ophthalmoplegia, and ptosis developed in 20% of cases of
`cavernous sinus thrombosis,6 but prompt treatment has
`eradicated these complications. Occasionally, traumatic
`carotid cavernous fistulas produce bilateral acute signs,
`including orbital bruits and visual loss. The history usually
`makes the diagnosis obvious.’ Inflammatory causes include
`pseudotumour and Wegener’s granulomatosis, which are less
`acute than cellulitis and respond dramatically to steroids.
`Blodi and Gass8 emphasised that pseudotumour is rarely
`bilateral and that this finding may indicate underlying
`systemic disease.9 Metastatic disease, usually from breast,
`lung, or kidney, may present with orbital signs, but in a series
`of 227 patients only 2 were bilatera1.lO
`The cardinal features of dysthyroid eye disease are orbital
`lid
`and
`and
`retraction,
`congestion,
`proptosis,
`lag
`ophthalmoplegia. The condition is usually chronic and
`bilateral and accompanied by ocular discomfort. Optic
`neuropathy occurs in only 5% of patients with Graves’
`disease." Visual loss is usually insidious, the symptoms and
`signs suggesting compression of the optic nerve. Symptoms
`include visual loss, flashing lights, and constricted fields.
`Poor colour vision and an afferent pupillary defect confirm
`optic nerve dysfunction. The visual fields may show central
`scotomas (94%) or arcuate defects, usually inferior (61%), but
`occasionally superior as well, to produce constricted fields. 12
`Optic disc swelling is an important sign. Most patients with
`dysthyroid eye disease have general clinical evidence of
`thyroid dysfunction.13-19 However, in one series 5% of
`patients with an ophthalmopathy were clinically euthyroid,
`though investigation of these patients showed evidence of
`disordered thyroid regulation. 17,20,21
`The orbital CT22 scan is a vital investigation in the diagnosis
`ofthese patients. Although patients with pseudotumour may
`have orbital myositis the affected muscles are diffusely
`thickened near their insertions. In dysthyroid eye disease
`generalised extraocular muscle enlargement is common, and
`Moseley and Sanders18 have emphasised that this occurs
`mainly towards the orbital apex, accounting for optic nerve
`involvement. The orbital CT scan appearances of grossly
`enlarged extraocular muscles prompted revision of the
`diagnosis to dysthyroid eye disease in the two cases reported
`here, even though the patients were clinically euthyroid. The
`scan also distinguished dysthyroid disease from invasive or
`other inflammatory conditions of the orbit and confirmed
`that the paranasal sinuses were clear.
`The immunology of dysthyroid eye disease is complex.
`Kodarma et a123 have reported a circulating autoantibody
`against soluble ocular muscle antigen in patients with
`ophthalmic Graves’ disease but not in those with thyrotoxicosis
`or goitre.
`Both patients had high titres of thyroglobulin and
`microsomal antibodies, and one had the haplotype B35,
`previously reported with severe dysthyroid ophthalmopathy.24
`A dramatic response to steroids occurred in both patients,
`consistent with their known effect on immunoglobulin
`production and release oflysosomal enzymes. Although auto-
`antibodies are usually not thought to cause tissue damage in
`dysthyroid eye disease it is tempting to postulate such a role in
`these patients with acute ophthalmopathy and to speculate
`about a viral infection as a precipitating factor.
`We thank Dr D. Croft, under whose care patient 2 was admitted, and Mr N.
`Sarkies who referred patient 1; Miss Josephine Lace for secretarial assistance;
`and Mr Richard Dewhirst for preparing the figures.
`
`Correspondence should be addressed to M. D. S., Medical Eye Unit, St
`Thomas’ Hospital, Shel.
`
`433
`
`Preliminary Communication
`
`KETOCONAZOLE THERAPY FOR ADVANCED
`PROSTATE CANCER
`
`JOHN TRACHTENBERG
`
`ALLAN PONT
`
`Department of Surgery/Urology, University of Toronto, Toronto,
`Canada; and Department of Medicine, Children’s Hospital of San
`Francisco, San Francisco, California, USA
`
`Summary
`
`Fifteen patients with biopsy-proven prostate
`cancer were treated with ketoconazole
`400 mg every 8 h. Two patients withdrew from therapy, one
`for personal reasons and one because a paraspinal mass
`developed. The other thirteen patients completed at least 6
`months of therapy. Ketoconazole greatly reduced the need
`for analgesics; serum prostatic acid phosphatase levels fell to
`normal, and testosterone levels were reduced. After 6 months
`thirteen of fourteen evaluable patients were in remission. The
`side-effects of ketoconazole therapy were limited.
`
`INTRODUCTION
`
`PROSTATE cancer accounts for 18% of all clinically
`detected cancers and for 10% of all cancer-related deaths in
`
`T. J. K. LEONARD AND OTHERS: REFERENCES
`
`1. Docherty PTC. Acute endocrine exophthalmos. BrJ Ophthalmol 1976; 60: 482-85.
`2. Falta W. Die Erbrankungen d Blutdrussen Berlin Springer, 1913; 50.
`3. Dock G Diseases of the thyroid gland: Eyes. In: Osler W, McCrae T, eds System of
`medicine London: Oxford University Press, 1915; 862.
`4. Snow IE. Jakobiec FA, Nolan BT. Patient examination and introduction to orbital
`disease. In: Duane TD, Jaeger EA, eds. Clinical ophthalmology vol 2. Philadelphia:
`Harper and Row, 1982: 1-30.
`5. Watters EC, et. al Acute orbital cellulitis. Arch Ophthalmol 1976; 94: 785-88
`6. Jakobiec FA. Orbital inflammations. In. Duane TD, Jaeger EA, eds. Clinical
`ophthalmology vol 2 Philadelphia: Harper and Row, 1982: 51-53.
`7. Jakobiec FA, Jones IS. Vascular tumours, malformations and degenerations. In: Duane
`TD, Jaeger EA, eds. Clinical ophthalmology vol 2. Philadelphia: Harper and Row,
`1982: 35-37
`8. Blodi FC, Gass JDM. Inflammatory pseudotumour of the orbit Br J Ophthalmol 1968;
`52: 79-93
`9. Spalton DJ, Graham EM, Page NGR, Sanders MD. Ocular changes in limited forms of
`Wegener’s granulomatosis Br J Ophthalmol 1981; 65: 553-63.
`10. Ferry A, Font R. Carcinoma metastatic to the eye and orbit. 1. A clinicopathologic
`study of 227 cases. Arch Ophthalmol 1974; 92: 276-86.
`11. Werner SC, Ingbar SH. The thyroid. A fundamental and clinical test, 3rd ed. New
`York Harper and Row, 1971; 536.
`12. Trobe JD, Glaser JS, La Flamme P. Dysthyroid optic neuropathy. Arch Ophthalmol
`1978, 96: 1199-209.
`13. Munro RE, Lamki L, Row VV, Volpe R. Cell mediated immunity in the exophthalmos
`of Graves’ disease as demonstrated by the migration inhibiting factor (MIF) test. J
`Clin Endocrinol Metab 1973, 37: 286-92.
`14 Solomon DH, Chopra JJ, Chopra U, Smith FJ. Identification of subgroups of euthyroid
`Graves’s ophthalmopathy. N Engl J Med 1977; 296: 181-86.
`15. Volpe R. The role of autoimmunity in hypoendocrine function; with special emphasis
`on autoimmune thyroid disease Ann Intern Med 1977, 87: 86-99.
`16 Hamilton RD, Mayberry WE, McConahey WM, Hanson KC. Ophthalmopathy of
`Graves’ disease: a comparison between patients treated surgically and patients
`treated with radioiodide. Mayo Clin Proc 1967; 42: 812-18.
`17. Hesch D, Huefner M, Von Zurmuhlen A, Emrich D Truodothyronine levels in
`patients with euthyroid endocrine exophthalmos and during treatment of
`thyrotoxicosis. Acta Endocrinol 1974; 75: 514-22.
`18. Wyse EP, McConahey WM, Woolner LB, Scholz DA, Kearns TP. Ophthalmopathy
`without hyperthyroidism in patients with histological Hashimoto’s thyroiditis. J
`Clin Endocrinol Metab 1968; 28: 1623-29.
`19 Schultz RD, Van Allen MW, Blodi FC Endocrine ophthalmoplegia. Arch Ophthalmol
`1960; 63: 217-25
`20 Morney R, Fournier G, Berthezene F. Ophthalmic Graves’ disease. Mod Prob
`Ophthalmol 1975; 14: 426-31
`21. Adams DD, Kennedy TH. Evidence to suggest that LATS protector stimulates the
`human thyroid gland J Clin Endocrinol Metab 1971; 33: 47-51.
`22. Sergott RC, Feldberg NT, Savino PJ. Association of HLA antigen with severe Graves’
`ophthalmopathy. Invest Ophthalmol Visual Sci 1983; 24: 124.
`23. Kodarma K, Sikorsk AH, Bandy Defoc P, et al. Demonstration of circulating auto-
`antibody against soluble eye muscle antigen in Graves’ ophthalmopathy. Lancet 1982;
`ii: 1353-56
`24. Moseley IF, Sanders MD Computerised tomography in neuro-ophthalmology.
`London Chapman and Hall, 1982; 21-23.
`
`Amerigen Exhibit 1097
`Amerigen v. Janssen IPR2016-00286
`
`

`
`434
`
`TABLE I-ADMISSION STATUS OF PATIENTS
`
`*Measured by radioimmunoassay and expressed in ng/ml III patients 1-5
`ng/ml); measured by enzymic assay and expressed in IU/1 in
`(normal <3-4
`patients 6-15 (normal <I -1 IU/1).
`
`males.’
`1941, Huggins and Hodges reported that
`In
`hormonal manipulation could benefit patients with prostate
`cancer.2 It is now established that in 70-80% of patients with
`metastatic prostate cancer the disease regresses or stabilises
`when serum testosterone levels are lowered. 1,4 In clinical
`practice, testosterone levels are reduced by orchidectomy or
`by diethystilboestrol treatment. Bilateral orchidectomy may
`be psychologically unacceptable; and diethylstilboestrol can
`have side-effects such as gynaecomastia, fluid retention,
`thromboembolism, and myocardial ischaemia.6 Thus, other
`methods of lowering testosterone levels are being sought.
`Ketoconazole (’Nizoral’, Janssen Pharmaceutica, Beerse,
`Belgium) is an imidazole derivative which is active after oral
`administration against various pathogenic fungi in man.’ It is
`inhibitor of testicular and adrenal
`steroid
`potent
`synthesis.8,9 In patients taking ketoconazole for serious
`fungal disease high doses and frequent administration of the
`drug suppressed testosterone levels throughout the day. 10
`Therefore, ketoconazole seemed to have a potential use in the
`management of prostate cancer. It has the advantage over
`of also
`used
`adrenal
`lowering
`currently
`treatments
`androgens. 11 Our
`initial
`showed
`that
`case-report
`ketoconazole was objectively and subjectively beneficial in a
`patient with advanced disease. 12
`This study was designed to define the efficacy of high-dose
`ketoconazole in patients with stage D-2 previously untreated
`prostate carcinoma.
`
`a
`
`PATIENTS AND METHODS
`
`,
`
`Patients were eligible for study if they had biopsy-proven prostate
`cancer; pain; extrapelvic metastases as shown by bone scan or
`radiographs, high prostatic acid phosphatase level, or both; and no
`previous endocrine manipulations, chemotherapy, steroid therapy,
`or radiotherapy. All patients gave written informed consent. The
`
`study was approved by local’ and federal human research
`committees.
`Ten patients were studied in Toronto and five in San Francisco
`(table I). All fifteen had bony metastases and patients 4, 12, and 13
`took 400 mg
`All
`had urinary-tract
`patients
`obstructions.
`ketoconazole every 8 h by mouth. They were assessed clinically and
`biochemically every week for 4 weeks and once a month for 6
`months. Clinical evaluation included assessment of pain, activity,
`urological symptoms, and side-effects. Blood was drawn for
`blood count,
`determination of prostatic
`acid phosphatase,
`electrolytes, serum cholesterol, triglycerides, calcium, phosphorus,
`liver and kidney function tests, and serum testosterone and
`Serum
`androstenedione,
`ketoconazole
`concentrations.
`dehydroepiandrosterone, luteinising hormone (LH), corticotropin,
`and 24 h urine cortisol results have been reported elsewhere. 13
`Serum prostatic acid phosphatase was determined by enzymic
`assay14 in the Toronto patients and by radioimmunoassay (Roche
`Biochemical, Columbus, Ohio) in the San Francisco patients.
`Serum biochemistry tests were done with the multichannel analyser
`in the clinical laboratory. Serum testosterone was measured by
`radioimmunoassay. Results in San Francisco were originally
`expressed in ng/dl and have been converted to nmol/1 by multiplying
`by 0-03467. Normal testosterone levels for this population are
`10-35 nmol/1. Bone scans and electrocardiograms were repeated
`after 6 months of therapy.
`
`RESULTS
`
`Thirteen of the fifteen patients completed at least 6 months
`of therapy. One patient who experienced pain relief and a
`drop in prostatic acid phosphatase withdrew after 1 month
`for personal reasons. The other patient who withdrew
`initially had a normal prostatic acid phosphatase level and a
`histologically undifferentiated tumour; he had excellent pain
`relief for 3 months. A paraspinal mass, presumably from
`prostate cancer, then developed and the patient was assigned
`to conventional therapy.
`After 2 weeks of therapy, pain which had previously
`required narcotic analgesics had greatly diminished in all
`fifteen patients. Most patients had no further pain after 3
`Eight patients have completely stopped taking
`days.
`analgesics; three take acetominophen occasionally, and three
`require acetominophen-codeine preparations intermittently.
`After 1 month, three patients who had needed help with
`Severe
`ambulation could walk unaided.
`urinary-tract
`in
`the
`obstruction was relieved
`with
`three
`patients
`obstructions. Digital rectal examinations showed softening of
`prostatic tissue in all patients and disappearance of evidence
`of primary tumour in six patients.
`Prostatic acid phosphatase fell rapidly in the thirteen
`patients with initially raised levels (table II). After 6 weeks of
`therapy, the level was normal in nine of the thirteen. The
`level varied greatly in patient 1, who had difficulty in
`complying with therapy.
`After 1 week of ketoconazole therapy testosterone levels
`had declined to <3 - 5 nmol/1 in thirteen patients in multiple
`samples measured throughout the day. At 1 month, the levels
`
`-
`
`TABLE II-EFFECT OF KETOCONAZOLE
`
`n=15 to day 30, 14 for days 60 and 90, 13 for day 180.
`*Normal values for prostatic acid phosphatase by radioimmunoassay <3’4 4 ng/ml, by enzymic assay < I -1 1 IU/1.
`t In five San Francisco patients; normal=4-18 mIU/ml.
`
`

`
`had generally risen slightly but remained below 3 - 5 nmol/1 in
`seven of twelve patients in whom they were measured.
`Adrenal androgens were suppressed or undetectable in
`thirteen patients. LH levels rose with therapy in all patients
`(table II).
`Bone scans done after 6 months’ therapy showed that no
`patient had any new lesions. Nine of the thirteen patients had
`regression of some but not all lesions. In the one patient who
`had apparent progression of disease (paraspinal mass), no
`new lesions were visible on the bone scan at 3 months. No
`cardiac or thromboembolic events occurred during therapy
`and electrocardiograms did not change. Electrolytes, serum
`calcium and phosphorus, and blood count remained normal
`or improved. Transient rises in aspartate aminotransferase
`were seen in six patients, but all patients had normal liver
`function at 2 months despite continuing therapy. Serum
`cholesterol fell significantly in all patients (mean before
`treatment 176&plusmn;8 mg/dl, 139&plusmn;6 mg/dl at6 months).
`Mild transient nausea occurred in two patients and all
`patients experienced diminished libido or impotence, but the
`side-effects did not require that therapy be stopped in any
`patient. Slight non-tender gynaecomastia developed in three
`patients. After 3 months of ketoconazole therapy, two
`patients had symptoms suggesting mild Addison’s disease
`(darkening of skin and weakness). Urinary cortisol was
`borderline low and corticotropin raised in both patients.
`in amelioration of
`resulted
`Prednisone (5 mg daily)
`symptoms.
`
`. DISCUSSION
`
`Responses to androgen-ablative therapy, the primary
`treatment for advanced prostate cancer, average 18 months,
`and 25% of patients live 3 years. Several aspects of
`endocrine therapy remain controversial. Should only patients
`with symptoms be treated? Is reduction of adrenal androgens
`important? How can testosterone levels best be lowered?
`Both orchidectomy and diethylstilboestrol
`effectively
`lower testosterone levels. However, neither affects adrenal
`androgen production. Diethylstilboestrol therapy can be
`effects,6, 16 and
`associated with serious
`cardiac
`toxic
`orchidectomy is psychologically unacceptable to many
`patients. Thus, other means of lowering or blocking
`have been explored-gonadotropin-releasing
`androgens
`hormone agonists,17 aminoglutethimide,18 and flutamide.19
`testicular and adrenal steroid
`Ketoconazole inhibits
`synthesis by blocking a variety of P-450 enzyme systems.20,21
`At doses currently licensed for the treatment of fungal disease
`(200-400 mg daily), the antisteroid effects are clinically
`minor.8,9
`with
`doses
`and
`high
`frequent
`However,
`administration, ketoconazole suppresses testosterone levels
`azoospermia.10
`and
`400 mg
`induces
`In
`study
`our
`ketoconazole every 8 h persistently lowered testosterone and
`adrenal androgens13in patients with prostate cancer;
`testosterone fell to anorchid levels (<2
`nmol/1) within 72 h.
`Some patients subsequently experienced a moderate rise in
`testosterone, but the level generally remained below 3.55
`nmol/1. Initial analysis suggests that the slight rise in
`testosterone is LH-mediated (table II).
`The clinical response to ketoconazole has been exciting.
`After 6 months of therapy, thirteen of fourteen evaluable
`patients are in remission. The side-effects of therapy have
`been limited, but supplementary steroid therapy may be
`for some patients
`this
`of
`taking
`dosage
`necessary
`ketoconazole. Further research will define which patients
`with prostate cancer will derive greatest benefit from
`ketoconazole. The drug may be useful as sole therapy for
`
`435
`
`especially those with cardiac disease.
`many patients,
`Ketoconazole may also be beneficial in combination with
`gonadotropin-releasing-hormone agonists.22 It could help
`prevent the transient rise in testosterone levels induced by
`these agents22 and reduce adrenal androgen production.
`We thank Jane Loosli, San Francisco, and Kathleen Bryan, Toronto, for
`coordinating the study; and Dr Andrew Bruce, Dr William Kerr, Dr Norman
`Struthers, Dr Michael Robinette, Dr Williams Rider, Dr Richard Cohen, Dr
`Ira Sharlip, Dr David A. Stevens, Dr Richard Williams, and Dr John
`Masterson for helpful suggestions and referral of patients. Mr Robert
`Legendre and Dr Alain Raoult of Janssen Pharmaceutica (USA and Canada)
`provided encouragement and financial support for this study.
`
`Correspondence should be addressed to A. P., 3905 Sacramento Street, Suite
`101, San Francisco, California 94118, USA.
`
`REFERENCES
`
`1. Cancer Statistics, 1984. American Cancer Society. Ca 1984; 34: 7-23.
`2. Huggins C, Hodges CV. Studies in prostate cancer. Cancer Res 1941; 1: 293-97.
`3. Robinson MRG, Shearer RG, Ferguson JD. Adrenal suppression in the treatment of
`prostate carcinoma. Br J Urol 1974; 46: 555-59.
`4. Resnick MI, Grayhack JT. Treatment of stage IV carcinoma of the prostate. Urol Clin
`North Am 1975; 2: 141-61.
`5. Alder A, Burger H, Davis J, et al. Carcinoma of prostate: response of plasma luteinising
`hormone and testosterone to oestrogen therapy. Br Med J 1968; i: 28-31.
`6. Veteran’s Administration Cooperative Urological Research Group. Treatment and
`survival in patients with carcinoma of the prostate. Surg Gynecol Obstet 1967; 124:
`1011-17.
`7. Restrepo A, Stevens DA, Utz JP, eds. First International Symposium on Ketoconazole.
`Rev Infect Dis 1980; 2: 519-699.
`8. Pont A, Williams PL, Azhar S, et al. Ketoconazole blocks testosterone synthesis. Arch
`Intern Med 1982; 142: 2137-40.
`9. Pont A, Williams PL, Loose DS, et al. Ketoconazole blocks adrenal steroid synthesis.
`Ann Intern Med 1982; 97: 370-72.
`10. Pont A, Graybill JR, Craven PC, et al. Effect of high dose ketoconazole on adrenal and
`testicular function Clin Res 1983; 31: 91 (abstr).
`11. Pont A, Williams PL, Loose DL, et al. Ketoconazole inhibits adrenal steroid synthesis.
`Clin Res 1982; 30: 99 (abstr).
`12. Trachtenberg J, Halpern N, Pont A. Ketoconazole: a novel and rapid treatment for
`advanced prostatic cancer. J Urol 1983; 130: 152-53.
`13. Pont A, Trachtenberg J. Hormonal changes in patients on chronic high dose
`ketoconazole. Clin Res 1984; 32: 271 (abstr).
`14. Li CY, Chuda RA, Lamb WKW, Yam LT. Acid phosphatase in human plasma. J Lab
`Clin Med 1973; 82: 446-48.
`15. Walsh PC. Physiologic basis for hormonal therapy in carcinoma of the prostate. Urol
`Clin North Am 1975; 2: 125-40.
`16. Byar DP. Veterans Administration Cooperative Urologic Research Group. Treatment
`and survival of patients with cancer of the prostate. Cancer 1973; 32: 1126-30.
`17. Trachtenberg J. The treatment of metastatic prostate cancer with a potent luteinizing
`hormone releasing hormone analogue. J Urol 1983; 129: 1149-52.
`18. Worgul TJ, Santen RJ, Samojlik E, et al. Clinical and biochemical effect of
`aminoglutethimide in the treatment of advanced prostatic carcinoma. J Urol 1983;
`129: 51-55.
`19. Sogani PC, Whitmore WF Jr. Experience with flutamide in previously untreated
`patients with advanced prostate carcinoma. J Urol 1979; 122: 640-43.
`20. Loose DS, Kan PB, Hirst MA, et al. Ketoconazole blocks adrenal steroidgenesis by
`inhibiting cytochrome P-450 enzymes. J Clin Invest 1983; 71: 1495-99.
`21. Santen RJ, Van den Bossche H, Symoens J, et al. Site of action of low dose ketoconazole
`on androgen biosynthesis in men. J Clin Endocrinol Metab 1983; 57: 732-36.
`22. Allen JM, Kerle DJ, Ware H, et al. Combined treatment with ketoconazole and
`luteinizing hormone releasing hormone analogue: a novel approach to resistant
`progressive prostate cancer. Br Med J 1983; 287: 1766.
`
`"A physician treating a colleague needs to give time and to deliver his
`normal standard of good care; he may have to state clearly that
`normal routine management is being observed. Where several
`physicians are involved communication between them must be
`excellent so that the doctor-patient is assured that all are agreed on
`the plan of management. The doctor-patient knows that there is
`often a high degree of personal judgement in clinical decisions and he
`needs to understand the logic behind them. For a full understanding
`of the disorder, the concept of disease has to be discussed; detailed
`education about the condition might be necessary, just as for any
`other patient. Explanations must be honest and full. As for any
`patient, however, only a few new opinions should be introduced at a
`time so that self-esteem is not undermined. All doctors ought to
`know a general practitioner with whom they can have a professional
`is
`confidentiality
`that
`relationship,
`physician-to-patient
`so
`safeguarded, emotional problems can be aired and better long-term
`care can be provided. The ’corridor-consultation’ should be avoided
`because the doctor-patient is then denied the physician’s full
`attention, and poor communication could be the result."-I. G.
`FINLAY. Doctors as patients. J Roy Coll Gen Pract 1984; 34: 416.