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Ketoconazole high dose in management of hormonally pretreated patients with progressive metastatic prostate cancer
KETOCONAZOLE
HORMONALLY PROGRESSIVE
HIGH DOSE IN MANAGEMENT
PRETREATED
OF
PATIENTS WITH
METASTATIC PROSTATE CANCER
FRED J. WITJES, M.D. FRANS M. J. DEBRUYNE, M.D. PILAR FERNANDEZ
DEL
MORAL, M.D.
A. D. H. GEBOERS, M.D. DUTCH SOUTH-EASTERN UROLOGICAL COOPERATIVE GROUP From the Department of Urology, St. Radboudhospital, Catholic University, Nijmegen, The Netherlands.
ABSTRACT-Ketoconazole high dose (H.D.) effectively reduces the testosterone production in both adrenals and testes. Its use in the management of (metastatic) prostate cancer has been advocated. Even in relapsing patients, after previous hormonal therapy, ketoconazole H. D. could be of value. Twenty-eight relapsing patients, of whom 15 were evaluable at three months, have been treated with ketoconazole H.D. As could be expected, objective response was seen in only a small number of patients followed up till nine months. Subjective improvement, however, was noticed in the majority of symptomatic patients. The side effects and toxicity of the therapy remain a major limitation for the use of ketoconazole, be it as first line treatment or as therapy for relapsing patients.
Androgen suppression either by orchiectomy or by estrogen therapy has remained most prominent in the treatment of (metastatic) prostate cancer since its proposal by Huggins and Hodges in 1941. l However, the duration of hormonal sensitivity of prostate tumors is variable. Some tumors never respond; others, despite initial response, show signs of reactivation in a considerable number within a year or two.2 The reason for hormonal escape remains unclear although it is suggested that increased androgen production from the adrenals might at least partly play a role in the progression of the disease during hormonal treatment.3 Ketoconazole, an orally administered antifungal drug, has been demonstrated to block the synthesis of adrenal and testicular androgen
UROLOGY / MAY1989 / VOLUMEXxX111,NUMBER5
production, both in animal and man.4.5 Trachtenberg, Halpern, and Pants demonstrated first that high-dose ketoconazole could induce and maintain a remission in a patient with advanced prostatic cancer. Subsequently, Trachtenberg’ published favorable results in a small series of previously untreated patients with metastatic prostate cancer. Only a few cases on the use of high-dose ketoconazole in patients relapsing during hormonal treatment have been published so far.8,9 In view of the total androgen deprivation achieved with ketoconazole H. D., this therapeutic approach could be of value in patients with progressive The present study deals with the disease. management of such a group of patients with a high dose of ketoconazole.
411
Objective response according to E ORTC criteria
TABLE II.
Previous hormonal treatments
TABLE I.
Treatment
Number of Times
Orchiectomy Cyproterone acetate Ethinyl estradiol DES Estracyt Estradurin Bromocriptine LHRH
21 12 8 8 5 2 1 1
Material and Methods A total of 28 patients with relapsing prostatic cancer during hormonal treatment, as was noted by progression of their metastatic disease according to EORTC criteria, were included in this study. Seven patients had one, and 21 patients had several previous hormonal manipulations (Table I). All patients had a histopathologically proved disseminated adenocarcinoma of the prostate, in general with a moderately or poorly differentiated tumor (19 of 25). All patients had multiple skeletal metastases. The average age of the selected patients was 64.8 years (52-80 years). An expected survival time of at least three months was necessary for inclusion in this study. Patients were randomized in two treatment programs: 400 mg every eight hours (3 dd) (n = 17) or 600 mg every twelve hours (2 dd) (n = 11) of a ketoconazole suspension (80 mg/mL) taken with milk or some food. Assessments used in the follow-up were: performance status (score O-4) and pain severity (score O-5) according to WHO criterialO; body weight; plasma testosterone and cortisol; serum acid phosphatases and/or prostate specific acid phosphatases; serum calcium, phosphorus, bilirubin, and ketoconazole. These assessments were obtained before treatment (except serum ketoconazole) on days 2 and 4 (serum cortisol and testosterone only), on days 7 and 14, months 1, 2, and 3, and every three months thereafter. Before therapy and after every six months electrocardiogram (ECG) and chest xray film were done. Bone scans or x-ray findings were evaluated before therapy and every three or six months. Drug compliance, changes in concomitant treatments, side effects, and dosage changes were carefully monitored. Results The period of follow-up was minimally and maximally nine months.
412
28 No. of patients 1 Unevaluable 7(4+) Stopped because of side effect 7(7+) Stopped because of progress . . Progression * . Stable disease . . “Clinically stable” , . No g-month follow-up yet No. of pts. 13 remaining
Objective
(Months)3-6 6 6-9
9
13
13
10
9
5
::
::
::
::
::
. .
. .
. * 3(2+)
1 1
. .
1
2 7 4
. . . . . .
7
. .
1
. .
. .
. .
. .
. .
4
. .
13
10
95
4
5
response
Objective responses were judged according to the EORTC criteria.‘O An overview of the response is shown in Table II. Seven patients died within three months after starting the ketoconazole therapy and were in fact ineligible. The mortality reason was progressive metastatic disease in all 7 patients. One other patient was unevaluable and 7 patients dropped out because of drug-related toxicity. Thus after three months 13 patients were evaluable. Two patients were progressive, 7 in an objective stable disease, and 4 in a clinical stable disease (stable disease without radiologic control). After six months 5 patients were progressive. One patient was clinically stable and 7 patients objectively stable. Of the 5 patients already in study for nine months, 1 is progressive and 4 patients are objectively stable. During the observation period 13 patients died of their metastatic disease. Subjective
response
Subjective response, as judged by a pain severity score, was good. The pain score (O-5) reduced from an average of 2” to an average of 0.5 ‘. This meant a significant reduction in the use of nonsteroidal analgesics (Fig. 1). In 5 patients the reduction was maintained until nine months of follow-up. The mean performance status improved also during the first two weeks of therapy. Three patients experienced vanishing of gynecomastia and mastodynia due to previous estrogen therapy. Endocrinologic
six
-Period o-3 3
Response
findings
The timespan between blood sampling and the last prior dose of ketoconazole was kept as
UROLOGY
/
MAY 1989
/
VOLUME XxX111,
NUMBER 5
Biochemical
findings
Ketoconazole did not alter the level of calcium and phosphorus. The prostate specific acid phosphatases (PAP) are shown in Figure 4. Although normalization (< 3 W/L) was not to be expected in this group of patients, a further reduction of PAP was noted. The serum ketoconazole concentration (which has to be at least 4 PgimL to achieve testosterone concentration within the castrate range) showed a good correlation with the timespan between blood sampling and last ketoconazole intake. After seven to eight (3 dd 400 mg group) or eleven to twelve
--__ Ill IInI _ _.
r
_______._
-
.-
-
2
6
3
months
FI(:CIW 1. Mean pain score (“5 option pain score”). f) = no pain; 2 = continuous use of nonsteroidal analgcCsics.
0
4
7
FIGUIW 2.
14 days
1
2
3
6
9 months
Mean testosterone concentration.
mol/l C 0 R 1
I ,503
I S 0 L
0 !/I
2
4
7
14
1
2
days
FIGURE3.
/ MAY 1989
/ VOLUME
6 months
Mean cortisol concentration.
long as possible (i.e. 5 8 hours or 5 12 hours), in order to measure true plasma levels of ketoconazole. Testosterone, although already at castration level (30 ng/lOO mL), was further reduced (halved) in all patients within two days (no earlier assessments were done); later on, however, an increase of the mean testosterone level was observed probably due to drug intolerance caused by gastrointestinal side effects (Fig, 2). Cortisol levels had not been altered significantly (Fig. 3).
UROLOGY
3
XxX111. NUMBER 5
U/l
8
FICLIRE
taw.
413
(2 dd 600 mg group) hours the ketoconazole concentration was still sufficient. Side effects Seven patients had to discontinue the therapy after an average period of twelve days (3-28) because of severe gastrointestinal intolerance. Four of these patients died within two months dose reduc(Table II). In 3 cases a temporary tion, and once an antiemetic was sufficient to continue therapy. Other side effects were rare. Skin symptoms (itching, dry skin) occurred in 3 cases. Impotence was not noted as a side effect because all patients were already impotent as a result of previous therapy. No complications resulting from the adrenal suppression were observed. Comment High oral dose of ketoconazole has been found blocking the synthesis of androgens in both the testes and the adrenals, at the cytochrome P450 dependent step. The predominant effect is an inhibition of 17, 20-desmolase converting 17-CXOH progesterone or 17-(rOH pregnenolone into androstenedione, dihydroepiandrosterone and testosterone.4 This mode of action explains why ketoconazole H.D. can be used in patients with prostatic cancer. Trachthe clinitenberg et aZ.6.7clearly demonstrated cal efficacy of ketoconazole H.D. in patients with metastatic prostatic carcinoma. Our study shows that, even in patients relapsing after previous antiandrogen therapy, ketoconazole H.D. might be of some benefit. This can be explained by the theory postulated by Labrie et aL3 that residual adrenal androgens may contribute to the emergence of hormonal resistant prostatic cancer. In our patients a clear beneficial subjective effect has been noted in a substantial part of the patients. Although 15 of 28 patients could not be evaluated after three months (withdrawn from the study because of side effects or progression) a stabilization was achieved in a number of patients who previously had a clearly progressive disease. In some cases this stabilization lasted for a period of nine months or more. Compared with other studiesi1.12 the patients in this study had a bad prognosis since all patients were relapsing after previous hormonal therapy. For example, 7 patients were in fact ineligible because they died within three months of follow-up. It is unrealistic to expect a significant prolonged survival in this group of
414
patients. The clear subjective improvement in most of the patients and the objective stabilization in some others underline the possible role of ketoconazole H.D. in the management of patients with progressive metastatic disease. In this respect ketoconazole came up to our expectations. The clinical, biochemical, and endocrinologic results in both therapeutic regimens (400 mg every 8 hours, 600 mg every 12 hours) were similar. The 3 dd 400 mg schedule however, caused more often and more serious gastrointestinal side effects. All “drop outs” occurred in this group. Absorption of ketoconazole H .D. in the stomach takes place quickly and the endocrinologic response occurs within a few hours. However, in some patients drug resorption can be hampered due to atrophic gastritis.13 This is easily overcome when an acid (e.g., 2-3 g vitamin C) is added to the drug intake. This was necessary in 4 patients. In almost all patients sufficient serum levels of ketoconazole were observed indicating a reliable gastric resorption. In all patients an additional reduction in testosterone levels was obtained. Gastric intolerance poses a major problem. As in other studies”J4 we too encountered serious difficulties in this respect. Seven patients, all in the 3 dd 400 mg group, had to be excluded from further therapy due to severe gastrointestinal side effects such as gastric discomfort, loss of apetite, and vomiting. In such a group of seriously ill patients this is not acceptable. Good instruction of the patient, as well as the combination of ketoconazole H.D. with food or fluid (milk) and the use of antiemetic drugs can limit this side effect. There were no other side effects interfering with the therapy. In the literature an idiosyncratic hepatitis has been described with ketoconazole. This serious adverse reaction is, however, very rare (freq. < 0.01%) and not dose dependent.15.16 In our study no hepatic toxicity was observed. It is, however, advisable to exclude patients with liver function abnormalities (elevated bilirubin) from ketoconazole H.D. therapy, except in patients with hepatic metastases. Cortisol levels remained unchanged. There is a much less apparent effect on the production of cortisol, possibly as a result of a compensation by the increase of ACTH levels.5.‘7.18 Some authors, however, stress that the glucocorticoid reserve might be affected,4 and even life-threatening situations in case of stress due to fever or concomitant infections, might occur.” We did not
UROLOGY
I
MAY 1989
/
VOLUME XxX111, NUMBER 5
observe such severe complications. Patients at risk for infections should probably be excluded from this therapy or at least be followed more closely. Tests on glucocorticoid reserve were not performed in our study. The minor problems of a transient increase of transaminases, and a transient decrease of blood levels of calcium and phosphorus during the first weeks of therapy, normally easily controlled, were not seen in our study. From our study we can conclude that ketoconazole H.D. offers an additive to the therapeutic possibilities for prostatic cancer. Even in hormonally pretreated patients this therapy may give a reduction in pain and an improvement in the performance status. Major inconveniences remain- the gastrointestinal intolerance and possible hepatic toxicity. These serious side effects limit substantially the use of ketoconazole H.D. on a large scale. It is therefore mandatory that further studies should be done to overcome these problems, e.g., by the development of similarly effective but less toxic compounds. Until such compounds are available, in our opinion, ketoconazole H.D. cannot be advised as first line treatment for patients with metastatic prostate cancer. 6500 HB Nijmegen, The Netherlands (DR. DEBRUYNE) References 1. Huggins C, and Hodges CV: Studies in prostatic cancer I. The effect of castration. of estrogen and of androgen injection on
UROLOGY
/ MAY 1989
/ VOLUME
XXXIII,
NUMBER
5
serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1: 293 (1941). 2. Resnick MI, and Grayhack JT: Treatment ot stage I\’ carcinoma of the prostate. Urol Clin Sorth AnI 2: 141 (197s). 3. Labrie F. et al: New hormonal therapy in prostatic carcinoma: combined treatment with LHRH agonist and antiandrogen, Clin Invest 14ed 5: 267 (1982). 4. Pont A. ct (11: Ketoconazole blocks tc‘;totcrone y nthcsiy. Arch Intern Med 142: 2137 11982). 5. Pont A, it al: Ketoconazole blocks adrL,nal steroids! nthesis. Ann Intern Med 97: 370 (1982). 6. Trachtenberg J, Halpern N. and Pont A: Kc~toconazole: a novel and rapid treatment for advanced prostate cancer. J Ural 130: 152 (1983). 7. Trachtenberg J: Ketoconazole therapy in advanced I>rostatic cancer, J Urol 132: 61 (1984). 8. Allen JM, et al: Combined treatment \vith ketoconazole and luteinizing hormone releasing analogue: a novel approach ttr rcsistant progressive prostatic cancer. Br Med J 287: 1766 i 19X3), 9. Williams 6. et al: Objecti\-e resporrsc to ketoconazolc therapy in patients with relapsed progressive prortatic cancer, Br J Urol 58: 45 (1986). 10. World Health Organization: Handbook for reporting rcsults of cancer treatment. Geneva. 1979. 11. Denis I., Chaban M, and Mahler C: Clinical application of ketoconazole in prostatic cancer, Prog Clin Rio1 Rcs 185A: 319 (1985). 12. Baert I,: Ketoconazole H.D. in the treatment of prostatic cancer. Abstract of the 20th lnt. Congress of the Urological Society, Vienna. Austria, 1985. 13. Meer JWM vd, et al: The influence of gastric acidity on the bioavailability of ketoconazole. J .4ntimicr Chemother 6: 5% (1980). 14. Williams G: Ketoconazole for prostatic c’ancrr. Lancet 2: 696 (1984). 15. Janssen PAJ. and Symoens J: Hepatic reaction during ketoconazole treatment, Am J Med 74: 80 (1983). 16. Lewis JH, Zimmerman HJ. Benson GD. and Ishak KG: Hepatic injury associated with ketoconazolr therapy, Analysis of 33 cases, Gastroenterology 288: 188 (1984). 17. Kowal J: The effect of ketoconazole on the steroid avnthcais in cultured mouse adrenal cortex tumour cells, Endo&inoloq 112: 1541 (1983). 18. Loose DS, cf al: Ketoconazole blocks adrenal steroidgenesis by inhibiting cytochrome P 450 enzymes, J Clin Invest 71: 1495 (1983).
41Fj
HORMONALLY PROGRESSIVE
HIGH DOSE IN MANAGEMENT
PRETREATED
OF
PATIENTS WITH
METASTATIC PROSTATE CANCER
FRED J. WITJES, M.D. FRANS M. J. DEBRUYNE, M.D. PILAR FERNANDEZ
DEL
MORAL, M.D.
A. D. H. GEBOERS, M.D. DUTCH SOUTH-EASTERN UROLOGICAL COOPERATIVE GROUP From the Department of Urology, St. Radboudhospital, Catholic University, Nijmegen, The Netherlands.
ABSTRACT-Ketoconazole high dose (H.D.) effectively reduces the testosterone production in both adrenals and testes. Its use in the management of (metastatic) prostate cancer has been advocated. Even in relapsing patients, after previous hormonal therapy, ketoconazole H. D. could be of value. Twenty-eight relapsing patients, of whom 15 were evaluable at three months, have been treated with ketoconazole H.D. As could be expected, objective response was seen in only a small number of patients followed up till nine months. Subjective improvement, however, was noticed in the majority of symptomatic patients. The side effects and toxicity of the therapy remain a major limitation for the use of ketoconazole, be it as first line treatment or as therapy for relapsing patients.
Androgen suppression either by orchiectomy or by estrogen therapy has remained most prominent in the treatment of (metastatic) prostate cancer since its proposal by Huggins and Hodges in 1941. l However, the duration of hormonal sensitivity of prostate tumors is variable. Some tumors never respond; others, despite initial response, show signs of reactivation in a considerable number within a year or two.2 The reason for hormonal escape remains unclear although it is suggested that increased androgen production from the adrenals might at least partly play a role in the progression of the disease during hormonal treatment.3 Ketoconazole, an orally administered antifungal drug, has been demonstrated to block the synthesis of adrenal and testicular androgen
UROLOGY / MAY1989 / VOLUMEXxX111,NUMBER5
production, both in animal and man.4.5 Trachtenberg, Halpern, and Pants demonstrated first that high-dose ketoconazole could induce and maintain a remission in a patient with advanced prostatic cancer. Subsequently, Trachtenberg’ published favorable results in a small series of previously untreated patients with metastatic prostate cancer. Only a few cases on the use of high-dose ketoconazole in patients relapsing during hormonal treatment have been published so far.8,9 In view of the total androgen deprivation achieved with ketoconazole H. D., this therapeutic approach could be of value in patients with progressive The present study deals with the disease. management of such a group of patients with a high dose of ketoconazole.
411
Objective response according to E ORTC criteria
TABLE II.
Previous hormonal treatments
TABLE I.
Treatment
Number of Times
Orchiectomy Cyproterone acetate Ethinyl estradiol DES Estracyt Estradurin Bromocriptine LHRH
21 12 8 8 5 2 1 1
Material and Methods A total of 28 patients with relapsing prostatic cancer during hormonal treatment, as was noted by progression of their metastatic disease according to EORTC criteria, were included in this study. Seven patients had one, and 21 patients had several previous hormonal manipulations (Table I). All patients had a histopathologically proved disseminated adenocarcinoma of the prostate, in general with a moderately or poorly differentiated tumor (19 of 25). All patients had multiple skeletal metastases. The average age of the selected patients was 64.8 years (52-80 years). An expected survival time of at least three months was necessary for inclusion in this study. Patients were randomized in two treatment programs: 400 mg every eight hours (3 dd) (n = 17) or 600 mg every twelve hours (2 dd) (n = 11) of a ketoconazole suspension (80 mg/mL) taken with milk or some food. Assessments used in the follow-up were: performance status (score O-4) and pain severity (score O-5) according to WHO criterialO; body weight; plasma testosterone and cortisol; serum acid phosphatases and/or prostate specific acid phosphatases; serum calcium, phosphorus, bilirubin, and ketoconazole. These assessments were obtained before treatment (except serum ketoconazole) on days 2 and 4 (serum cortisol and testosterone only), on days 7 and 14, months 1, 2, and 3, and every three months thereafter. Before therapy and after every six months electrocardiogram (ECG) and chest xray film were done. Bone scans or x-ray findings were evaluated before therapy and every three or six months. Drug compliance, changes in concomitant treatments, side effects, and dosage changes were carefully monitored. Results The period of follow-up was minimally and maximally nine months.
412
28 No. of patients 1 Unevaluable 7(4+) Stopped because of side effect 7(7+) Stopped because of progress . . Progression * . Stable disease . . “Clinically stable” , . No g-month follow-up yet No. of pts. 13 remaining
Objective
(Months)3-6 6 6-9
9
13
13
10
9
5
::
::
::
::
::
. .
. .
. * 3(2+)
1 1
. .
1
2 7 4
. . . . . .
7
. .
1
. .
. .
. .
. .
. .
4
. .
13
10
95
4
5
response
Objective responses were judged according to the EORTC criteria.‘O An overview of the response is shown in Table II. Seven patients died within three months after starting the ketoconazole therapy and were in fact ineligible. The mortality reason was progressive metastatic disease in all 7 patients. One other patient was unevaluable and 7 patients dropped out because of drug-related toxicity. Thus after three months 13 patients were evaluable. Two patients were progressive, 7 in an objective stable disease, and 4 in a clinical stable disease (stable disease without radiologic control). After six months 5 patients were progressive. One patient was clinically stable and 7 patients objectively stable. Of the 5 patients already in study for nine months, 1 is progressive and 4 patients are objectively stable. During the observation period 13 patients died of their metastatic disease. Subjective
response
Subjective response, as judged by a pain severity score, was good. The pain score (O-5) reduced from an average of 2” to an average of 0.5 ‘. This meant a significant reduction in the use of nonsteroidal analgesics (Fig. 1). In 5 patients the reduction was maintained until nine months of follow-up. The mean performance status improved also during the first two weeks of therapy. Three patients experienced vanishing of gynecomastia and mastodynia due to previous estrogen therapy. Endocrinologic
six
-Period o-3 3
Response
findings
The timespan between blood sampling and the last prior dose of ketoconazole was kept as
UROLOGY
/
MAY 1989
/
VOLUME XxX111,
NUMBER 5
Biochemical
findings
Ketoconazole did not alter the level of calcium and phosphorus. The prostate specific acid phosphatases (PAP) are shown in Figure 4. Although normalization (< 3 W/L) was not to be expected in this group of patients, a further reduction of PAP was noted. The serum ketoconazole concentration (which has to be at least 4 PgimL to achieve testosterone concentration within the castrate range) showed a good correlation with the timespan between blood sampling and last ketoconazole intake. After seven to eight (3 dd 400 mg group) or eleven to twelve
--__ Ill IInI _ _.
r
_______._
-
.-
-
2
6
3
months
FI(:CIW 1. Mean pain score (“5 option pain score”). f) = no pain; 2 = continuous use of nonsteroidal analgcCsics.
0
4
7
FIGUIW 2.
14 days
1
2
3
6
9 months
Mean testosterone concentration.
mol/l C 0 R 1
I ,503
I S 0 L
0 !/I
2
4
7
14
1
2
days
FIGURE3.
/ MAY 1989
/ VOLUME
6 months
Mean cortisol concentration.
long as possible (i.e. 5 8 hours or 5 12 hours), in order to measure true plasma levels of ketoconazole. Testosterone, although already at castration level (30 ng/lOO mL), was further reduced (halved) in all patients within two days (no earlier assessments were done); later on, however, an increase of the mean testosterone level was observed probably due to drug intolerance caused by gastrointestinal side effects (Fig, 2). Cortisol levels had not been altered significantly (Fig. 3).
UROLOGY
3
XxX111. NUMBER 5
U/l
8
FICLIRE
taw.
413
(2 dd 600 mg group) hours the ketoconazole concentration was still sufficient. Side effects Seven patients had to discontinue the therapy after an average period of twelve days (3-28) because of severe gastrointestinal intolerance. Four of these patients died within two months dose reduc(Table II). In 3 cases a temporary tion, and once an antiemetic was sufficient to continue therapy. Other side effects were rare. Skin symptoms (itching, dry skin) occurred in 3 cases. Impotence was not noted as a side effect because all patients were already impotent as a result of previous therapy. No complications resulting from the adrenal suppression were observed. Comment High oral dose of ketoconazole has been found blocking the synthesis of androgens in both the testes and the adrenals, at the cytochrome P450 dependent step. The predominant effect is an inhibition of 17, 20-desmolase converting 17-CXOH progesterone or 17-(rOH pregnenolone into androstenedione, dihydroepiandrosterone and testosterone.4 This mode of action explains why ketoconazole H.D. can be used in patients with prostatic cancer. Trachthe clinitenberg et aZ.6.7clearly demonstrated cal efficacy of ketoconazole H.D. in patients with metastatic prostatic carcinoma. Our study shows that, even in patients relapsing after previous antiandrogen therapy, ketoconazole H.D. might be of some benefit. This can be explained by the theory postulated by Labrie et aL3 that residual adrenal androgens may contribute to the emergence of hormonal resistant prostatic cancer. In our patients a clear beneficial subjective effect has been noted in a substantial part of the patients. Although 15 of 28 patients could not be evaluated after three months (withdrawn from the study because of side effects or progression) a stabilization was achieved in a number of patients who previously had a clearly progressive disease. In some cases this stabilization lasted for a period of nine months or more. Compared with other studiesi1.12 the patients in this study had a bad prognosis since all patients were relapsing after previous hormonal therapy. For example, 7 patients were in fact ineligible because they died within three months of follow-up. It is unrealistic to expect a significant prolonged survival in this group of
414
patients. The clear subjective improvement in most of the patients and the objective stabilization in some others underline the possible role of ketoconazole H.D. in the management of patients with progressive metastatic disease. In this respect ketoconazole came up to our expectations. The clinical, biochemical, and endocrinologic results in both therapeutic regimens (400 mg every 8 hours, 600 mg every 12 hours) were similar. The 3 dd 400 mg schedule however, caused more often and more serious gastrointestinal side effects. All “drop outs” occurred in this group. Absorption of ketoconazole H .D. in the stomach takes place quickly and the endocrinologic response occurs within a few hours. However, in some patients drug resorption can be hampered due to atrophic gastritis.13 This is easily overcome when an acid (e.g., 2-3 g vitamin C) is added to the drug intake. This was necessary in 4 patients. In almost all patients sufficient serum levels of ketoconazole were observed indicating a reliable gastric resorption. In all patients an additional reduction in testosterone levels was obtained. Gastric intolerance poses a major problem. As in other studies”J4 we too encountered serious difficulties in this respect. Seven patients, all in the 3 dd 400 mg group, had to be excluded from further therapy due to severe gastrointestinal side effects such as gastric discomfort, loss of apetite, and vomiting. In such a group of seriously ill patients this is not acceptable. Good instruction of the patient, as well as the combination of ketoconazole H.D. with food or fluid (milk) and the use of antiemetic drugs can limit this side effect. There were no other side effects interfering with the therapy. In the literature an idiosyncratic hepatitis has been described with ketoconazole. This serious adverse reaction is, however, very rare (freq. < 0.01%) and not dose dependent.15.16 In our study no hepatic toxicity was observed. It is, however, advisable to exclude patients with liver function abnormalities (elevated bilirubin) from ketoconazole H.D. therapy, except in patients with hepatic metastases. Cortisol levels remained unchanged. There is a much less apparent effect on the production of cortisol, possibly as a result of a compensation by the increase of ACTH levels.5.‘7.18 Some authors, however, stress that the glucocorticoid reserve might be affected,4 and even life-threatening situations in case of stress due to fever or concomitant infections, might occur.” We did not
UROLOGY
I
MAY 1989
/
VOLUME XxX111, NUMBER 5
observe such severe complications. Patients at risk for infections should probably be excluded from this therapy or at least be followed more closely. Tests on glucocorticoid reserve were not performed in our study. The minor problems of a transient increase of transaminases, and a transient decrease of blood levels of calcium and phosphorus during the first weeks of therapy, normally easily controlled, were not seen in our study. From our study we can conclude that ketoconazole H.D. offers an additive to the therapeutic possibilities for prostatic cancer. Even in hormonally pretreated patients this therapy may give a reduction in pain and an improvement in the performance status. Major inconveniences remain- the gastrointestinal intolerance and possible hepatic toxicity. These serious side effects limit substantially the use of ketoconazole H.D. on a large scale. It is therefore mandatory that further studies should be done to overcome these problems, e.g., by the development of similarly effective but less toxic compounds. Until such compounds are available, in our opinion, ketoconazole H.D. cannot be advised as first line treatment for patients with metastatic prostate cancer. 6500 HB Nijmegen, The Netherlands (DR. DEBRUYNE) References 1. Huggins C, and Hodges CV: Studies in prostatic cancer I. The effect of castration. of estrogen and of androgen injection on
UROLOGY
/ MAY 1989
/ VOLUME
XXXIII,
NUMBER
5
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