EuropeanUrology European Urology 45 (2004) 581–585

An Evaluationof Intermediate-Dose Ketoconazole inHormone Refractory Prostate CancerSimon Wilkinson*, Gerald ChodakThe Midwest Prostate and Urology Health Center, Weiss Memorial Hospital, 4646 North Marine Drive, Chicago, IL 60640, USA

Accepted 26 November 2003

Published online 29 January 2004

AbstractObjectives: The management of hormone refractory prostate cancer remains controversial. Among the options,second-line hormonal therapy is commonly used. We investigated the efficacy of ketoconazole, an inhibitor oftesticular and adrenal androgen biosynthesis, for treating patients with advanced hormone refractory prostate cancer.Methods: The study comprised 38 patients with progressive disease despite combined androgen blockade.Treatment consisted of intermediate-dose ketoconazole (300 mg three times daily) and replacement hydrocortisone.Patients were monitored clinically and with serial PSA measurements every 3 months. The principal endpoint wasPSA response.Results: Of the 38 patients, 21 (55.3%) showed a decrease in PSA >50% (95% confidence interval 38.3%–71.4%)with a median duration of 6 months (range 3–48 months). A PSA reduction >50% was seen in 21 of 34 patients(61.8%) with established metastases. Thirteen patients (34.2%), all of whom had metastases, exhibited a PSAdecrease >80% (95% confidence interval 19.6%–51.4%) with a median duration of 9 months (range 3–48 months).

Age, PSA at diagnosis, Gleason score and bone scan result were not significantly associated with response toketoconazole treatment in univariate or multivariate analyses. For the entire study group, the median time toprogression was 5 months (range 0–27 months) and the median survival was 12 months (range 3–48 months).

Overall, 12 patients (31.6%) reported toxicity related to intermediate-dose ketoconazole but only 6 patients(15.8%) discontinued therapy due to intolerable side effects.Conclusion: It is apparent from this study that a reasonable percentage of patients failing standard hormonal therapyrespond favourably to intermediate-dose ketoconazole and that toxicity is mild. In the absence of studiesdemonstrating better survival with chemotherapy, we believe that a trial of ketoconazole should be consideredwhen progression occurs on hormone therapy.# 2004 Elsevier B.V. All rights reserved.

Keywords: Prostate; Cancer; Ketoconazole

1. Introduction

Cancer of the prostate is a major public health threat.It is now the second leading cause of death from cancerin the United States, exceeded only by lung cancer.Even with localized disease at diagnosis, most patientseventually progress and develop metastases. Althoughthe majority of these patients initially respond to

hormonal ablation, most will ultimately fail andrequire further therapy. Anti-androgen withdrawalrepresents one option, with responses ranging between15% and 33% [1–3]. However, any response tends to beshort-lived usually lasting only about 3 months, afterwhich the PSA starts rising again. The pathophysiologyof the anti-androgen withdrawal response is not com-pletely understood, although androgen receptor genemutations are a likely explanation. Whatever themechanism, this paradoxical phenomenon demon-strates the heterogeneity of prostate cancer cells intheir response to different hormonal maneuvers. This

* Corresponding author. Tel. þ773-564-5006; Fax: þ773-564-5007.

E-mail address: simonmwilkinson@hotmail.com (S. Wilkinson).

0302-2838/$ – see front matter # 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.eururo.2003.11.031

ability to retain hormonal sensitivity has encouragedinvestigators to evaluate other second-line hormonalmanipulations in metastatic prostate cancer.

Ketoconazole, an orally active broad-spectrum anti-fungal agent, was first reported to have activity againstprostate cancer almost 20 years ago [4]. It blocks bothtesticular and adrenal androgen biosynthesis by inhibit-ing cytochrome P450 enzymes involved in steroidogen-esis. Within 48 hours of initiation, ketoconazole reducesthe concentration of circulating androgens to castratelevels [5]. Ketoconazole also has direct cytotoxic effectsagainst prostate cancer cells in the absence of androgens.In human cell lines of prostate cancer, ketoconazoleexerted a cytostatic effect by inhibiting DNA synthesis[6]. In another in vitro study, exposure to ketoconazolereduced cell viability by 26% of the control [7].

Compared to other options for managing hormonerefractory prostate cancer, ketoconazole is an attractivealternative because of its convenience and flexibility ofadministration. In clinical trials, responses rangingbetween 31.0% and 62.5% have been reported usinghigh doses of ketoconazole (400 mg three times daily)[8,9]. Unfortunately, the potential toxicity of ketoco-nazole remains a major limitation for using this drug.Indeed, it was recently reported that 20% of patientsdiscontinue high-dose ketoconazole due to intolerableside effects [9]. In order to reduce toxicity, oneapproach is to administer lower doses. However, themain concern with this approach is that therapeuticefficacy may be compromised. With this in mind, weinvestigated the response of patients to intermediate-dose ketoconazole (300 mg three times daily).

2. Methods

We reviewed the medical records of 38 consecutive patients withhistologically confirmed prostate cancer who had been treated withketoconazole by one clinician (GWC). To be included in this study,patients met the following requirements: (1) there was biochemicalprogression despite combined androgen blockade and subsequentanti-androgen withdrawal, (2) anti-androgens were withdrawn atleast 2 months before treatment, (3) luteinizing hormone releasinghormone (LHRH) agonists were continued alongside treatment,and (4) no other concurrent therapies were being used. We definedbiochemical progression as 3 consecutive PSA rises that were atleast one month apart.

Unlike the majority of previous studies, which reported onpatients taking ketoconazole 400 mg three times daily, we treatedpatients with a lower dose regime of 300 mg three times daily. Allpatients received replacement doses of hydrocortisone, 20 mg inthe morning and 10 mg at night, to counteract potential adrenalinsufficiency induced by ketoconazole.

Prostate specific antigen (PSA) levels and liver function testswere performed one month after initiation of ketoconazole andsubsequently every 3 months. At each clinic appointment, patients

also underwent a physical examination, and were specificallyquestioned about side effects. Termination of therapy was under-taken if there was no PSA response within 3 months or if sideeffects were intolerable. The principal endpoint was PSA response.This was defined according to the guidelines of the ProstateSpecific Antigen Working Group [10].

3. Results

At the time of data collection, 12 patients (31.6%)were still alive. Median age at last follow-up or deathwas 73 years (range 46–91 years). Median age atdiagnosis of prostate cancer was 66 years (range 45–86 years). Serum PSA at diagnosis of prostate cancervaried between 5 and 868 ng/ml, with a median of33 ng/ml. Of the 38 patients, 28 (73.4%) had estab-lished metastatic disease on bone scintigraphy. Amongthe 10 patients with a normal bone scan, 6 had histo-logically proven iliac lymph node involvement. Thirtypatients were being treated with LHRH analogues,while the remaining 8 patients had undergone bilateralorchidectomy. The distributions of Gleason score andprimary treatment are shown in Table 1.

The median interval from diagnosis of prostatecancer to initiation of ketoconazole was 5 years (range1–21 years). At commencement of therapy, the medianPSA was 37 ng/ml (range 2.7–794).

Of the 38 patients, 21 (55.3%) showed a decrease inPSA of >50% (95% confidence interval 38.3%–71.4%)with a median duration of 6 months (range 3–48months). Of these responders, 7 (33.3%) had a durableresponse lasting more than a year. Five patients con-tinued to exhibit a response at last follow-up. A PSAreduction of >50% was seen in 21 of 34 patients (61.8%)with established metastases.

Thirteen patients (34.2%), all of whom had metas-tases, exhibited a PSA decrease of >80% (95%

Table 1Distribution of Gleason score and primary treatment

Number Percentage

Gleason score*

5 4 11.1

6 3 8.3

7 16 44.5

8 3 8.3

9 9 25.0

10 1 2.8

Primary treatment

Radical prostatectomy 6 15.8

Radiotherapy 8 21.0

Brachytherapy 2 5.3

Hormonal therapy 22 57.9

* Gleason scores were available for 36 of the 38 patients.

582 S. Wilkinson, G. Chodak / European Urology 45 (2004) 581–585

confidence interval 19.6%–51.4%) with a median dura-tion of 9 months (range 3–48 months). The medianPSA reduction was 47.5%.

Age, PSA at diagnosis, Gleason score, bone scanresult, lymph node involvement, PSA at ketoconazoleinitiation and duration of hormonal ablation were notsignificantly associated with response to ketoconazolein univariate or multivariate analyses. However, if thePSA was greater than 40 ng/ml at ketoconazole initia-tion, the >50% response rate was significantly higher(72%) than if the PSA was below this level (40%)( p ¼ 0:046). In fact, the odds of having a PSA response>50% for patients with a PSA >40 ng/ml were 3.9 timesthose for patients with a PSA <40 ng/ml.

For the entire study group, the median time toprogression was 5 months (range 0–27 months) andthe median survival was 12 months (range 3–48 months(Fig. 1). Using the >50% response criteria, the mediansurvival time for responders was 24 months comparedto 9 months for the non-responders ( p ¼ 0:0089). Forthe >80% response, the median survival time forresponders was 33 months versus 9 months for thenon-responders ( p ¼ 0:0142).

Overall, 12 patients (31.6%) reported toxicity relatedto ketoconazole. The principle complaints were nausea(13.2%), fatigue (10.6%), diarrhea (2.6%), visual dis-turbance (2.6%) and abnormal liver function tests(2.6%). Six patients (15.8%) discontinued ketocona-zole due to intolerable side effects.

4. Discussion

For patients with hormone refractory prostate cancerduration of survival is variable, ranging between 7 and

27 months [11]. The optimum management of thesepatients remains uncertain as no prospective rando-mized trials have yet to show a survival benefit.Furthermore, no universally accepted algorithm hasbeen developed to manage these patients. Thus second-line hormonal agents, cytotoxic therapies, growth fac-tor inhibitors, antisense oligonucleotides and bispho-sphonates all seem reasonable options to discuss withpatients. Since most patients are asymptomatic initi-ally, these therapies should offer the potential forsubjective and/or objective responses without signifi-cantly compromising quality of life.

Our results indicate that intermediate-dose ketocona-zole (300 mg three times daily) can induce objectiveclinical responses in some patients with hormone refrac-tory prostate cancer. The response rate of 55.3% com-pares favorably to studies employing high-doseketoconazole (400 mg three times daily). In one studyusing this high-dose regime, 30 of 48 patients (62.5%)demonstrated a PSA reduction >50% with a medianduration of 3.5 months [8]. For a PSA reduction >80%,our response rate of 34.2% is also consistent with thatreported in other studies [9]. For patients contemplatingketoconazole, it would therefore seem reasonable to tryan intermediate-dose regime before moving to a higherdose.

Unfortunately, information regarding lower doseregimes of ketoconazole in prostate cancer therapyis sparse. To our knowledge, the only other publishedstudy employing a low-dose regime (200 mg threetimes daily) yielded a >50% PSA reduction in 13 of28 patients (46%) [12]. Combined with our data,these observations suggest that therapeutic efficacymay not be compromised by reducing the dose ofketoconazole.

Regarding toxicity, our intermediate-dose schedulewas well tolerated, with only 15% ceasing treatmentdue to unacceptable side effects. This compares favor-ably to a discontinuation rate greater than 20% forhigh-dose ketoconazole regimes (400 mg three timesdaily) [9].

Disappointingly, a survival benefit could not bedemonstrated in our study population. This is con-sistent with other efficacy trials of ketoconazole, andfurther studies are needed to define its ultimate rolein treating this disease. The Eastern CooperativeOncology Group is pursuing one such study. ECOG1899 is a phase III randomized trial for evaluatingsecond-line hormonal therapy (ketoconazole/hydro-cortisone) versus combination chemotherapy (doce-taxel/estramustine) on progression free survival inpatients with hormone refractory prostate cancer[13].

1.00

0.75

0.50

0.25

0.00

50403020100

Months since start of treatment

Fig. 1. Kaplan–Meier survival estimate.

S. Wilkinson, G. Chodak / European Urology 45 (2004) 581–585 583

Until such trials are completed, many prostate cancerspecialists may feel more comfortable combining keto-conazole with various chemotherapy regimes, giventhe symbiotic relationship that seems to exist. Bycombining ketoconazole with doxorubicin, responsesranging between 36% and 55% have been reported[9,14]. Furthermore, alternating this regime with estra-mustine and vinblastine improves therapeutic efficacyfurther, with responses reaching 60% to 67% [15,16]. Itis believed that ketoconazole exerts this symbioticeffect by blocking the multidrug resistance gene(MDR), which is largely responsible for inducingchemotherapy drug resistance [17].

We acknowledge that concurrent corticosteroidadministration may be a significant confoundingvariable. Indeed, use of hydrocortisone alone afteranti-androgen withdrawal has been associated withresponses ranging between 19% and 22% [18–20].

However, our objective response rate of 55.3% sug-gests that ketoconazole is responsible for the majorityof this activity.

We also acknowledge that our primary endpoint ofPSA response remains controversial and there is still noconsensus defining disease progression. Nevertheless,it has been demonstrated that PSA responses of >50%correlate with improvement in time to treatment failureand survival [21].

In summary, there appears to be a reasonable num-ber of patients with hormone refractory prostate can-cer who may derive some benefit from intermediate-dose ketoconazole. Our findings support the rationalefor further investigation of ketoconazole as a viabletherapeutic strategy for patients with advanced dis-ease. Future studies should also incorporate quality-of-life measures, given the limited prognosis of thesepatients.

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Editorial CommentA. Heidenreich, Cologne, Germany

The clinical trial conducted in a small series ofpatients by Wilkinson et al. reports on an importanttherapeutic option in patients with PSA progressionfollowing initial androgen deprivation. Contrary to theauthors, however, I would suggest that the treatedcohort of patients represents androgen refractory, buthormone sensitive prostate cancer which might benefitfrom secondary hormonal manipulations such as ster-oids, estrogens or inhibitors of adrenal androgen synth-esis such as ketokonazole [1]. The current trialhighlights several important aspects in the manage-ment of metastatic PCA failing androgen deprivation

1. Ketokonazole/hydrocortisone represents a validtherapeutic secondary hormonal measure resultingin a median duration of response of 6 months [2–4].

2. PSA# �50% appears to represent a significantsurrogate marker of survival in the group ofpatients with androgen refractory but hormonesensitive prostate cancer as has already beendemonstrated in HRPCA [5].

3. PSA response to ketokonazole can be identifiedwithin the first 6 to 8 weeks of therapy allowing anearly identification of responders and non-respon-ders. Responders will benefit from continuation oftherapy with a median survival of about 2 yearsand non-responders might be recruited for cyto-toxic regimes at an early stage.

There is, however, one major drawback in the inter-pretation of therapeutic efficacy since it remainsunclear if the PSA responses are due to the activity

of ketokonazole or if the concurrent administration ofhydrocortisone represents a confounding variable. Ithas been shown for aminogluthetimide—another inhi-bitor of adrenal androgen synthesis—that the additionof hydrocortisone results in a significant improvementof response and survival rates [6].

Nevertheless, the combination of ketokonazole andhydrocortisone represents a valuable therapeutic optionfor the management of PCA failing initial androgendeprivation. Following antiandrogen withdrawal, thiscombination should be tried in most patients; sincecytotoxic regimes even with taxanes still lack to demon-strate a survival benefit the development of effectivesecondary measures with low morbidity and mainte-nance of quality of life are of clinical importance.

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