Bririrh Jnurnul of Urnlog) ( 1 986). 58,45 5 I
`( 19x6 B r i h h Journal of Urology
`
`Objective Responses to Ketoconazole Therapy in
`Patients with Relapsed Progressive Prostatic Cancer
`
`GORDON WILLIAMS, D. J. KERLE, H. WARE, A. DOBLE, HELEN DUNLOP, C. SMITH,
`JANET ALLEN, T. Y E 0 and S. R. BLOOM
`
`Departments of Surgery and Medicine, Hammersmith Hospital and Ro yal Postgraduate Medical School,
`London
`
`Summary-The contribution of adrenal androgens to the maintenance and progression of so-called
`hormone-unresponsive prostatic carcinoma was studied in 20 patients with advanced relapsed
`disease. The role played by testicular androgens had been negated by prior orchiectomy or
`concurrent LHRH analogue therapy. Ketoconazole, an antifungal agent which inhibits adrenal and
`testicular androgenesis, administered in a dose of 400 mg 8- hourly, resulted in optimal suppression
`of adrenal androgens. The mean serum androstenedione concentration fell from 8.01 f 0.84 nMol/l
`to 1.55 f 0.25 nMol/l, P< 0.001, and serum testosterone from 1.25 f 0.1 4 nMol/l to 0.36 f
`0.06 nMol/l, P<O.Ol, after 6 months treatment. There was, however, no significant difference
`between patients receiving 400 and those receiving 200 mg. Androgen suppression resulted in six
`objective and ten subjective clinical responses. Ablation of both testicular and adrenal androgens
`can now be achieved using ketoconazole in combination with orchiectomy or LHRH analogues, but
`the high incidence of side effects may preclude its use in all patients with prostatic cancer. The
`results of this study support the concept of "total androgen ablation" as primary therapy in advanced
`prostatic cancer as a possible means of improving survival in this common malignancy.
`
`Endocrine treatment of advanced prostatic cancer
`has been aimed at suppressing the major source of
`circulating testosterone from the testes and is
`achieved by either oestrogen administration, which
`inhibits pituitary secretion of gonadotrophins, or
`orchiectomy. Initial clinical response rates of 70 to
`80% following either form of therapy have been
`reported (Resnick and Grayhack, 1975; White-
`head, 1981). However, most of these patients will
`relapse in 2 to 3 years of commencing endocrine
`therapy, and once relapse occurs 50% will die
`within 6 months. These therapies do not suppress
`adrenal androgens, which may
`increase after
`orchiectomy and encourage continued tumour
`growth (Sciarra et al., 1973). Attempts to inhibit
`adrenal androgen production using pituitary abla-
`tion, adrenalectomy (Murphy et al., 1971) or ami-
`noglutethimide (Sanford et al., 1976; Worgul et al.,
`__. .~~~ ~-
`Accepted for publication 9 April 1985
`
`~~
`
`~
`
`1983) have been made in patients who have failed
`conventional endocrine treatment. These latter
`therapies all have considerable disadvantages and
`when instituted for end-stage relapsed disease, ob-
`jective response rates are poor and of short
`duration (Sanford et al., 1976; Fitzpatrick et al.,
`1980; Worgul et al., 1983). The use of these forms
`of therapy as a component of primary endocrine
`treatment has not been attempted because of the
`high incidence of serious side effects. Steroid sup-
`plements, which are obligatory following pituitary
`ablation or aminoglutethimide therapy, may be re-
`sponsible in part for the adrenal suppression
`achieved.
`Ketoconazole, an imidazole antifungal agent,
`has been shown to inhibit both testicular and
`adrenal androgenesis (Pont et al., 1982a and b).
`Objective responses following ketoconazole ad-
`ministration in patients with newly diagnosed pros-
`tatic cancer have been reported (Trachtenburg and
`
`45
`
`JANSSEN EXHIBIT 2020
`Mylan v. Janssen IPR2016-01332
`
`

`

`46
`
`Pont, IY84), but serum testosterone did not reach
`castrate levels in all patients and its short duration
`of action necessitates a strict 8-hourly dose regime.
`We have previously reported two patients with
`relapsed progressive disease treated with ketocona-
`zole who have shown an improvement in objective
`response measurements (Allen et al., 1983). We
`now present our experience of ketoconazole
`administration in a further 20 patients.
`
`Patients and Methods
`Informed consent was obtained prior to treatment
`from 20 patients aged 55 to 77 years (mean 68.5)
`with histologically confirmed prostatic carcinoma
`who had relapsed following single or multiple se-
`quential endocrine therapy (Table 1). Each patient
`
`Table 1 Previous Hormonal Therapies
`
`Previous liormonui ireuiment
`
`LHRH
`Oestrogen + orchiectomy
`Oestrogcn + LHRH
`Orchiectomy+ LHRH
`Orchiectomy + oestrogen +
`LHRH
`Orchiectomy + cyproterone
`acetate+ LHRH
`
`Time from initial
`diugnosrs 10
`introduction o/
`ketoconazole
`(months)
`
`8.5
`24
`23
`29
`
`43
`
`60
`
`1
`
`underwent the following staging procedures: digital
`rectal examination, tartrate labile acid phospha-
`tase, alkaline phosphatase, intravenous urography,
`technetium labelled bone scanning with appropri-
`ate radiographs, and in one patient a sagittal sec-
`tion nuclear magnetic resonance scan before and 6
`months after treatment. All objective response
`measurements were documented at regular inter-
`vals throughout the study, using the British Pros-
`tate Group Criteria.
`Subjective criteria were recorded before treat-
`ment and at each subsequent visit using a scoring
`system for activity, pain and analgesia (Oken et al.,
`1982). Blood for measurement of serum testoster-
`one and dihydrotestosterone (Ghanadian et al.,
`1975), androstenedione (Ghanadian and Puah,
`1 Y83), cortisol by “Gamma Coat” kit (Clinical As-
`says, Cambridge, USA), ACTH (Rees et al., 1971)
`and LH (Marshall et al., 1973) were taken before
`treatment, at 5 days, 2 weeks, 1 month and
`monthly thereafter. All samples for endocrine as-
`sessment were collected between 9 and 10a.m. On
`
`BRITISH JOURNAL OF UROLOGY
`
`the first treatment day 4- and 8-h samples were
`taken to measure the acute response of androstene-
`dione to a single dose of ketoconazole. The diurnal
`rhythm of serum cortisol and ACTH was studied in
`all patients after 6 months of ketoconazole therapy.
`Those patients who had not received a prior
`orchiectomy and were taking the LHRH analogue
`ICI 118630, 250 pg daily, were continued on this
`therapy.
`Ketoconazole was administered to 15 patients at
`a dose of 400mg 8-hourly (high dose) but was
`reduced to 200 mg 8-hourly (low dose) in 6 patients
`because of anorexia and nausea, after a mean inter-
`val of 30 days (range 5-70). The remaining five
`patients started on 200mg tds. A satisfactory clini-
`cal response has been reported at this lower dose
`(Trachtenburg et d., 1983). Endocrine data were
`analysed in accordance with the dose of ketocona-
`zole being administered at the time of each follow-
`up visit and were expressed as mean f SEM. Sig-
`nificance was determined using paired and
`unpaired Students t tests.
`
`Results
`Clinicul
`Eight patients died of progressive metastatic dis-
`ease within 14 weeks of commencing treatment
`(mean 7.5 weeks, range 4-14) (Fig. I). Six of these
`
`13
`12
`1 1
`10
`9 E
`
`0
`
`2
`
`4
`
`6
`Months
`Fig. 1
`Clinical outcome in 20 patients with advanced relapsed
`prostatic cancer following two dose regimes of ketoconazole.
`
`8
`
`10
`
`1
`12
`
`patients were on low dose and two on high dose
`regimes.
`Eleven patients have survived for more than 14
`weeks. Four maintained on low dose therapy are
`alive for a mean period of 8 months. Partial objec-
`tive response was documented in one patient and
`
`

`

`OBJECTlVE RESPONSES TO KETOCONAZOLE THERAPY
`
`47
`
`Table 2 Changes in Objective Response Measurements and Resulting Clinical Response (British Prostate Group) in
`1 I Patients Following 6 Months of Ketoconazole Therapy
`
`Puiicvr
`
`Dose
`
`2
`3
`4
`5
`6
`9
`11
`I
`7
`8
`10
`
`1200 mg/day
`
`1.
`
`1.
`
`., 1.
`
`, I
`
`1,
`
`,, 7,
`
`> >
`
`9 1
`
`1,
`
`1,
`
`600 mg/day
`.. ,.
`
`7 ,
`
`I ,
`
`1,
`
`7.
`
`T srage
`
`TO-TO
`T4-+T4
`TI -+TO
`TO+TO
`T4 -+ T4
`T3+T4
`TO-TO
`T3 +TO
`TO-TO
`T4-+T4
`T4-T4
`
`Acidphos. (iu/l)
`
`I25 - 322
`
`28-25
`20-6
`
`2.9-N
`6-N
`6-N
`9-N
`68-69
`5.4-N
`1.8-2.1
`241 -6.5
`
`Bone .scans
`
`Clinical response
`
`Stable
`Stable
`Improved
`Stable
`Improved
`Worse
`Complete resolution
`Stable
`Worse
`Worse
`Resolution some lesions
`
`Stable
`Partial
`Partial
`Partial
`Partial
`Progression
`Complete
`Stable
`Progression
`Progression
`Partial
`
`A
`
`Sagittal section nuclear magnetic resonance (NMR) scans (A) before and (B) after 6 months ketoconazole 400 mg tds. Pros-
`Fig. 2
`tatic turnour volume has halved and the previously stenosed bowel lumen is clearly visible.
`
`another has stable disease, but the other two have
`shown evidence of disease progression manifest by
`worsening bone scans. Seven patients have been on
`high dose therapy throughout and have shown evi-
`dence of response (Table 2). The likelihood of a re-
`sponse to ketoconazole did not appear to relate to
`any previous combination of therapies,
`
`resonance scanning (Figs. 2A and B) and serial
`ultrasonography. Digital assessment in the remain-
`ing patients showed a prostate tumour volume
`reduction of at least 50% in two patients (4 and 6).
`Downstaging of the prostatic tumour occurred in
`one of these. No change in the state of local disease
`was detected in the remaining four patients.
`
`Objective Response
`1. Local disease
`The volume of prostatic tumour halved and uni-
`
`2. Prostatic Acid Phosphatuse
`The tartrate labile acid phosphatase was elevated in
`11 of 12 patients who commenced and continued
`on high dose therapy for at least 1 month. Values
`fell by more than 50% in seven of these within this
`first manth of treatment and have reached the nor-
`
`

`

`48
`
`.-.
`
`-J +
`
`
`
`i
`40 -1
`
`201
`
`r~
`0
`
`1
`
`I
`2
`
`I
`3
`
`I
`I
`5
`4
`Months
`Fig. 3 The tartrate labile acid phosphatase fell by more than
`50% in seven patients following ketoconazole 400mg tds. This
`initial fall is maintained in six patients and three have normal
`valucs after 6 months' treatment.
`
`1
`6
`
`I
`7
`
`I
`8
`
`I
`9
`
`BRITISH JOURNAL OF UROLOGY
`
`Table 3 Changes in the Subjective Scores After Keto-
`conazolc. Significant Responses are Indicated by an
`Improvement ofTwo or More Points (Rees r t a/., 1971)
`
`Subjective scnre: points improve-
`ment
`
`Time
`_
`One month
`
`_
`
`Threemonths
`
`Six months
`
`Dose
`
`~
`
`High
`Low
`High
`Low
`High
`Low
`
`1 2 2
`~
`5
`6
`6
`I
`7
`2
`
`I
`2
`
`1
`
`4 orrnorc
`
`
`
`6
`
`~
`
`3
`
`1
`
`0.12 nMol/l (n = 6, P> 0.1) after 6 months' high
`
`dose treatment and to 0.64 f 0.06nMol/l (n = 6,
`P>0.3) after 3 months of low dose therapy.
`Serum cortisol remained within
`the normal
`range (200-700 nMol/l) during the course of study
`in all patients. The mean serum concentration
`changed from 747 f 77 nMol/l (n = 17) to 548 f
`80nMol/l (n=6, P>O.O5) after 6 months of high
`dose ketoconazole treatment. Low dose resulted in
`a fall to 544.5nMol/l in two patients after 6
`months.
`The serum ACTH was in the normal range (10-
`80ng/l) in 12 of 14 patients studied prior to treat-
`ment. Six of these patients (five high dose and one
`low dose) showed elevation of serum ACTH (range
`88-31 1 ng/l) within 3 days of commencing treat-
`ment. There was a progressive rise in four of these
`patients alive after 3 months' treatment. Of the two
`patients alive at 6 months, the serum ACTH has
`returned to normal in one. The six patients with no
`rise in ACTH at the beginning of treatment re-
`mained normal throughout the period of study.
`Five further patients had ACTH estimations for
`the first time after 6 months' treatment and four
`(two high and two low dose) were elevated (range
`89-260 ng/l).
`The diurnal variation of serum cortisol and
`ACTH was studied in seven patients (four high and
`three low dose) between 6 and 12 months of keto-
`conazole therapy. The 8a.m. serum cortisol was
`normal in all patients but at midnight four patients
`(two high and two low dose) had elevated levels
`(range 260-450 nmol/l; normal range < 250 nmol/
`1).
`
`Correspondingly, four patients (three high and
`one low dose) had elevated serum ACTH concen-
`trations at 8a.m. (range 154-260ng/l) and three
`were normal. At midnight all ACTH values were
`elevated (range 27-94 ng/l; normal range < 10 ng/l).
`
`ma1 range in three of eight patients treated with
`high dose therapy for 3 months (Fig. 3).
`
`3. Bone Scans
`Seven patients who had been on high dose therapy
`for 6 months had a further bone scan. Three scans
`have improved, with resolution of lesions con-
`firmed radiographically, and three remain stable.
`Patient 4 had an improvement in both local tumour
`and bone scan but also a steady rise in acid phos-
`phatase; the bone scan showed no new lesions,
`improvement of existing lesions and resolution of
`some. These changes in objective response param-
`eters are summarised in Table 2.
`
`Subjective Response
`The changes in the subjective scores are shown in
`Table 3. The maximum benefit was seen in the first
`month's treatment.
`
`Endocrine Response
`A prompt fall in the mean serum androstene-
`dione concentration was seen within 8 h of com-
`mencing therapy and was most marked in patients
`on high dose (Fig. 4A). The continuing fall in both
`groups is shown in Figure 4B. All patients had cas-
`trate levels of serum testosterone before treatment.
`Further falls in the mean serum concentrations of
`testosterone are shown in Figure 5.
`The mean serum concentration of dihydrotestos-
`terone fell from 0.85 f 0.07 nMol/l
`to 0.47 f
`
`

`

`1 1 3
`
`OBJECTIVE RESPONSES TO KETOCONAZOLE THERAPY
`
`5
`
`1 8
`
`-
`0
`c E
`aJ
`C
`
`0 .- B
`c
`al U
`m e
`D c a
`
`l o 8
`
`(
`
`5
`
`
`
`K
`
`J.
`8
`
`49
`
`5
`
`2
`
`I
`2
`
`I
`6
`
`1
`8
`
`B
`
`0
`
`10
`
`20
`
`90
`
`180
`
`210
`
`A
`
`f
`0
`
`~
`
`I
`30
`4
`Days
`Hours
`Fig. 4 Mean serum androstenedione concentrations following institution of ketoconazole therapy (K) 400 mg tds
`and
`- -. (A) Suppression is seen after 8 h of single dose of 200 mg (P=0.04) and 400mg of ketoconazole (P = 0.005). (B) A
`200mg tds
`significant difference between the two dose regimes after 8 h (Pi0.001) is not maintained during long-term follow-up.
`1.6 7
`
`5
`
`1 9
`T
`
`I
`K
`
`: 0 . 8
`e
`
`0 . 0 J
`
`1
`
`-+l-+l-+fl
`0
`10
`
`20
`
`90
`
`180
`
`300
`
`30
`Days
`Fig. 5 Mean serum testosterone following institution of keto-
`conazole therapy (K) 400 mg tds --
`200 mg tds. A
`and --
`significant fall below castrate concentrations is seen following
`180 days of high dose therapy (P <O.OI).
`
`~
`
`Side Effects
`Eleven of the 20 patients complained of nausea and
`anorexia immediately after institution of ketocona-
`zole therapy (8 high dose and 3 low dose). Dosage
`was reduced to 200 mg 8-hourly in six of the eight
`high dose patients but nausea persisted in four,
`requiring withdrawal of the drug in one. A persis-
`tent but acceptable level of nausea was tolerated by
`six high dose and three low dose patients through-
`out the treatment period.
`Six high dose patients showed a transient rise in
`
`~
`
`the serum aspartate transaminase (range 5 1-77 iu/k
`normal range 21-40) which occurred between 5
`days and 2 months following the start of ketocona-
`zole. In only one patient was this associated with
`elevation of serum bilirubin to 22 pmol/l (normal
`range 4-17) after 1 month of therapy. The serum
`bilirubin rose transiently in two further patients,
`one high dose and one low dose, to I8 pmol/l after 2
`months and 21 pmol/l after 3 months’ treatment
`respectively but returned to normal without drug
`withdrawal. None of the patients who have been on
`therapy for more than six months has any abnor-
`mality of liver function.
`Hypocalcaemia developed in two patients, one
`high dose and one low dose. The serum calcium fell
`to 1.87nmol/l after 5 days’ treatment in the high
`dose patient (normal range 2.15-2.65) and re-
`mained low during 4 months of ketoconazole treat-
`ment. The low dose patient was hypocalcaemic
`prior to ketoconazole treatment but fell further to
`1.65 nmol/l after introduction of the drug.
`
`Discussion
`Between 60 and 80% of patients with prostatic
`cancer respond to endocrine therapy aimed at low-
`ering serum testosterone. Because of this success in
`the palliation of symptoms there has been little de-
`viation from conventional treatment using oestro-
`gens or orchiectomy as primary therapy.
`
`

`

`50
`
`However, after 2 to 3 years’ treatment the major-
`ity of patients will relapse and this is thought to in-
`dicate the development of tumour cells growing
`independently of their hormone environment. It is
`not surprising that further clinical responses are
`rarely seen following additional hormonal manipu-
`lation directed solely at the pituitary gonadal axis
`(Stone et ul., 1980; Allen et al., 1984).
`Man is unique in having adrenals which secrete
`large quantities of pre-cursor steroids which are
`converted into potent androgens. The adrenal out-
`put accounts for up to 10% of androgen produc-
`tion and remains unaffected by conventional
`endocrine therapy with oestrogens or orchiectomy.
`Furthermore, following such therapy intraprosta-
`tic concentration of dihydrotestosterone, the most
`active androgen within the prostate, remains as
`high as 50% of levels found in intact patients
`(Geller ef ul., 1979). High doses of ketoconazole, a
`widely used drug for the treatment of fungal dis-
`eases, blocks the synthesis of testosterone in both
`the testes and the adrenals at a cytochrome P450
`dependent step, i.e. where I7 alpha, 20 alpha
`dihydroxy-progesterone
`is
`transformed
`into
`androstcnedione.
`This inhibition of adrenal androgen production
`by ketoconazole has allowed us to evaluate the role
`of these androgens in patients with advanced
`relapsed prostatic cancer-tumours
`thought to be
`hormone-independent. Recent
`refinements
`in
`radioimmunoassay techniques for androgen assay
`and the acceptance of standard response criteria in
`prostate cancer have enabled us to correlate adre-
`nal androgen suppression with clinical response.
`The patients treated all had severe disease, eight
`dying from their malignancy within 14 weeks. Sub-
`jective improvement was seen in 10 patients within
`the first 3 months of treatment, though the major-
`ity of these were in the first month. One patient on
`high dose ketoconazole, who had been confined to
`bed with severe perineal pain, was able to mobilise
`to near-normal activity and withdraw from narco-
`tic analgesia. This degree of improvement was
`unlikely to be due to a placebo effect. Of the I I
`patients alive at 6 months and assessed by the
`British Prostate Group criteria of response (Chis-
`holm and Beynon, 1983), one complete and five
`partial responses were seen. The objective re-
`sponses of some patients were dramatic, in particu-
`lar the relief of almost total rectal occlusion by a
`massive encircling tumour (Fig 2A and B), and a
`complete resolution of secondaries confirmed by
`bone scan in another.
`This study has shown that ketoconazole mark-
`
`BRITISH JOURNAL OF UROLOGY
`
`edly inhibits production of androstenedione at
`both dose regimes and produces further significant
`falls in the already castrate levels of testosterone
`and dihydrotestosterone; although not measured in
`this study, an elevation of progestogens could be
`expected.
`These results strongly suggest that adrenal
`androgens play a significant role in the mainten-
`ance of some so-called hormone-unresponsive
`prostatic tumours and provide further evidence for
`the concept of total androgen ablation (Znter-
`nutionnl Journal of’ Andrology, 1984) for the prim-
`ary treatment of prostatic cancer.
`Alterations in serum cortisol occurred at some
`stage in most patients during the course of treat-
`ment. However, no patient had levels below the
`normal range and cortisol supplements were not
`required. Maintenance of a cortisol within the nor-
`mal range has been achieved by elevation of ACTH
`in most patients. Medical adrenalectomy achieved
`with, aminoglutethimide (Sanford et al., 1976; Fitz-
`patrick et al., 1980) invariably requires cortisol re-
`placement and this may, in part, account for the
`clinical effects seen.
`Aminoglutethimide, an alternative means of pro-
`ducing a medical adrenalectomy, is not without
`side effects, nor is ketoconazole. Six patients were
`unable to tolerate high dose therapy because of
`persistent nausea, although this does not appear to
`be a problem when ketoconazole syrup is used
`rather than ketoconazole tablets. Ketoconazole is
`also hepatotoxic in some patients (Heiberg and
`Sveggaard, 1981; Lewis et nl., 1984) and has
`recently been the subject of a warning by the Com-
`mitkee on Safety of Medicines. The incidence of
`liver disease is approximately 1 in 15,000 and does
`not appear to be dose-related (Hay, 1985). Some
`transient abnormalities of liver function occurred
`in 50% of our patients but resolved despite con-
`tinuation of therapy.
`Fifty per cent of patients with progressive hor-
`monally unresponsive prostatic cancer will die
`within 6 months.
`Chemotherapy is not particularly effective and
`significant side effects are almost invariable in this
`elderly group of patients (Murphy, 1984). Signifi-
`cant objective benefit from aminoglutethimide is
`unusual and severe lethargy makes it unacceptable
`in many patients. We therefore feel that ketocona-
`zole does have a role in this group of patients pro-
`vided they are shown to have no pre-existing liver
`disease and that they are adequately monitored in
`specialist centres.
`We cannot support the view of Trachtenburg
`
`

`

`OBJECTIVE RESPONSES TO KETOCONAZOLE THERAPY
`
`and Pont (1984) for the use of ketoconazole as a
`single primary therapy because of its inadequate
`testosterone control in the intact male. It may have
`a role in combination with orchiectomy or an
`LHRH analogue aiming for total androgen abla-
`tation. These studies are under way.
`
`References
`Allen, J. M., Kerle, D., Ware, H., Dohle, A., Williams, G. and
`Bloom, S. R. (1983). Combined treatment with ketoconazole
`and LHRH analogue: a novel approach to resistant progress-
`ive prostate cancer. Briti,sh Medicul Journal, 287, 1766.
`Allen, J. M., Williams, G., O’Shea, J. P., Smith, C., Yeo, T.,
`Kerle, D. and Bloom, S. R. (1984). The effect of previous
`endocrine therapy on responses to a single dose of an LHRH
`analogue. Urologicul Reseurch, 12, 249-25 I .
`Chisholm, G. D. and Beynon, L. L. (1983). The response of
`malignant prostate to endocrine treatment. In The Endocrin-
`ologj, of’ Prosfute Tumours, ed. Ghanadian. R. Pp. 241-262.
`Lancaster: MTP Press.
`Fitzpatrick, J. M., Gardiner, R. A., Williams, J. P., Riddle, P. R.
`and O’Donoghue, E. P. N. (1980). Pituitary ablation in the re-
`lief of pain in advanced prostatic carcinoma. British Journal
`of Urology. 52, 301-304.
`Celler, J., Albert, J. and Loza, D. (1979). Steroid levels in cancer
`of the prostate; markers of tumour differential and adequacy
`of antiandrogen therapy. Journal ofsteroid Biochemistry, 11,
`63 1-636.
`Ghanadian, R., Lewis, J. G. and Chisholm, G. D. (1975). Serum
`testosterone and dihydrotestosterone changes with age in rat.
`Steroid.c. 25. 753-762.
`Ghanadian, R. and Puah, C. M. (1983). The clinical significance
`of steroid hormone measurements in the management of
`patients with prostatic cancer. World Journal of Urology. i,
`49-54.
`Hay, R. J. (1985). Ketoconazole: a re-appraisal. British Medical
`Journal. 290, 260.
`Heiherg, J. K. and Svejgaard, E. (198 I). Toxic hepatitis during
`ketoconazole treatment. British Medical Journal, 228, 825-
`826.
`International Journal of Andrology (1984). A new approach in
`the hormonal treatment of prostate cancer: complete instead
`of partial blockade of androgens. Internationul Journal of’
`An(lro1og.v. 7. 1-4.
`Lewis, J. H., Zimmerman, H. J., Benson, G. D. and Isak, K. G.
`(1984). Hepatic injury associated with ketoconazole therapy:
`analysis of 33 cases. Gastroenterology, 86, 503-51 3.
`Marshall, J. C., Anderson, D. C., Fraser, T. R. and Harsoulis, P.
`(1973). Human luteinising hormone in man. Studies of
`metabolism and biological action. Journal qf Endocrinology,
`56,43 1-439.
`Murphy, G. P. (1984). Chemotherapy: is it effective in treatment
`of prostatic cancer? Supplernenf of Urology, 24,5,41-47.
`Murphy, G . P., Reynoso, G., Schoonees, R., Gailani, S., Bourke,
`R., Kenny, G. M., Mirand, E. A. and Schalch, D. S. (1971).
`Hypophysectomy and adrenalectomy for disseminated pros-
`tate carcinoma. Journal of Urology, 105, 817-825.
`Oken, M. M., Creech, F. H., Tormey, D. C., Harton, J., Davis,
`T. E., McFadden, E. T. and Carbone, P. P. (1982). Toxicity
`
`51
`
`and response criteria of the Eastern Cooperative Oncology
`groups. American Journal oJClinicu1 Oncology, 6, 649-655.
`Pont, A., Williams, P. L., Azhar, S., Reitz, R. E., Bochra, C.,
`Smith, E. R. and Stevens, D. A. (1982a). Ketoconazole blocks
`testosterone synthesis. Archives of Internal Medicine, 142,
`2 137-2 140.
`Pont. A., Williams, P. L., Loose, D. S., Feldman, D., Reitz,
`R. G., Bochra, C. and Stevens, D. A. (1982b). Ketoconazole
`blocks adrenal steroid synthesis. Annals oflnlernul Medicine,
`97. 370-372.
`Rees, L. H., Cook, D. M., Kendall, J. W., Allen, C. F., Kramer,
`R. M., Ratcliffe, J. G. and Knight, R. A. (1971). A radio-
`immunoassay for rat plasma ACTH. Endocrinology, 89, 254-
`261.
`Resnick, M. and Grayhack, J. T. (1975). Treatment of stage IV
`carcinoma of the prostate. Urologic Clinics ofNorth America,
`2, 17.5- 182.
`Sciarra, F., Sorcini, G., Di Silverio, F. and Gagliardi, V. (1973).
`Testosterone and androstenedione after orchiectomy in pros-
`tatic adenocarcinoma. Clinical Endocrinology, 2, 101 -109.
`Sanford, E. J., Drago, J. R., Rohner, T. J., Santen, R. and Lip-
`ton, A. ( 1976). Aminoglutethimide medical adrenalectomy for
`advanced prostatic carcinoma. Journal of’ Urology, 115, 170-
`174.
`Stone, A. R., Hargreave, T. B. and Chisholm, G. D. (1980). The
`diagnosis of oestrogen escape and the role of secondary
`orchiectomy in prostatic cancer. British Journal of Urology,
`52,535-538.
`Trachtenberg, J., Halpern, N. and Pont, A. (1983). Ketocona-
`zole: a novel and rapid treatment for advanced prostatic
`cancer. Journal of Urology, 130, 152-1 53.
`Trachtenberg, J. and Pont, A. (1984). Ketoconazole therapy for
`advanced prostate cancer. Lancet, 2,433-43.5.
`Whitehead, E. D. (1981). Management of prostate carcinoma.
`New York State JournalofMedicine, 81, 1481-1485.
`Worgul, T. J., Santen, R. J., Samojlik, E., Veldhuis, J. O., Lip-
`ton, A., Harvey, H. A., Drago, J. R. and Rohner, T. J. (1983).
`Clinical and biochemical effect of aminoglutethimide in the
`treatment of advanced prostatic carcinoma. Journal qf Urol-
`ogy, 129.51-55.
`
`The Authors
`
`Gordon Williams, FRCS, Consultant Urologist.
`D . J. Kerle, FRCS, Senior Urological Registrar.
`H. Ware, MB,BS, Senior House Officer, Department of Urol-
`ogy.
`A. Doble, MB,BS, Senior House Officer, Department of Urol-
`ogy.
`Helen Dunlop, BSc, Research Assistant, Department of Urol-
`ogy.
`C. Smith, MA, MPhil, Research Assistant, Department of Urol-
`ogy,
`Janet Allen, BSc, MRCP, Medical Registrar.
`T. Yeo, BSc, PhD, Senior Biochemist, Department of Medicine.
`S. R. Bloom, DSc, FRCP, Professor, Department of Endocrin-
`ology.
`
`Requests for reprints to: Gordon Williams, Department of
`Urology, Hammersmith Hospital, Du Cane Road, London
`W12OHS.
`
`