urological Association. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: castration-resistant prostate cancer hormone manipulation ketoconazole prostate cancer
1. Introduction Androgen deprivation therapy can achieve a castration status for a period, but prostate cancer eventually progresses to castration resistance. Several mechanisms allow androgen receptor signaling to persist. It is believed that androgen receptors are frequently overexpressed and appear to be activated by castration levels of androgen and adrenal androgens.1 The adrenal glands secrete w10% of the circulating androgen in humans. Ketoconazole, a broad-spectrum azole antifungal agent, inhibits cytochrome P450 and suppresses testicular and adrenal androgen production through inhibiting both adrenocortical 11b-hydroxylase and cholesterol side-chain cleavage.2 A phase III trial (CALGB 9583) has demonstrated that antiandrogen withdrawal (AAWD) together with high-dose ketoconazole, 400 mg three times daily, and * Corresponding author. Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Rd., Taipei 100, Taiwan, ROC. E-mail address: [email protected] (C.-Y. Huang).
hydrocortisone, 30 mg each morning and 10 mg each evening, was associated with an objective prostate-specific antigen (PSA) response, and 8.6 months median time to PSA progression in 32% of 128 patients with castration-resistant prostate cancer (CRPC).3 Low-dose ketoconazole, at 200 mg three times daily, with replacement doses of hydrocortisone (20 mg every morning and 10 mg at bedtime), was associated with a PSA response and 30 weeks median duration of PSA response in 46% of 28 patients.4 Here, we conducted a retrospective study to share our experience of using ketoconazole in patients with CRPC at National Taiwan University Hospital. The toxicity profiles and predictors of the PSA response were also evaluated. 2. Materials and methods We retrospectively reviewed the medical records of consecutive patients with CRPC from May 2006 to December 2008. The definition of CRPC was based on European Association of Urology guidelines.5 The inclusion criteria were: (1) receiving 200 or 400 mg ketoconazole three times daily and replacement doses of
1879-5226/$ e see front matter Copyright Ó 2012, Taiwan Urological Association. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.urols.2012.04.004
B.-J. Chiang et al. / Urological Science 23 (2012) 48e51
prednisolone; (2) AAWD for at least 2 months before ketoconazole treatment; and (3) no prior cytotoxic agents or other CYP17 inhibitors. Patients’ characteristics, time to PSA progression, duration of PSA response, and toxicity profiles were evaluated according to guidelines of the Prostate Specific Antigen Working Group and National Cancer Institute Common Toxicity Criteria.6 Results were analyzed with commercial statistical software. Age and PSA were compared using the median test. Categorical data were compared using a c2 test and Fisher’s exact test. For all tests, a two-tailed p value <0.05 was regarded as significant.
49
Table 2 Clinical outcomes in the separate groups.
AAWD response 50% PSA decline, n (%) 75% PSA decline, n (%) Among 50% PSA decline Median time to progression, mo (range) Median duration of PSA response, mo (range)
Group A
Group B
p value
8 14 (37.8%) 8 (21.6%)
1 4 (57.1%) 1 (14.3%)
0.644 0.175 0.585
7.5 (1e87)
11.5 (4e16.5)
1
5.5 (0.5e86)
9.0 (2e13)
1
3. Results
Group A, 200 mg ketoconazole three times daily; Group B, 400 mg ketoconazole three times daily; AAWD ¼ antiandrogen withdrawal; PSA ¼ prostate-specific antigen.
3.1. Patient characteristics
3.2. Clinical outcomes
In total, 44 patients with CRPC were included, with a median age of 73 years (range, 55e88 years). Median serum PSA at diagnosis of prostate cancer was 74.5 ng/mL (range, 4.3e3310 ng/mL). Four patients (9.1%) underwent radical prostatectomy as definitive local therapy at the time of prostate cancer diagnosis, and 10 patients (22.7%) underwent external beam radiotherapy. At the start of ketoconazole therapy, 36 patients (81.8%) had bone metastasis, and the median PSA level was 30.9 ng/mL (range, 5.2e350.2 ng/mL). Thirty-eight patients (86.4%) received luteinizing hormone releasing hormone agonist (LHRHa), and two patients (4.5%) underwent bilateral orchiectomy as androgen deprivation therapy. Four patients (9.1%) received LHRHa and subsequent bilateral orchiectomy. Initial Gleason scores are given in Table 1. The mean duration of hormone therapy before ketoconazole therapy was 32 months (range, 6e208 months). Patient characteristics were categorized into ketoconazole 200 mg three times daily (Group A) and 400 mg three times daily (Group B) and are listed in Table 1. There were no significant differences in patients’ characteristics between the groups.
Of the 44 patients, 37 patients received 200 mg ketoconazole three times daily (Group A), and seven patients received 400 mg ketoconazole three times daily (Group B). Eighteen patients experienced a PSA decline of 50% after ketoconazole therapy. Of the 37 patients in Group A, 14 (37.8%) had a 50% PSA decline, and eight (21.6%) had a 75% PSA decline. Of the seven patients in Group B, four (57.1%) had a 50% PSA decline, and one (14.3%) had a 75% PSA decline. There was no significant difference between the two groups. Median time to progression in those who experienced a > 50% PSA decline was 7.5 months and 11.5 months in Group A and Group B, respectively. Median duration of PSA response was 5.5 and 9.0 months in Group A and Group B, respectively. There were no differences in the time to progression or duration of the PSA response between the two groups. Clinical outcomes for the separate groups are listed in Table 2. Clinical factors of those with a > 50% response and the others were compared. Neither age (p ¼ 0.417), initial PSA level (p ¼ 0.651), duration between diagnosis of prostate cancer and initiation of ketoconazole (p ¼ 0.759), PSA level on initiation of ketoconazole (p ¼ 0.759), prior radical prostatectomy (p ¼ 1.0), prior radiotherapy (p ¼ 0.504), prior LHRHa (p ¼ 0.634), prior orchiectomy (p ¼ 0.067), metastasis at diagnosis (p ¼ 0.515), nor Gleason score (p ¼ 0.14) could independently predict PSA response.
Table 1 Patient characteristics categorized into Group A (ketoconazole 200 mg three times daily) and Group B (ketoconazole 400 mg three times daily).
Median age, yr (range) Median PSA, ng/mL, at diagnosis (range) Median PSA, ng/mL, at initiation of ketoconazole (range) Median duration (mo) between diagnosis of prostate cancer and initiating ketoconazole (range)
Group A
Group B
73 (55e88) 92.6 (4.3e3310)
76 (59e86) 74.5 (13.9e330.5)
29.5 (5.2e350.2)
32.2 (13.8e221.2)
30 (6e174)
32 (6e204)
Gleason score, n 4e6 7 8e10
5 10 19
2 1 4
Definitive local therapy, n Radical prostatectomy Radiotherapy
4 8
0 2
31 2 4
7 0 0
20 10 2
5 1 0
Castration therapy LHRHa Orchiectomy LHRHa and subsequent orchiectomy Metastasis before ketoconazole Bone metastasis Bone and soft-tissue metastasis Soft-tissue metastasis only
LHRHa ¼ luteinizing hormone releasing hormone agonist.
4. AAWD response Nine patients (20.5%) experienced AAWD response before treatment with ketoconazole. There was no significant difference between the two groups. 4.1. Adverse events Table 3 shows a summary of adverse events during treatment with ketoconazole. Of the 44 patients, 13 (29.5%) experienced adverse events. The most common adverse event was elevation of the liver function. Four patients (9.1%) had grade 1/2, and one patient had grade 3 elevated liver function. The patient Table 3 Summary of adverse events during treatment with ketoconazole. Adverse event
Grade 1/2
Grade 3
Fatigue Arrhythmia Vertigo Epigastralgia Nausea Headache Elevation of liver function
2 1 1 2 1 1 4
e e e e e e 1
Two patients in Group B experienced adverse events of nausea and vertigo.
50
B.-J. Chiang et al. / Urological Science 23 (2012) 48e51
experiencing grade 3 elevation of liver function withdrew from treatment. Two patients (4.5%) had grade 1/2 fatigue. One (2.3%) patient had grade 1 arrhythmia and stopped treatment. One (2.3%) patient had grade 1 vertigo. Two patients (4.5%) had epigastralgia and stopped treatment. One (2.3%) patient had grade 1 nausea. One (2.3%) patient had grade 1 headache. There was no significant difference in the total number of adverse events between the two groups (p ¼ 1.0). Four patients (9.1%) terminated treatment with ketoconazole due to adverse events, all of whom were in Group A. 5. Discussion Previous studies have reported the use of a > 50% decrease in PSA as an intermediate marker of survival.7e9 Mark et al have reported that a > 75% decline in PSA in response to high-dose ketoconazole therapy predicts better survival.10 Table 4 lists biochemical response rates of ketoconazole therapy reported in the literature. The use of ketoconazole as secondary hormone manipulation therapy for CRPC achieved 27e63% PSA responses.4,9e13 In the present study, we demonstrated the PSA response to different doses of ketoconazole therapy: 37.8% and 21.6% of patients who received 200 mg ketoconazole three times daily experienced > 50% and > 75% PSA declines, and 57.1% and 14.3% of patients who received 400 mg ketoconazole three times daily experienced > 50% and > 75% PSA declines, respectively. The number of patients in Group B who tended to achieve 50% PSA decline was insignificant, perhaps because of the low case number. Ketoconazole suppresses androgen production in the testes and adrenal gland. In the CALGB 9583 study,3 the largest prospective study to evaluate adrenal androgen levels in patients treated with ketoconazole,dehydroepiandrosterone (DHEA) and androstenedione achieved a modest increase in adrenal androgen levels at the time to progression. Suppression of androgen was partially reversed at the time of disease progression. Additional responses occurred in some patients after dose escalation.14 The biochemical response was influenced by the dose of ketoconazole. This suggests that the dose might be insufficient to suppress production of adrenal androgen in those patients who had no PSA response. However, in the present study, we failed to determine statistically if more patients who received 400 mg ketoconazole three times daily had a PSA response than those who received 200 mg three times daily due to the small sample size. Ketoconazole absorption from the gastrointestinal tract is variable. Its dissolution is dependent on gastric acidity. The elimination half-life is 6.5e10 hours. Changes in plasma testosterone levels vary among individuals,15 and the ability to measure serum ketoconazole levels is still unavailable. Considering the adverse effects, the dose of ketoconazole should be individualized. Therapy can begin with a low dose of ketoconazole that is well tolerated and has moderate activity.4 Subsequent escalation to a high dose can be applied if patients encounter PSA progression.14
None of the six patients who underwent an orchiectomy in the present study had a PSA response, although there was a borderline unfavorable effect on the PSA response rate (p ¼ 0.067). Oka et al have reported that LHRHa significantly decreases serumDHEA, whereas orchiectomy does not decrease serum DHEA.16 This suggests that patients receiving simultaneous LHRHa and ketoconazole therapy might tend to have a PSA response. Previous studies have failed to demonstrate the impact of surgical castration on the PSA response rate.4,9e12 Further studies are required to determine the efficacy of ketoconazole therapy in surgically castrated patients. In the present study, 29.5% of patients experienced adverse events during treatment. Four patients stopped ketoconazole due to adverse events. Two of the four patients had epigastralgia. One patient experienced grade 3 elevation of liver function. One patient had arrhythmia. All of these patients were in Group B. In the CALGB 9583 study,3 21% of patients receiving 400 mg ketoconazole three times daily had grade 3/4 toxicity. Fatigue and neurotoxicity were the most common adverse effects and were seen in 4% of patients. In this study, the most common adverse events were elevation of liver function, epigastralgia, and fatigue. Abiraterone acetate, a more potent adrenolytic agent, was recently approved by the US Food and Drug Administration for treating metastatic CRPC in men with prior docetaxel chemotherapy. It also inhibits 17 a-hydroxylase/C17,20 lyase and results in suppression of subsequent formation of DHEA and androstenedione. The inhibition of androgen biosynthesis prolonged the overall survival by about 4 months in a phase III study.17 Although new adrenolytic agents have been developed in the past decade, ketoconazole still plays a role in treating CRPC because it is less expensive and is involved in new treatment schemes.18 Our study had several limitations. This was a retrospective study in which the authors reviewed the medical records of patients with CRPC. It lacked demographic data, including Eastern Cooperative Oncology Group performance status scores, and patient compliance data. The administration of replacement doses of prednisolone also lacked consistency and varied among physicians. In conclusion, the present study demonstrated that ketoconazole contributed to the PSA response in patients with CRPC. The efficacy and toxicity profiles were comparable to those in previous studies. Orchiectomy had a borderline unfavorable effect on the PSA response rate. Further studies are required to confirm the efficacy of ketoconazole therapy in surgically castrated patients. Conflicts of interest statement The authors declare that they have no financial or non-financial conflicts of interest related to the subject matter or materials discussed in the manuscript. Funding No specific funding.
Table 4 Studies of ketoconazole therapy in castration-resistant prostate cancer. Reference
No. of cases
Dosage
Small et al. (1997) Harris et al. (2001) Millikan et al. (2001) Small et al. (2004) Wilkinson et al. (2004) Scholz et al. (2005)
48 28 45 128 38 78
400 200 400 400 300 400
Chiang et al. (2011)
37
200 mg tid
mg mg mg mg mg mg
Percent of subjects with 50% PSA decline tid tid tid tid tid tid
PSA ¼ prostate-specific antigen; tid ¼ three times daily.
63% 46% 40% 27% 55% 44% of subjects had a 75%PSA decline 37.8%
Acknowledgments The authors declare that there is no conflict of interest. References 1. Reid AH, Attard G, Barrie E, de Bono JS. CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Clin Pract Urol 2008;5:610e20. 2. Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987;317:812e8. 3. Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-
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4.
5. 6.
7.
8.
9.
10.
independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 2004;22:1025e33. Harris KA, Weinberg V, Bok RA, Kakefuda M, Small EJ. Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J Urol 2002;168:542e5. Heidenreich A, Bolla M, Joniau S, Mason MD, Matveev V, Mottet N, et al. Guidelines on prostate cancer. European Association of Urology; 2010. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999;17:3461e7. Smith Jr JA, Lange PH, Janknegt RA, Abbou CC, deGery A. Serum markers as a predictor of response duration and patient survival after hormonal therapy for metastatic carcinoma of the prostate. J Urol 1997;157:1329e34. Kelly WK, Curley T, Leibretz C, Dnistrian A, Schwartz M, Scher HI. Prospective evaluation of hydrocortisone and suramin in patients with androgenindependent prostate cancer. J Clin Oncol 1995;13:2208e13. Small EJ, McMillan A, Meyer M, Chen L, Slichenmyer WJ, Lenehan PF, et al. Serum prostate-specific antigen decline as a marker of clinical outcome in hormone-refractory prostate cancer patients: association with progression-free survival, pain end points, and survival. J Clin Oncol 2001;19:1304e11. Scholz M, Jennrich R, Strum S, Brosman S, Johnson H, Lam R, et al. Long-term outcome for men with androgen independent prostate cancer treated with ketoconazole and hydrocortisone. J Urol 2005;173:1947e52.
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11. Small EJ, Baron AD, Fippin L, Apodaca D. Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol 1997;157:1204e7. 12. Millikan R, Baez L, Banerjee T, Wade J, Edwards K, Winn R, et al. Randomized phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer. Urol Oncol 2001;6:111e5. 13. Wilkinson S, Chodak G. An evaluation of intermediate-dose ketoconazole in hormone refractory prostate cancer. Eur Urol 2004;45:581e4. 14. Nakabayashi M, Xie W, Regan MM, Jackman DM, Kantoff PW, Oh WK. Response to low-dose ketoconazole and subsequent dose escalation to high-dose ketoconazole in patients with androgen-independent prostate cancer. Cancer 2006;107:975e81. 15. Glass AR. Ketoconazole-induced stimulation of gonadotropin output in men: basis for a potential test of gonadotropin reserve. J Clin Endocrinol Metab 1986;63:1121e5. 16. Oka H, Negoro H, Sugino Y, Iwamura H, Moroi S, Kawakita M. Change of serum adrenal androgens in prostatic cancer patients after bilateral orchidectomy or LHRH agonist treatment. Hinyokika Kiyo. 2003;49:521e5 [in Japanese]. 17. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364: 1995e2005. 18. Womble PR, Vanveldhuizen PJ, Nisbet AA, Reed GA, Thrasher JB, Holzbeierlein JM. A phase II clinical trial of neoadjuvant ketoconazole and docetaxel chemotherapy before radical prostatectomy in high risk patients. J Urol 2011;186:882e7.
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Urological Science journal homepage: www.urol-sci.com
Original article
Ketoconazole in Taiwanese castration-resistant prostate cancer patients: Evaluation of response rates, durations, and predictors Bing-Juin Chiang, Yeong-Shiau Pu, Hong-Jeng Yu, Chao-Yuan Huang* Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 May 2011 Received in revised form 16 August 2011 Accepted 26 October 2011 Available online 11 May 2012
Background/purpose: To evaluate the efficacy of ketoconazole in castration-resistant prostate cancer. Materials and methods: We reviewed the medical records of consecutive patients with pathologically confirmed prostate cancer from May 2006 to December 2008. The inclusion criteria were: (1) receiving 200 or 400 mg ketoconazole three times daily and replacement doses of prednisolone; (2) antiandrogen withdrawal for at least 2 months before ketoconazole treatment; and (3) no prior cytotoxic agents or other CYP17 inhibitors. Treatment consisted of ketoconazole at 200 mg three times daily (Group A) and 400 mg three times daily (Group B). Patients’ characteristics, time to prostate-specific antigen (PSA) progression, duration of PSA response, and adverse events were evaluated. Results: Of the 37 patients in Group A, 14 (37.8%) experienced a PSA response. Of the seven patients in Group B, four (57.1%) experienced a PSA response. Median durations of time to progression in those who experienced a > 50% PSA decline were 7.5 and 11.5 months in Group A and Group B, respectively. Median duration of PSA response was 5.5 and 9.0 months in Group A and Group B, respectively. There was no difference in the PSA response or time to progression between the two groups. Orchiectomy had a borderline unfavorable effect on the PSA response rate (p ¼ 0.067). Conclusion: The present study demonstrated that ketoconazole contributed to the PSA response in patients with castration-resistant prostate cancer. The efficacy and toxicity profiles were comparable to those in previous studies. Orchiectomy had a borderline unfavorable effect on PSA response rate. Further studies are required to confirm the efficacy of ketoconazole therapy in surgically castrated patients. Copyright Ó 2012, Taiwan Urological Association. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: castration-resistant prostate cancer hormone manipulation ketoconazole prostate cancer
1. Introduction Androgen deprivation therapy can achieve a castration status for a period, but prostate cancer eventually progresses to castration resistance. Several mechanisms allow androgen receptor signaling to persist. It is believed that androgen receptors are frequently overexpressed and appear to be activated by castration levels of androgen and adrenal androgens.1 The adrenal glands secrete w10% of the circulating androgen in humans. Ketoconazole, a broad-spectrum azole antifungal agent, inhibits cytochrome P450 and suppresses testicular and adrenal androgen production through inhibiting both adrenocortical 11b-hydroxylase and cholesterol side-chain cleavage.2 A phase III trial (CALGB 9583) has demonstrated that antiandrogen withdrawal (AAWD) together with high-dose ketoconazole, 400 mg three times daily, and * Corresponding author. Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Rd., Taipei 100, Taiwan, ROC. E-mail address: [email protected] (C.-Y. Huang).
hydrocortisone, 30 mg each morning and 10 mg each evening, was associated with an objective prostate-specific antigen (PSA) response, and 8.6 months median time to PSA progression in 32% of 128 patients with castration-resistant prostate cancer (CRPC).3 Low-dose ketoconazole, at 200 mg three times daily, with replacement doses of hydrocortisone (20 mg every morning and 10 mg at bedtime), was associated with a PSA response and 30 weeks median duration of PSA response in 46% of 28 patients.4 Here, we conducted a retrospective study to share our experience of using ketoconazole in patients with CRPC at National Taiwan University Hospital. The toxicity profiles and predictors of the PSA response were also evaluated. 2. Materials and methods We retrospectively reviewed the medical records of consecutive patients with CRPC from May 2006 to December 2008. The definition of CRPC was based on European Association of Urology guidelines.5 The inclusion criteria were: (1) receiving 200 or 400 mg ketoconazole three times daily and replacement doses of
1879-5226/$ e see front matter Copyright Ó 2012, Taiwan Urological Association. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.urols.2012.04.004
B.-J. Chiang et al. / Urological Science 23 (2012) 48e51
prednisolone; (2) AAWD for at least 2 months before ketoconazole treatment; and (3) no prior cytotoxic agents or other CYP17 inhibitors. Patients’ characteristics, time to PSA progression, duration of PSA response, and toxicity profiles were evaluated according to guidelines of the Prostate Specific Antigen Working Group and National Cancer Institute Common Toxicity Criteria.6 Results were analyzed with commercial statistical software. Age and PSA were compared using the median test. Categorical data were compared using a c2 test and Fisher’s exact test. For all tests, a two-tailed p value <0.05 was regarded as significant.
49
Table 2 Clinical outcomes in the separate groups.
AAWD response 50% PSA decline, n (%) 75% PSA decline, n (%) Among 50% PSA decline Median time to progression, mo (range) Median duration of PSA response, mo (range)
Group A
Group B
p value
8 14 (37.8%) 8 (21.6%)
1 4 (57.1%) 1 (14.3%)
0.644 0.175 0.585
7.5 (1e87)
11.5 (4e16.5)
1
5.5 (0.5e86)
9.0 (2e13)
1
3. Results
Group A, 200 mg ketoconazole three times daily; Group B, 400 mg ketoconazole three times daily; AAWD ¼ antiandrogen withdrawal; PSA ¼ prostate-specific antigen.
3.1. Patient characteristics
3.2. Clinical outcomes
In total, 44 patients with CRPC were included, with a median age of 73 years (range, 55e88 years). Median serum PSA at diagnosis of prostate cancer was 74.5 ng/mL (range, 4.3e3310 ng/mL). Four patients (9.1%) underwent radical prostatectomy as definitive local therapy at the time of prostate cancer diagnosis, and 10 patients (22.7%) underwent external beam radiotherapy. At the start of ketoconazole therapy, 36 patients (81.8%) had bone metastasis, and the median PSA level was 30.9 ng/mL (range, 5.2e350.2 ng/mL). Thirty-eight patients (86.4%) received luteinizing hormone releasing hormone agonist (LHRHa), and two patients (4.5%) underwent bilateral orchiectomy as androgen deprivation therapy. Four patients (9.1%) received LHRHa and subsequent bilateral orchiectomy. Initial Gleason scores are given in Table 1. The mean duration of hormone therapy before ketoconazole therapy was 32 months (range, 6e208 months). Patient characteristics were categorized into ketoconazole 200 mg three times daily (Group A) and 400 mg three times daily (Group B) and are listed in Table 1. There were no significant differences in patients’ characteristics between the groups.
Of the 44 patients, 37 patients received 200 mg ketoconazole three times daily (Group A), and seven patients received 400 mg ketoconazole three times daily (Group B). Eighteen patients experienced a PSA decline of 50% after ketoconazole therapy. Of the 37 patients in Group A, 14 (37.8%) had a 50% PSA decline, and eight (21.6%) had a 75% PSA decline. Of the seven patients in Group B, four (57.1%) had a 50% PSA decline, and one (14.3%) had a 75% PSA decline. There was no significant difference between the two groups. Median time to progression in those who experienced a > 50% PSA decline was 7.5 months and 11.5 months in Group A and Group B, respectively. Median duration of PSA response was 5.5 and 9.0 months in Group A and Group B, respectively. There were no differences in the time to progression or duration of the PSA response between the two groups. Clinical outcomes for the separate groups are listed in Table 2. Clinical factors of those with a > 50% response and the others were compared. Neither age (p ¼ 0.417), initial PSA level (p ¼ 0.651), duration between diagnosis of prostate cancer and initiation of ketoconazole (p ¼ 0.759), PSA level on initiation of ketoconazole (p ¼ 0.759), prior radical prostatectomy (p ¼ 1.0), prior radiotherapy (p ¼ 0.504), prior LHRHa (p ¼ 0.634), prior orchiectomy (p ¼ 0.067), metastasis at diagnosis (p ¼ 0.515), nor Gleason score (p ¼ 0.14) could independently predict PSA response.
Table 1 Patient characteristics categorized into Group A (ketoconazole 200 mg three times daily) and Group B (ketoconazole 400 mg three times daily).
Median age, yr (range) Median PSA, ng/mL, at diagnosis (range) Median PSA, ng/mL, at initiation of ketoconazole (range) Median duration (mo) between diagnosis of prostate cancer and initiating ketoconazole (range)
Group A
Group B
73 (55e88) 92.6 (4.3e3310)
76 (59e86) 74.5 (13.9e330.5)
29.5 (5.2e350.2)
32.2 (13.8e221.2)
30 (6e174)
32 (6e204)
Gleason score, n 4e6 7 8e10
5 10 19
2 1 4
Definitive local therapy, n Radical prostatectomy Radiotherapy
4 8
0 2
31 2 4
7 0 0
20 10 2
5 1 0
Castration therapy LHRHa Orchiectomy LHRHa and subsequent orchiectomy Metastasis before ketoconazole Bone metastasis Bone and soft-tissue metastasis Soft-tissue metastasis only
LHRHa ¼ luteinizing hormone releasing hormone agonist.
4. AAWD response Nine patients (20.5%) experienced AAWD response before treatment with ketoconazole. There was no significant difference between the two groups. 4.1. Adverse events Table 3 shows a summary of adverse events during treatment with ketoconazole. Of the 44 patients, 13 (29.5%) experienced adverse events. The most common adverse event was elevation of the liver function. Four patients (9.1%) had grade 1/2, and one patient had grade 3 elevated liver function. The patient Table 3 Summary of adverse events during treatment with ketoconazole. Adverse event
Grade 1/2
Grade 3
Fatigue Arrhythmia Vertigo Epigastralgia Nausea Headache Elevation of liver function
2 1 1 2 1 1 4
e e e e e e 1
Two patients in Group B experienced adverse events of nausea and vertigo.
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B.-J. Chiang et al. / Urological Science 23 (2012) 48e51
experiencing grade 3 elevation of liver function withdrew from treatment. Two patients (4.5%) had grade 1/2 fatigue. One (2.3%) patient had grade 1 arrhythmia and stopped treatment. One (2.3%) patient had grade 1 vertigo. Two patients (4.5%) had epigastralgia and stopped treatment. One (2.3%) patient had grade 1 nausea. One (2.3%) patient had grade 1 headache. There was no significant difference in the total number of adverse events between the two groups (p ¼ 1.0). Four patients (9.1%) terminated treatment with ketoconazole due to adverse events, all of whom were in Group A. 5. Discussion Previous studies have reported the use of a > 50% decrease in PSA as an intermediate marker of survival.7e9 Mark et al have reported that a > 75% decline in PSA in response to high-dose ketoconazole therapy predicts better survival.10 Table 4 lists biochemical response rates of ketoconazole therapy reported in the literature. The use of ketoconazole as secondary hormone manipulation therapy for CRPC achieved 27e63% PSA responses.4,9e13 In the present study, we demonstrated the PSA response to different doses of ketoconazole therapy: 37.8% and 21.6% of patients who received 200 mg ketoconazole three times daily experienced > 50% and > 75% PSA declines, and 57.1% and 14.3% of patients who received 400 mg ketoconazole three times daily experienced > 50% and > 75% PSA declines, respectively. The number of patients in Group B who tended to achieve 50% PSA decline was insignificant, perhaps because of the low case number. Ketoconazole suppresses androgen production in the testes and adrenal gland. In the CALGB 9583 study,3 the largest prospective study to evaluate adrenal androgen levels in patients treated with ketoconazole,dehydroepiandrosterone (DHEA) and androstenedione achieved a modest increase in adrenal androgen levels at the time to progression. Suppression of androgen was partially reversed at the time of disease progression. Additional responses occurred in some patients after dose escalation.14 The biochemical response was influenced by the dose of ketoconazole. This suggests that the dose might be insufficient to suppress production of adrenal androgen in those patients who had no PSA response. However, in the present study, we failed to determine statistically if more patients who received 400 mg ketoconazole three times daily had a PSA response than those who received 200 mg three times daily due to the small sample size. Ketoconazole absorption from the gastrointestinal tract is variable. Its dissolution is dependent on gastric acidity. The elimination half-life is 6.5e10 hours. Changes in plasma testosterone levels vary among individuals,15 and the ability to measure serum ketoconazole levels is still unavailable. Considering the adverse effects, the dose of ketoconazole should be individualized. Therapy can begin with a low dose of ketoconazole that is well tolerated and has moderate activity.4 Subsequent escalation to a high dose can be applied if patients encounter PSA progression.14
None of the six patients who underwent an orchiectomy in the present study had a PSA response, although there was a borderline unfavorable effect on the PSA response rate (p ¼ 0.067). Oka et al have reported that LHRHa significantly decreases serumDHEA, whereas orchiectomy does not decrease serum DHEA.16 This suggests that patients receiving simultaneous LHRHa and ketoconazole therapy might tend to have a PSA response. Previous studies have failed to demonstrate the impact of surgical castration on the PSA response rate.4,9e12 Further studies are required to determine the efficacy of ketoconazole therapy in surgically castrated patients. In the present study, 29.5% of patients experienced adverse events during treatment. Four patients stopped ketoconazole due to adverse events. Two of the four patients had epigastralgia. One patient experienced grade 3 elevation of liver function. One patient had arrhythmia. All of these patients were in Group B. In the CALGB 9583 study,3 21% of patients receiving 400 mg ketoconazole three times daily had grade 3/4 toxicity. Fatigue and neurotoxicity were the most common adverse effects and were seen in 4% of patients. In this study, the most common adverse events were elevation of liver function, epigastralgia, and fatigue. Abiraterone acetate, a more potent adrenolytic agent, was recently approved by the US Food and Drug Administration for treating metastatic CRPC in men with prior docetaxel chemotherapy. It also inhibits 17 a-hydroxylase/C17,20 lyase and results in suppression of subsequent formation of DHEA and androstenedione. The inhibition of androgen biosynthesis prolonged the overall survival by about 4 months in a phase III study.17 Although new adrenolytic agents have been developed in the past decade, ketoconazole still plays a role in treating CRPC because it is less expensive and is involved in new treatment schemes.18 Our study had several limitations. This was a retrospective study in which the authors reviewed the medical records of patients with CRPC. It lacked demographic data, including Eastern Cooperative Oncology Group performance status scores, and patient compliance data. The administration of replacement doses of prednisolone also lacked consistency and varied among physicians. In conclusion, the present study demonstrated that ketoconazole contributed to the PSA response in patients with CRPC. The efficacy and toxicity profiles were comparable to those in previous studies. Orchiectomy had a borderline unfavorable effect on the PSA response rate. Further studies are required to confirm the efficacy of ketoconazole therapy in surgically castrated patients. Conflicts of interest statement The authors declare that they have no financial or non-financial conflicts of interest related to the subject matter or materials discussed in the manuscript. Funding No specific funding.
Table 4 Studies of ketoconazole therapy in castration-resistant prostate cancer. Reference
No. of cases
Dosage
Small et al. (1997) Harris et al. (2001) Millikan et al. (2001) Small et al. (2004) Wilkinson et al. (2004) Scholz et al. (2005)
48 28 45 128 38 78
400 200 400 400 300 400
Chiang et al. (2011)
37
200 mg tid
mg mg mg mg mg mg
Percent of subjects with 50% PSA decline tid tid tid tid tid tid
PSA ¼ prostate-specific antigen; tid ¼ three times daily.
63% 46% 40% 27% 55% 44% of subjects had a 75%PSA decline 37.8%
Acknowledgments The authors declare that there is no conflict of interest. References 1. Reid AH, Attard G, Barrie E, de Bono JS. CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Clin Pract Urol 2008;5:610e20. 2. Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987;317:812e8. 3. Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-
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