Europeali
`l.iriJli.>gy'
`
`European Urology 45 (2004) 58l—585
`
`An Evaluation of Intermediate-Dose Ketoconazole in
`
`Hormone Refractory Prostate Cancer
`-
`.
`.
`.
`3‘
`
`Simon Wilkinson , Gerald Chodak
`The Midwest Prostate urn.’ Urology Health Center. W;ei,rs' Memorial Hospital. 4646 North M’rm'rie Drive. C’hit'ago, IL 60640. USA
`Accepted 26 November 2003
`
`Published online 29 January 2004
`
`
`
`
`
`Abstract
`
`t’)ii§jecIt‘ves.- The management of hormone refractory prostate cancer remains controversial. Among the options,
`second-line hormonal therapy is commonly used. We investigated the efficacy of keroconazole, an inhibitor of
`testicular 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 interrnediate—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 was
`PSA response.
`Resrilrss Of the 38 patients, 2| (55.3%) showed a decrease in PSA >50% (95% confidence interval 38.3%—7l.4%)
`with a median duration of 6 months (range 3-43 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 PSA
`decrease >80% (95% confidence interval l9.6%—51.4%) with a median duration of 9 months (range 348 months).
`Age, PSA at diagnosis, Gleason score and bone scan result were not significantly associated with response to
`ketoconazole treatment in univariate or multivariate analyses. For the entire study group,
`the median time to
`progression 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.
`{,‘oncitzsi0n.' It is apparent from this study that a reasonable percentage of patients failing standard hormonal therapy
`respond favourably to intermediate-dose ketoconazole and that
`toxicity is mild.
`In the absence of studies
`deino 1- survival with chemotherapy, we believe that a trial of ketoconazole should be considered
`when 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 cancer
`in the United States, exceeded only by lung cancer.
`Even with localized disease at diagnosis, most patients
`eventually progress and develop metastases. Although
`the majority of these patients initially respond to
`
`‘Corresponding author. Tel. +773-S64-SO06‘. Fax: +773-S64-5007.
`E—mm1' ad¢t':'e.r.s': simoninwilkinsonnjtholniail,com (S, Wilkiiison),
`
`hormonal ablation, most will ultimately fail and
`require further
`therapy. Anti—androgen withdrawal
`represents one option, with responses ranging between
`15% and 33% {I-3}. However, any response tends to be
`short—lived usually lasting only about 3 months, after
`which the PSA starts rising again. The pathophysiology
`of the anti—androgen withdrawal response is not com-
`pletely understood, although androgen receptor gene
`mutations are a
`likely explanation. Whatever
`the
`mechanism,
`this paradoxical phenomenon demon-
`strates the heterogeneity of prostate cancer cells in
`their response to different hormonal maneuvers. This
`
`0302-28Zl8l$ — see front matter Q"? ‘Z004 Elsevier B.V. All rights reserved.
`doi: I U. 10 I 5r'j.cu1'uro 1003.1 L031
`
`
`
`Amerigen Exhibit 1077
`Amerigen Exhibit 1077
`Amerigen v. Janssen IPR2016-00286
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`
`

`

`582
`
`S. Wilkr'rt.s'0n, G. Cl'trJdr1Jc/Eurr;pnmn UI'rJIrJ_tg_v 45 (2004) 5v$’1'—585
`
`ability to retain hormonal sensitivity has encouraged
`investigators to evaluate other second—line hormonal
`manipulations in metastatic prostate cancer.
`Ketoconazole, an orally active broad-spectrum anti-
`fungal agent, was first reported to have activity against
`prostate cancer almost 20 years ago [4]. It blocks both
`testicular and adrenal androgen biosynthesis by inhibit-
`ing cytochrome P459 enzymes involved in steroidogen—
`esis. Within 48 hours of initiation, ketoconazole reduces
`the concentration of circulating androgens to castrate
`levels [5]. Ketoconazole also has direct cytotoxic effects
`against prostate cancer cells in the absence of androgens.
`In human cell lines of prost.ate cancer, ketoconazole
`exerted a cytostatic effect by inhibiting DNA synthesis
`[6}. In another in vitro study, exposure to ketoeoriazole
`reduced cell viability by 26% of the control E7}.
`Compared to other options for managing hormone
`refractory prostate cancer, ketoeonazole is an attractive
`alternative because of its convenience and flexibility of
`administration.
`In clinical
`trials,
`responses ranging
`between 31.0% and 62.5% have been reported using
`high doses of ketoeonazole (400 mg three times daily)
`[8,9]. Unfortunately, the potential toxicity of ketoeo—
`nazole remains a major limitation for using this drug.
`Indeed, it was recently reported that 20% of patients
`discontinue high-dose ketoconazole due to intolerable
`side effects [9].
`In order
`to reduce toxicity, one
`approach is to administer lower doses. However. the
`main concern with this approach is that therapeutic
`efficacy may be compromised. With this in mind, we
`investigated the response of patients to intermediate-
`dose ketoconazole (300 mg three times daily).
`
`2. Methods
`
`We reviewed the medical records of 38 consecutive patients with
`histologically confirmed prostate cancer who had been treated with
`ketoconazole by one clinician (GWC). To be included in this study,
`patients met the following requirements: (1) there was biochemical
`progression despite combined androgen blockade and subsequent
`anti—androgen withdrawal, (2) anti-androgens were withdrawn at
`least 2 months before treatment. (3) luteinizing hormone releasing
`hormone (LHRH) agonists were continued alongside treatment.
`and (4) no other concurrent therapies were being used. We defined
`biochemical progression as 3 consecutive PSA rises that were at
`least one month apart.
`Unlike the majority of previous studies, which reported on
`patients taking ketoconazole 400 mg three times daily, we treated
`patients with a lower dose regime of 300 mg three times daily. All
`patients received replacement doses of hydrocortisone, 20 mg in
`the morning and 10 mg at night, to counteract potential adrenal
`insufficiency induced by ketoconazole.
`Prostate specific antigen (PSA) levels and liver function tests
`were performed one month after initiation of ketoconazole and
`subsequently every 3 months. At each clinic appointment. patients
`
`also underwent a physical examination, and were specifically
`questioned about side effects. Termination of therapy was under-
`taken if there was no PSA response within 3 months or if side
`effects were intolerable. The principal endpoint was PSA response.
`This was defined according to the guidelines of the Prostate
`Specific Antigen Working Group {l0}.
`
`3. Results
`
`At the time of data collection, 12 patients (31.6%)
`were still alive. Median age at last follow—up or death
`was 73 years (range 4@9l years). Median age at
`diagnosis of prostate cancer was 66 years (range 45-
`86 years). Serum PSA at diagnosis of prostate cancer
`varied between 5 and 868 ng/ml, with a median of
`33 ng/ml. Of the 38 patients, 28 (73.4%) had estab-
`lished metastatic disease on bone seintigraphy. Among
`the 10 patients with a normal bone scan, 6 had histo-
`logically proven iliac lymph node involvement. Thirty
`patients were being treated with LHRH analogues,
`while the remaining 8 patients had undergone bilateral
`orchideetomy. The distributions of Gleason score and
`primary treatment are shown in Table l.
`The median interval
`from diagnosis of prostate
`cancer to initiation of ketoconazole was 5 years (range
`l~2l years). At commencement of therapy, the median
`PSA was 37 ng/ml (range 271-794).
`Of the 38 patients, 21 (55.3%) showed a decrease in
`PSA of >50% (95% confidence interval 38.3%—7l .4%)
`with a median duration of 6 months (range 3-48
`months). Of these responders, 7 (33.3%) had a durable
`response lasting more than a year. Five patients con-
`tinued to exhibit a response at last follow—up. A PSA
`reduction 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%
`
`Table1
`Distribution of Gleason score and primary treatment
`
`Number
`
`Ptzrcenlage
`
`Gleason score‘
`‘
`6
`7
`3
`9
`I0
`Primary treatment
`Radical prostatectomy
`Radiotherapy
`Brachytherapy
`Hormonal therapy
`
`4
`3
`16
`5
`9
`I
`
`6
`8
`2
`22
`
`' Gleason scores were available for 36 of the 38 patients.
`
`ll 1
`8 3
`44.5
`8.3
`25 0
`2 8
`
`15.8
`2| 0
`5 3
`57.9
`
`

`

`S. Wilkirisrart, G. Cfirirlctk/Etirupmrz Umlog-_\‘ 45 (2004) 58.7-58.5
`
`583
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`0.00
`
`0
`
`10
`
`30
`20
`Months since start of
`treatment
`
`40
`
`50
`
`Fig.
`
`I. Kaplan-Meier survival estimate.
`
`confidence interval l9.6%—5l .4%) with a median dura-
`tion of 9 months (range 3-48 months). The median
`PSA reduction was 47.5%.
`
`Age, PSA at diagnosis, Gleason score, bone scan
`result, lymph node involvement, PSA at ketoconazole
`initiation and duration of hormonal ablation were not
`
`significantly associated with response to ketoconazole
`in univariate or multivariate analyses. However, if the
`PSA 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 = 0.046). In fact, the odds of having a PSA response
`>50% for patients with a PSA >40 ng/ml were 3.9 times
`those for patients with a PSA <40 ng/ml.
`For the entire study group,
`the median time to
`progression was 5 months (range 0-27 months) and
`the median survival was 12 months (range 3-48 months
`(Fig. 1). Using the >50% response criteria, the median
`survival time for responders was 24 months compared
`to 9 months for the non-responders (p = 0.0089). For
`the >80% response,
`the median survival
`time for
`responders was 33 months versus 9 months for the
`non-responders (p = 0.0142).
`Overall, 12 patients (3 l.6%) reported toxicity related
`to 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 ket0cona—
`zole due to intolerable side effects.
`
`4. Discussion
`
`For patients with hormone refractory prostate cancer
`duration of survival is variable, ranging between 7 and
`
`27 months [ E l]. The optimum management of these
`patients remains uncertain as no prospective rando-
`mized trials have yet
`to show a survival benefit.
`Furthermore, no universally accepted algorithm has
`been 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 with
`patients. Since most patients are asymptomatic initi-
`ally,
`thesc therapies should offer the potential for
`subjective andfor objective responses without signifi-
`cantly compromising quality of life.
`Our results indicate that intermediate-dose ketocona-
`
`zole (300 mg three times daily) can induce objective
`clinical responses in some patients with hormone refrac-
`tory prostate cancer. The response rate of 55.3% com-
`pares
`favorably to
`studies
`employing high-dose
`ketoconazole (400 mg three times daily). In one study
`using this high—dose regime, 30 of 48 patients (62.5%)
`demonstrated a PSA reduction >50% with a median
`
`duration of 3.5 months [8]. For a PSA reduction >80%,
`our response rate of 34.2% is also consistent with that
`
`reported in other studies [9]. For patients contemplating
`ketoconazole, it would therefore seem reasonable to try
`an intermediate-dose regime before moving to a higher
`dose.
`
`information regarding lower dose
`Unfortunately,
`regimes of ketoconazole in prostate cancer therapy
`is sparse. To our knowledge, the only other published
`study employing a low-dose regime (200 mg three
`times daily) yielded a >50% PSA reduction in 13 of
`28 patients (46%)
`[i2}. Combined with our data,
`these observations suggest that therapeutic cfficacy
`may not be compromised by reducing the dose of
`keloconazole.
`
`Regarding toxicity, our intermediate—dose schedule
`was well tolerated, with only 15% ceasing treatment
`due to unacceptable side effects. This compares favor-
`ably to a discontinuation rate greater than 20% for
`high-dose ketoconazole regimes (400 mg three times
`daily) [9].
`Disappointingly. a survival benefit could not be
`demonstrated in our study population. This is con-
`sistent with other efficacy trials of ketoconazolc, and
`further studies are needed to define its ultimate role
`
`in treating this disease. The Eastern Cooperative
`Oncology Group is pursuing one such study. ECOG
`i899 is a phase III randomized trial for evaluating
`second—linc hormonal
`therapy (ketoconazole/hydro
`cortisone) versus combination chemotherapy (doce-
`taxel/estramustine) on progression free survival
`in
`patients with hormone refractory prostate cancer
`[13].
`
`

`

`584
`
`5'. Wilkinson. G. Cliodctk/Eumpecuz Umfrigrv 45 (2004) 58l'—585
`
`Until such trials are completed, many prostate cancer
`specialists may feel tnore comfortable combining keto-
`conazole with various chemotherapy regimes, given
`the symbiotic relationship that seems to exist. By
`combining ketoconazole with doxorubicin, responses
`ranging between 36% and 55% have been reported
`[9,]-‘ll. Furthermore, alternating this regime with estra-
`mustine and vinblastine improves therapeutic efficacy
`further, with responses reaching 60% to 67% [15,16]. It
`is believed that ketoconazole exerts this symbiotic
`
`effect by blocking the multidrug resistance gene
`(MDR), which is largely responsible for
`inducing
`chemotherapy drug resistance [17].
`We acknowledge that concurrent corticosteroid
`administration may be 21
`significant confounding
`variable. Indeed, use of hydrocortisone alone after
`anti-androgen withdrawal has been associated with
`responses ranging between 19% and 22% [l8—20].
`
`However, our objective response rate of 55.3% sug-
`gests that ketoconazole is responsible for the majority
`of this activity.
`We also acknowledge that our primary endpoint of
`PSA response remains controversial and there is still no
`consensus defining disease progression. Nevertheless.
`it has been demonstrated that PSA responses of >50%
`correlate with improvement in time to treatment failure
`and 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 rationale
`for further investigation of ketoconazole as a viable
`therapeutic strategy for patients with advanced dis-
`ease. Future studies should also incorporate quality-
`of-life measures. given the limited prognosis of these
`patients.
`
`References
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`[J] Small FJ. Srinivas S. The antiandrogen withdrawal
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`J Clin Oncol
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`[3] Figg WI), Sanor 0, Cooper MR. Thibault A, Bergan RC, Dawson N,
`et al. Prostate specific antigen decline following the discontinuation
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`[4] Trachtenberg J. Halpcrn N. Punt A. Ketoconazolez a novel and
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`[5] Porn A, Williams PL. Azhar S. Reitz RE. Bochra C, Smith ER. ct al.
`Ketoconazole blocks
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`l982;l42[l2i:2l37—40.
`[6] Blagosklonny MV. Dixon SC. Figg WD. Efficacy of microtubulc-
`active drugs followed by ketoconazole in human metastatic prostate
`cancer cell lines. .J Urol 2000;l63[3):l022—6.
`[7] Dixon SC. Zalles A, Giordano C. Lush RM. Venzon D. Reed E, et al.
`In vitro effect of gallium nitrate when combined with ketoconazole in
`the prostate cancer cell line PC-3. Cancer Lctt l997:| l3( 1/2}: l
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`[3] Small EJ, Baron AD, Fippin L. Apodaca D. Ketoconazoie retains
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`|ll| Halabi S. Small EJ, Kantofi PW. Kattan MW. Kaplan EB. Dawson
`NA, et al. Prngnostit: model
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`I-larris KA, Weinberg V, l30l( RA. Kakcfuda M. Small EJ. Low dose
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`[14] Sella A, Kilbourn R, Amato R, Btii C, Zukiwski AA, Ellerhorst J.
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`Gottesman MM. Ketoconaztile
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`RC. et al. Antitumor activity of suramin in hormone-refractory
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`controlling for hydrocortisone
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`
`

`

`S. Wilkirzxorz, G. C'Froa’uf</Errmpmn Umlogy 45 (2004) 581-585
`
`585
`
`Editorial Comment
`
`A. Heidenreich, Cologne, Germany
`
`The clinical
`
`trial conducted in a small series of
`
`patients by Wilkinson et al. reports on an important
`therapeutic option in patients with PSA progression
`following initial androgen deprivation. Contrary to the
`authors. however,
`I would suggest
`that
`the treated
`cohort of patients represents androgen refractory, but
`hormone sensitive prostate cancer which might benefit
`from secondary hormonal maniputations such as ster-
`oids, estrogens or inhibitors of adrenal androgen synth-
`esis
`such as ketokonazole [1]. The current
`trial
`highlights several important aspects in the manage-
`ment of metastatic PCA failing androgen deprivation
`
`l, Ketokonazole/hydrocortisone represents a valid
`therapeutic secondary hormonal measure resulting
`in a median duration of response of 6 months [2—4].
`2. PSAL 250% appears to represent a significant
`surrogate marker of survival
`in the group of
`patients with androgen refractory but hormone
`sensitive prostate cancer as has already been
`demonstrated in HRPCA [5].
`3. PSA response to ketokonazole can be identified
`within the first 6 to 8 weeks of therapy allowing an
`early identification of responders and non—respon—
`ders. Responders will benefit from continuation of
`therapy with a median survival of about 2 years
`and non—respor1ders 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
`remains
`unclear if the PSA responses are due to the activity
`
`of ketokonazole or if the concurrent administration of
`
`It
`hydrocortisone represents a confounding variable.
`has been shown for arninogluthetimjde—another inhi-
`bitor of adrenal androgen synthesis~—that the addition
`of hydrocortisone results in a significant improvement
`of response and survival rates [6].
`Nevertheless, the combination of ketokonazole and
`
`hydrocortisone represents a valuable therapeutic option
`for the management of PCA failing initial androgen
`deprivation. Following antiandrogen withdrawal,
`this
`combination should be tried in most patients; since
`cytotoxic regimes even with taxanes still lack to demon-
`strate a survival benefit the development of effective
`secondary measures with low morbidity and mainte-
`nance of quality of life are of clinical importance.
`
`References
`
`[1]
`
`I-leidenreich A, von Knobloch R, Hofrnann R. Current status of
`cytotoxic chemotherapy in hormone refractory prostate cancer. Eur
`Urol 20(}l;39:l2l—3tl.
`[2} Johnson DE, Babaian RJ. von Eschenbach AC, ct al. Kelokonaznle
`therapy for honnonally refractive metastatic prostate cancer. Urology
`1988-,3l:l32—4.
`[3] Small EJ, Baron AD, Fippin L. et al. Kctokonazole retains activity in
`advanced prostate cancer patients with progression despite fiutamid
`withdrawal. J Urol
`l997;|57:l204-7'.
`[4] Small El. Baron AD. Bok R, et al. Simultaneous antiandrogcn
`withdrawal and treatment with ketokonazole and Irydiocortisnne in
`patients with advanced prostate carcinoma. Cancer l997'.80: I7-'55—9.
`[5] Smith DC, Dunn LR, Strawdcrrrian MS, Pienta K}. Change in serum
`prostate-specific antigen as a marker of response to cytotoxic therapy for
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`[6] Dowsett M. Shearer R5. Ponder BA]. at
`al. The effects: of
`aminogluthetiniide and hydrocortisnne, alone and in combined, on
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`Cancer l988;57:l90—2.
`
`

`

`