0022-534710211682-054?J0
`Tm: JOURNAL or Unoi.ocv°
`Copyright 6 2002 by AMERICAN UROIDGIGAL ASSOCIATION, Inc.’
`
`Vol. 168, 542-545, August 2002
`Printed in U.S.A.
`
`LOW DOSE KETOCONAZOLE VVITH REPLACEMENT DOSES OF
`
`HYDROCORTISONE IN PATIENTS WITH PROGRESSIVE ANDROGEN
`
`INDEPENDENT PROSTATE CANCER
`
`KATHERINE A. HARRIS, VIVIAN WEINBERG, ROBERT A. BOK, MIKA KAKEFUDA AND
`ERIC J. SMALL
`
`F'rom the University of California, San Francisco, UCSF Comprehensive Cancer Center, San Francisco, California
`
`ABSTRACT
`
`Purpose: High-dose (400 mg.) oral ketoconazole 3 times daily with replacement doses of
`hydrocortisone has become a standard treatment option for patients with advanced prostate
`cancer which progresses after androgen deprivation. However, toxicity can hinder the ability to
`deliver treatment and the cost of the regimen can be substantial. Therefore, a prospective phase
`II study was conducted to assess the efficacy and safety of a regimen of low dose (200 mg.) oral
`ketoconazole 3 times daily with replacement doses of hydrocortisone in men with androgen
`independent prostate cancer.
`Materials and Methods: The study included 28 patients with progressive prostate cancer
`despite anorchid levels of testosterone and ongoing testicular androgen suppression. Treatment
`consisted of low dose ketoconazole and replacement doses of oral hydrocortisone (20 mg. every
`morning and 10 mg. at bedtime). At the time of disease progression patients were treated with
`high dose ketoconazole and continued on the same dose of hydrocortisone. Adrenal androgen
`levels were measured, and baseline and followup levels correlated with clinical outcome.
`Results: Overall, 13 (46%) of 28 patients had a prostate specific antigen decrease of more than
`50% (95% confidence interval 27.5% to 66.1%). Median duration of prostate specific antigen
`decrease for all responders was 30+ weeks and 5 patients continue to exhibit a response, ranging
`from 36+ to 53+ weeks. In general, therapy was well tolerated. There were no grade 4 toxicities.
`Grade 3 toxicities included hepatotoxicity in 1 patient and depression in 2. The most common
`toxicities were nausea (29% grades 1 and 2), dry skin (18% grade 1) and fatigue (14% grade 1).
`Four (14%) patients discontinued low dose ketoconazole due to toxicities. Of the 16 patients who
`received high dose ketoconazole after disease progression with low dose ketoconazole, 3 were
`removed from treatment due to toxicity and no patient responded to high dose ketoconazole.
`There was no diflerence in the distribution of pretreatment endocrine values between responders
`and nonresponders, and the magnitude of change in adrenal androgen levels was not associated
`with response to therapy, although a potential association could easily have been missed due to
`small sample size.
`Conclusions: The regimen of low dose ketoconazole with replacement doses of hydrocortisone is
`well tolerated and has moderate activity in patients with progressive androgen independent
`prostate cancer.
`
`KEY WORDS: prostatic neoplasms, ketoconazole, hydrocortisone
`
`It has been reported that in some patients with progressive
`androgen independent prostate cancer some cells retain some
`degree of hormonal sensitivity and can be stimulated by
`adrenal androgens} In this context it is of note that ketocon-
`azole, a systemic antifimgal agent, is a clinically useful an-
`tagonist of adrenal steroidogenesis. Ketoconazole inhibits cy-
`tochrome P-450 and effectively suppresses testicular and
`adrenal androgen production?-3 Interestingly, it may also
`have direct cytotoxic effects on prostate tumor cells.‘ Origi-
`nally used as a therapy for advanced prostate cancer before
`the advent of prostate specific antigen (PSA) as a tumor
`marker, high dose (400 mg.) oral ketoconazole 3 times daily
`was reported to produce objective clinical responses in ap-
`proximately 10% of patients with androgen independent
`prostate cancer and stable disease in another 35%.‘-5 More
`recently, we have reported that ketoconazole has moderate
`activity in patients with androgen independent prostate can-
`cer with durable PSA decrease of greater than 50% observed
`
`Accepted for publition February 1, 2002.
`Supported by Janssen Pharmaceutical and CaPCURE.
`
`in 63% of patients who had previously undergone antiandro-
`gen withdrawal7 and in 55% of those undergoing simulta-
`neous antiandrogen withdrawal.“ While toxicity is generally
`mild to moderate, up to 20% of patients experience grades 1
`and 2 nausea and emesis,"»3 requiring dose reduction or
`cessation of the drug. In addition, 20% of patients will have
`minor skin toxicity, 10% grade 1 or 2 fatigue and 10% revers-
`ible grade 1 or 2 hepatotoxicity.7-3 Patients with unaccept-
`able toxicity are fiequently treated empirically with a dose
`reduction of oral ketoconazole by half to 200 mg. 3 times
`daily.
`High dose ketoconazole with replacement doses of hydro-
`cortisone has become a commonly used treatment option for
`patients with disease progression afler androgen deprivation
`due to its efficacy and relative ease of administrationf’ While
`the mechanism of action of high dose ketoconazole is not fully
`understood, this dose of ketoconazole has been shown to
`suppress adrenal androgen production.‘ However, response
`to treatment with ketoconazole has to date not been shown to
`
`correlate with suppression of adrenal androgen levels. LDK
`542
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`KETOCONAZOLE AND HYDROCORTISONE FOR PROSTATE CANCER
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`543
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`may be an attractive alternative to high dose ketoconazole.
`Toxicity with high dose ketoconazole can limit the ability to
`deliver treatment. Anecdotal evidence suggests that low dose
`ketoconazole is better tolerated, although this question has
`not been addressed in a rigorous fashion. In addition, the cost
`of the high dose regimen is substantial, and a low dose
`regimen would bring down costs. While clinical responses to
`low dose ketoconazole have been reported,10 the low dose has
`not been systematically studied.
`Given anecdotal evidence suggesting that low dose keto-
`conazole has reduced toxicity while maintaining efficacy, a
`prospective phase II study of this regimen in patients with
`androgen independent prostate cancer was conducted. Re-
`placement doses of oral hydrocortisone (20 mg. every morn-
`ing, 10 mg. at bedtime) were also administered, since hydro-
`cortisone as a single agent is known to have activity in
`advanced prostate cancer and we wished to compare the
`efficacy of low dose with historical high dose ketoconazole
`data. In addition, there were no compelling data available to
`suggest whether adrenal insufficiency occurred at this dose
`of ketoconazole,11 so that concerns regarding patient safety
`mandated the use of replacement hydrocortisone.
`
`PATIENTS AND METHODS
`Eligible patients had histologically confirmed adenocarci-
`noma of the prostate with progressive disease, as defined by
`the Prostate Specific Antigen Working Group Consensus
`Criteria.12 All patients had previously undergone antiandro-
`gen withdrawal for a minimum of 8 weeks. Any other hor-
`monal therapies, including any dose of megestrol acetate,
`finasteride or systemic corticosteroids, had to have been dis-
`continued at least 4 weeks before study enrollment. Required
`laboratory parameters included total bilirubin and aspartate
`transaminase less than 2 times the upper limit of normal. All
`patients had a Karnofsky performance status of 60% or
`greater and a life expectancy of at least 3 months. Prior
`therapy with 1 nonchemotherapeutic, nonhormonal investi-
`gational agent was permitted, provided it had been discon-
`tinued at least 30 days before study enrollment. Exclusion
`criteria were prior treatment with chemotherapy, aminoglu-
`tethimide, ketoconazole or herbal products such as saw pal-
`metto or PC-SPES. Given drug interactions with ketocon-
`azole, the concurrent use of terfenadine, astemizole or
`cisapride was not allowed. Radiation therapy within 28 days
`or radiopharmaceutical therapy within 60 days was not per-
`mitted.
`Eligible patients were evaluated with a history and phys-
`ical examination at study entry and monthly thereafter. In
`addition to a complete history and physical examination at
`each visit, patients were evaluated for adverse events. For-
`mal quality of life or pain assessment was not performed.
`Complete blood count, PSA, total bilirubin, alkaline phospha-
`tase, aspartate transaminase, creatinine and glucose were
`measured at baseline and then monthly. An endocrine panel
`including androstendione, dehydroepiandrosterone sulfate
`(DHEAS), dehydroepiandrosterone (DHEA) and testosterone
`was obtained at baseline and after 2 months of treatment. A
`bone scan and, if clinically indicated, computerized tomogra-
`phy of the abdomen and pelvis were obtained at baseline. If
`imaging studies were positive at baseline they were repeated
`every 3 months.
`Patients received 200 mg. ketoconazole orally 3 times daily
`on an empty stomach along with replacement doses of oral
`hydrocortisone (20 mg. every morning with food and 10 mg.
`at bedtime with food). At the time progressive disease was
`documented as defined by the consensus criteria,12 the dose
`of ketoconazole was increased to 400 mg. orally 3 times daily
`and continued until disease progression. Replacement doses
`of hydrocortisone were continued as long as the patient was
`receiving ketoconazole. When the patient was no longer re-
`
`ceiving ketoconazole, hydrocortisone was tapered by 5 mg.
`every 3 days until completely discontinued. Antacids, H-2
`blockers and proton pump inhibitors were avoided.
`At each visit toxicity was graded according to the National
`Cancer Institute common toxicity criteria (version 2.0) and
`recorded. In the event of grade 3 or higher hepatotoxicity or
`symptomatic peptic ulcer or gastritis, patients were removed
`from protocol treatment. If nausea was reported, the patient
`was instructed to take ketoconazole with meals. Antiemetics
`other than corticosteroids were permitted. If grade 2 or 3
`nausea persisted despite these measures, the patient was
`removed from therapy. Patients with other grade 3 or higher
`toxicity had treatment withheld until toxicity resolved to
`grade 1 or better. Any patient with grade 4 toxicity or grade
`3 toxicity persisting for more than 4 weeks (except as out-
`lined previously) was removed from protocol treatment.
`The primary end points of this prospective phase II study
`were to determine the response proportion and duration of
`response to low dose ketoconazole and replacement doses of
`hydrocortisone in patients with progressive prostate cancer
`despite androgen deprivation. PSA responses were defined
`according to the consensus criteria.12 The secondary objec-
`tives of this trial were to determine the toxicity profile of this
`regimen, to assess the use of increasing ketoconazole to high
`dose in patients with disease progression on low dose and to
`correlate response to treatment with suppression of adrenal
`androgen levels.
`The study included 28 patients. This sample size was suf-
`ficient to detect a response frequency of at least 40% com-
`pared to the null hypothesis of 20% with power of approxi-
`mately 80% (0.79). Descriptive statistics were used to
`characterize the patient and disease features as well as tox-
`icity. Nonparametric Spearman correlation was calculated to
`evaluate the association between adrenal androgens. The
`change in endocrine measurements from before treatment to
`2 months after low dose ketoconazole was analyzed using the
`nonparametric Wilcoxon test for paired data. The distribu-
`tions of adrenal androgens for responders and nonresponders
`were compared using the Mann-Whitney test.
`
`RESULTS
`Patient characteristics. A total of 28 patients with andro-
`gen independent prostate cancer was treated and all were on
`study at least 2 months and were evaluable for toxicity and
`response. Pretreatment patient characteristics are listed in
`table 1. Median patient age was 76 years (range 49 to 91). Of
`the patients 17 had bone only disease, 3 had bone and soft
`tissue disease, and 8 had PSA elevation as the only manifes-
`tation of progressive disease. At the start of therapy median
`PSA was 48.9 ng./ml. (range, 6.3 to 557.8), alkaline phospha-
`tase 97 units/l. (range, 61 to 489), hemoglobin 13.1 gm./dl.
`
`TABLE 1. Pretreatment patient characteristics
`
`Age:
`Median
`Range
`No. extent of disease:
`PSA only
`Bone only
`Bone and soft tissue
`PSA (ng./ml.):
`Median
`Range
`Alkaline phosphatase (units per l.):
`Median
`Range
`Hemoglobin (gm./dl.):
`Median
`Range
`Performance status:
`Median
`Range
`
`76
`49–91
`
`8
`17
`3
`
`48.9
`6.3–557.8
`
`97
`61–489
`
`13.1
`10.1–14.3
`
`0
`0–1
`
`Page 2
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`544
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`KETOCONAZOLE AND HYDROCORTISONE FOR PROSTATE CANCER
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`(range 10.1 to 14.3) and Eastern Cooperative Oncology Group
`performance status 0 (range, 0 to 1).
`Clinical outcome. Overall, 13 (46%) of 28 patients had a
`PSA decrease of more than 50% (95% confidence interval
`27.5%–66.1%). PSA responses were seen regardless of distri-
`bution of disease, although proportionately more PSA de-
`creases were seen in patients with PSA only disease. PSA
`decreases of greater than 50% were seen in 6 (35%) of 17
`patients with bone only disease, 1 (33%) of 3 with bone and
`soft tissue disease, and 6 (75%) of 8 patients with PSA ele-
`vation only. No responses were observed on bone scans or CT.
`Median duration of PSA decrease for all responders was 30⫹
`weeks and 5 patients continued to exhibit a response ranging
`from 36⫹ to 53⫹ weeks. In 16 patients disease was unre-
`sponsive to low dose ketoconazole and the ketoconazole dose
`was increased to 400 mg. orally 3 times daily. Of these 16
`patients 3 were taken off high dose ketoconazole due to
`toxicity and the remaining 13 did not respond to high dose
`ketoconazole. However, 2 patients remain on high dose keto-
`conazole with stable disease at 16⫹ and 19⫹ weeks.
`Toxicity. Toxicity following low dose ketoconazole for all 28
`patients is listed in table 2. In general, therapy was well
`tolerated. There were no grade 4 toxicities. Grade 3 toxicities
`included hepatotoxicity in 1 patient and depression in 2. The
`most common toxicities were grades 1 and 2 nausea (29%),
`grade 1 dry skin (18%) and grade 1 fatigue (14%). Four
`patients (14%) discontinued low dose ketoconazole due to
`persistent grade 2 nausea (1), grade 3 depression (2) and
`grade 3 hepatotoxicity (1). High dose ketoconazole was dis-
`continued due to persistent grade 2 nausea in 2 patients and
`grade 2 gastric ulcer with grade 1 gastrointestinal bleeding
`in 1.
`Adrenal androgen levels. Adrenal androgen (androstenedi-
`one, DHEA, and DHEAS) levels were measured at baseline and
`after 2 months of treatment (table 3). The baseline DHEA value
`significantly correlated with androstenedione (p ⫽ 0.02) and
`DHEAS (p ⫽ 0.002). There was no significant difference in the
`baseline endocrine values between responders and nonre-
`sponders but there was a significant decrease in all 3 parame-
`ters after 2 months of therapy. Median change was ⫺0.49 ng./
`ml. (range ⫺1.98, 0.02) in androstenedione, ⫺1.4 ng./ml. (range
`⫺5.2, ⫺0.3) in DHEA and ⫺327.1 ng./ml. (range ⫺1318.9,
`⫺23.0) in DHEAS. However, the degree of adrenal androgen
`suppression was not associated with response nor was the de-
`gree of suppression predicted by response to low dose ketocon-
`azole.
`
`DISCUSSION
`A PSA response proportion of 46% was demonstrated in
`this prospective trial of low dose ketoconazole with replace-
`ment doses of hydrocortisone. While the use of PSA as an
`intermediate marker of response and outcome remains con-
`troversial, an emerging body of literature supports the use of
`a greater than 50% decrease in PSA as an intermediate
`marker of survival13–16 in patients with androgen indepen-
`dent prostate cancer treated with secondary hormones, cyto-
`toxic agents or suramin. Although it is not appropriate to
`
`TABLE 2. Toxicity to low dose ketoconazole
`No. (%)
`Grade 2
`
`Grade 1
`
`Toxicity
`
`Nausea
`Dry skin
`Fatigue
`Bruising
`Liver (aspartate transaminase, alanine
`transaminase)
`Stomatitis
`Depression
`Insomnia
`
`5 (18)
`5 (18)
`4 (14)
`1 (4)
`0
`
`0
`0
`0
`
`3 (11)
`0
`0
`0
`1 (4)
`
`1 (4)
`0
`1 (4)
`
`Grade 3
`
`0
`0
`0
`0
`1 (4)
`
`0
`2 (7)
`0
`
`TABLE 3. Adrenal androgen levels
`Before Treatment
`Median Ng./Ml.
`(range)
`
`No.
`
`No.
`
`After 2 Mos.
`Median Ng./Ml.
`(range)
`
`0.30 (0.10–0.73)
`25
`0.71 (0.33–2.62)
`27
`Androstenedione
`1
`(0.5–1.7)
`25
`2.3 (0.9–6.0)
`27
`DHEA
`50
`(9–588.1)
`25
`364.8 (50–1,907)
`27
`DHEAS*
`* Two-month values which were reported as less than 50 were coded as 50
`for calculations.
`
`compare the results for this trial directly with the results of
`retrospective series using high dose ketoconazole with hydro-
`cortisone replacement, the PSA response proportion observed
`seemed close to the historic high dose ketoconazole response
`rate of 50%. Furthermore, increase to high dose ketoconazole
`failed to “capture” any patients who had progressive disease
`despite low dose ketoconazole. While this observation clearly
`does not demonstrate equivalence between low dose ketocon-
`azole and high dose ketoconazole, it suggests that the mech-
`anism of action is unlikely to be significantly different.
`Ketoconazole is a substituted imidazole that suppresses
`testicular and adrenal steroidogenesis by inhibition of the
`conversion of cholesterol to pregnenolone. Because ketocon-
`azole is a potent inhibitor of all adrenal steroid synthetic
`pathways, replacement doses of hydrocortisone may be re-
`quired. Glucocorticoids alone may have antitumor effects
`mediated either by direct interaction with androgen recep-
`tors or by feedback inhibition of the hypothalamic-pituitary-
`adrenal axis. Contemporary studies have tried to control for
`the beneficial effects of antiandrogen withdrawal in this set-
`ting. Kelly et al reported on 30 patients treated with 40 mg.
`hydrocortisone daily and found that 20% had a decrease of at
`least 50% in serum PSA maintained for a median of 4
`months.14 Dawson et al treated 34 patients with hormone
`refractory disease with 30 mg. hydrocortisone daily and
`found a 29% PSA response proportion.17 In a recent random-
`ized trial hydrocortisone was evaluated alone or in combina-
`tion with mitoxantrone in patients with hormone refractory
`prostate cancer.18 A greater than 50% decrease in PSA was
`observed in 22% of patients treated with hydrocortisone
`alone. Finally, in a large study comparing suramin plus hy-
`drocortisone to placebo plus hydrocortisone in patients with
`metastatic hormone refractory disease and opioid analgesic
`requirements 38 (16%) of 230 treated with 40 mg. hydrocor-
`tisone daily plus placebo had a greater than 50% reduction in
`PSA.19 Taken together, these data suggest that 16% to 29% of
`patients will have a greater than 50% reduction in PSA when
`treated with 30 to 40 mg. hydrocortisone daily. The response
`proportion observed with hydrocortisone plus low dose keto-
`conazole appears to be considerably higher than that ex-
`pected with hydrocortisone alone, and supports prior experi-
`ence that suggested that ketoconazole is an active agent in
`this group of patients. However, the true benefit of adding
`ketoconazole to hydrocortisone can only be adequately ad-
`dressed in a randomized trial.
`Baseline levels of androstenedione, DHEA and DHEAS did
`not differ between responders and nonresponders. While all 3
`of these endocrine parameters decreased significantly after 2
`months of therapy, the degree of decrease was not predicted
`by response. Of note, low dose ketoconazole clearly sup-
`presses adrenal steroidogenesis. Therefore, replacement
`doses of hydrocortisone are recommended, even when keto-
`conazole is administered at low doses, despite the possibility
`that it may not be necessary in all patients. While high dose
`and low dose ketoconazole have been shown to suppress
`adrenal androgen production,5, 11 no study has shown an
`association between response to treatment and changes in
`adrenal androgen levels. While our study was likely too small
`to detect an association with adequate power, this question is
`being addressed in a recently completed cancer and leukemic
`
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`KETOCONAZOLE AND HYDROCORTISONE FOR PROSTATE CANCER
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`545
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`group B phase III study of antiandrogen withdrawal alone or
`with high dose ketoconazole. It is intriguing that preliminary
`results from this trial revealed that the baseline level of
`DHEA appeared to be an independent predictor of survival.20
`Low dose ketoconazole is attractive because of its favorable
`toxicity profile, ease of use and its reduced cost compared to
`high dose ketoconazole. All medications are given orally and
`patients need only monthly laboratory followup. As with high
`dose ketoconazole, nausea was the most frequent toxicity.
`However, nausea was generally mild to moderate, and only 1
`patient discontinued low dose ketoconazole due to persistent
`grade 2 nausea. Only 3 patients (11%) experienced grade 3
`toxicity (hepatotoxicity in 1 and depression in 2), and no
`patient experienced grade 4 toxicity. While the relative effi-
`cacy and toxicity of low dose compared with high dose keto-
`conazole can only be assessed in a phase III trial, these data
`suggest that low dose ketoconazole should be considered as a
`treatment option in this patient population.
`
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