TREATMENT OF ADRENOCORTICAL CARCINOMA: A CASE REPORT AND REVIEW OF THE LITERATURE
Carol A. May and William R. Garnett
ABSTRACT: A case report of adrenocortical carcinoma is presented, and its natural history and treatment are discussed. Adrenocortical carcinoma is a rare malignant disease. The mean survival time for untreated patients is less than three months. The tumor is classified as functioning or nonfunctioning depending on biochemical and clinical evidence of steroid overproduction.
Surgical resection of the tumor is the primary treatment. Chemotherapy is indicated for antitumor and antihormonal effects.
Mitotane is a direct adrenolytic, and is the only drug currently available that has extended survival in patients with this disease. Its clinical usefulness is limi 1 by its gastrointestinal and neurological toxicity. Aminoglutethimide inhibits steroid synthesis by blocking the conversion of cholesterol to pregnenolone. It has no antitumor effect in adrenocortical carcinoma, but is effective in relieving the signs and symptoms of excessive hormone production in functioning tumors.
Both mitotane and aminoglutethimide have complex mechanisms of action. Their combined use in the treatment of adrenocortical carcinoma requires a complete understanding of their individual actions and awareness of the potential for additive effects, both therapeutic and toxic.
Drug Intell Clin Pharm 1986;20:24-32. KEY WORDS: carcinoma, adrenocortical; mitotane; aminoglutethimide.
THE PRIMARY TREATMENT of adrenocortical carcinoma is surgical resection. When chemotherapy is indicated, mitotane and aminoglutethimide are the accepted stan- dard agents. Because the incidence of adrenocortical carcinoma is rare, experience in using chemotherapy is somewhat limited. The following case illustrates the treatment of adrenocortical carcinoma with mitotane and aminoglutethimide.
CASE REPORT
A 25-year-old white female underwent a total right adrenalec- tomy in December 1979 for adrenocortical carcinoma. The tumor was believed to be encapsulated and the resection thought to be curative. The left adrenal was not believed to be involved. She was well until June 1980, when a 30-pound weight-gain was noted over the previous month. Hypertension developed and she was referred to the university hospital for
CAROL A. MAY, Pharm.D., is Clinical Pharmacist, The Good Samaritan Hospi- tal, Baltimore, MD; WILLIAM R. GARNETT, Pharm.D., is Associate Professor, Department of Pharmacy and Pharmaceutics, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA. Reprints: William R. Garnett, Pharm.D., School of Pharmacy, Medical College of Virginia, Virginia Commonwealth Univer- sity, Box 581, MCV Station, Richmond, VA 23298.
E I This article has been selected for PharmaCE testing. It may be used for continuous education credit in the United States and Canada. DICP is a member of the Council on The Continuing Education Unit (CEU) and is approved by the American Council on Pharmaceutical Education as a provider of con- tinuing pharmaceutical education (provider number 180-407).
admission on July 6. Her physical exam showed an extremely Cushingoid, anxious young woman. On physical examination, the patient exhibited central obesity, moon facies, a buffalo hump, purplish stria skin without petechiae, an increase in fine facial hair, and 4 + pitting edema bilaterally to the thighs. A distinct right subcostal mass was detected. Laboratory values on admission included: sodium 147 mEq/L, potassium 2.3 mEq/L, blood urea nitrogen 26 mg/dL, and glucose 198 mg/dL.
The diagnosis of Cushing’s syndrome secondary to metastatic adrenocortical carcinoma was made. Her plasma and urinary steroid levels are listed in Table 1. She had been treated with hydrochlorothiazide 50 mg/d, which was stopped on admis- sion. Potassium supplementation was initiated with KCI 80 mEq/d.
On July 9, diuresis with spironolactone 100 mg/d was begun. At this time, scheduled potassium supplementation was stopped. On July 11, aminoglutethimide 250 mg qid and mito- tane 3 g tid were begun, and within four days the patient responded with a decrease in steroid levels and a reversal of hypokalemia (Table 1), hypertension, and edema as evidenced by weight loss. The patient complained of nausea, vomiting, and fatigue but tolerated therapy well. Because of the patient’s concern about the slow diuresis and relief of edema, on July 15 hydrochlorothiazide 100 mg/d and potassium supplemen- tation in the form of Slow K 24 mEq bid were reinstituted. Spironolactone was stopped.
Replacement therapy with dexamethasone 0.5 mg qid was started when the plasma cortisol level reached 21.3 µg/dL. The patient received a five-day course of fluorouracil 750 mg begin- ning July 17, and was discharged on July 22 on mitotane, aminoglutethimide, hydrochlorothiazide, dexamethasone, and Slow K.
On July 25, she developed oral ulcers and stopped her medi- cations. On July 28, she was readmitted for treatment of cel- lulitis and her medications were restarted. On August 1, she passed grossly bloody urine and a cystoscopy was performed. A diagnosis of hemorrhagic cystitis secondary to mitotane was made and the drug was discontinued until her urine was clear. She was subsequently discharged on mitotane and aminoglutethimide. In September, on routine follow-up, her serum thyroxine level was low and levothyroxine was started. Several days later, the results of her thyroid stimulating hor- mone level were reported and were within normal limits. Levothyroxine therapy was stopped. On September 20, the dos- age of mitotane was decreased to 2 g tid because of nausea and vomiting and mitotane was stopped completely on Sep- tember 30. The patient died October 9th of metastatic adreno- cortical carcinoma.
Adrenocortical carcinoma is a rare malignant disease with an incidence of 0.2 per million population each year (personal communication, Edwin Silverberg, American Cancer Society). The mean age at diagnosis is the fourth decade and two-thirds of all reported cases are females.1 The tumor is often metastasized by the time of diagno- sis and, if untreated, the mean survival is 2.9 months.2
The tumor is classified as either functioning or non- functioning depending on biochemical and clinical evi-
dence of steroid overproduction. The most common presenting signs and symptoms include abdominal pain, weight loss, abdominal mass, malaise, Cushing’s syn- drome, and virilization or feminization.3-5
Treatment
Surgery and chemotherapy are useful in treating adrenocortical carcinoma. Surgical resection of the tumor remains the primary treatment.1,4.6-8 In general, radiation therapy has been unsuccessful but it may be useful as palliative treatment for metastasis.5-7.9,10 Chemotherapy is indicated for antitumor and antihor- monal effects. Regardless of the type of treatment, the goals of therapy are to remove the tumor, prevent recur- rence, and minimize the side effects of excessive hor- mone production.
Chemotherapy
In choosing a chemotherapy plan for adrenocortical carcinoma, agents are selected on the basis of antitumor activity and the ability to alleviate tumor complications. Response is gauged by both steroid and tumor response. Plasma cortisol levels are the most accurate index of steroid response.11 Tumor regression is measured by pal- pation or radiography. If tumor size decreases and steroid levels diminish, the drug is viewed as effective.
Mitotane is indicated for the treatment of inopera- ble adrenocortical carcinoma. It is the only drug cur- rently available that has extended the survival of patients with this disease. Although there is controversy regard- ing the prophylactic use of mitotane following appar- ently successful surgical resection, it should be considered following surgery in the event metastatic
seeding has already occurred. Intensive therapy with mitotane should be instituted at the first signs of increas- ing cortisol production.3,12
Although many other antineoplastic drugs have been used in the treatment of adrenocortical carcinoma, none has been consistently effective.13-16 There is one case of successful treatment of adrenocortical carcinoma with mitotane and fluorouracil.17 This prompted the use of fluorouracil in the presented patient. There is also a recent report indicating that cisplatin may have some activity in adrenocortical carcinoma.18 However, at this time, it would be premature to recommend antitumor treatment with any drug other than mitotane.
Metyrapone and aminoglutethimide have no antitumor or cytotoxic effect but have been used with mitotane in an attempt to alleviate the signs and symp- toms of Cushing’s syndrome in functioning tumors. In general, metyrapone has been found to be ineffective in relieving the biochemical and clinical manifestations of Cushing’s syndrome in adrenocortical carcinoma.8,11 Mitotane is effective, but there is a lag time of two to four weeks after initiation of therapy before a biochem- ical or clinical response occurs.9 Aminoglutethimide is also effective in producing symptomatic relief and its onset of effect is immediate, with biochemical and clin- ical response occurring within days.11.19,20
Mitotane
Mitotane (2,2-bis[2-chlorophenyl-4-chlorophenyl]1,1 dichloroethane) is an isomer of the insecticide DDD (1,1 dichloro-2,2-bis[chlorophenyl]ethan) and a chemical congener of the insecticide DDT (1,1,1-trichloro-2,2-bis [p-chlorophenyl]ethane). In the late 1940s, it was shown
| DATE | ALDOSTERONE (URINE) 2-26 ug/d* | CORTISOL (PLASMA) 7-25 µg/dL* | 17 OHCSt (URINE) 2-9 mg/d* | 17KSţ (URINE) 4-15 mg/d* (FEMALE) | K + (SERUM) 3.5-5.0 mEq/L* | ||
|---|---|---|---|---|---|---|---|
| Admission | 7/06 | 43.6 | 2.3 | KCI started | |||
| 7/09 | 3.2 | KCI discontinued; spironolac- tone started | |||||
| 7/10 | 66.9 | 3.5 | |||||
| Mitotane and | 7/11 | 39 | 2.9 | ||||
| aminoglutethimide started | |||||||
| 7/12 | 3.4 | ||||||
| 7/14 | 3.8 | ||||||
| 7/15 | 22.4 | 7.7 | 7.2 | 4.1 | discontinued spironolactone hydrochlorothiazide and Slow K started | ||
| 7/16 | 21.3 | 4.5 | |||||
| 7/17 | 23.6 | ||||||
| Dexamethasone started | 7/18 | 28.2 | 4.4 | ||||
| Discharged | 7/22 | 27.8 | 9.1 | 5.4 | |||
| Mitotane and amino- glutethimide stopped | 7/25 | hydrochlorothiazide and Slow K stopped | |||||
| Readmitted | 7/28 | 42.6 | |||||
| Mitotane and amino- | 8/18 | 13.5 | 5.3 | 4.0 | |||
| glutethimide restarted | |||||||
| 9/16 | 5.0 | 4.4 |
*Normal values.
+17 hydroxyccorticosteroids.
17 ketosteroids.
that feeding DDD to dogs resulted in adrenal atrophy.21 The ortho-ara isomer o,p’-DDD (mitotane) was shown to have adrenolytic activity in man, with the first suc- cessful clinical trial of mitotane in patients with inoper- able metastatic adrenal carcinoma reported in 1960.22
MECHANISM OF ACTION
Mitotane is a direct adrenolytic. Chronic administra- tion of more than 3 g/d results in adrenal atrophy and necrosis. Mitotane at doses of 0.5 to 3.0 g/d inhibits steroid synthesis and alters the extraadrenal metabolism of cortisol.11.23 The exact biochemical mechanism of action by which mitotane interferes with steroid synthe- sis is not known.
Mitotane has been shown to decrease the activity of glucose-6-phosphate dehydrogenase in dogs.24 This enzyme is responsible for the generation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH), which is an essential cofactor in hydroxylation reactions for steroid synthesis, such as the conversion of cholesterol to 45-pregnenolone. This has been suggested as mitotane’s possible mechanism in inhibiting steroid synthesis in man. The mechanism by which mitotane alters the extraadrenal metabolism of cortisol is better defined. Bledsoe and associates demonstrated that mito- tane caused a 50 to 80 percent decrease in urinary 17-hydroxycorticosteroids (17-OHCS) in patients with functioning adrenal glands and patients with Addison’s disease who were receiving constant doses of exogenous cortisol. The effect was often apparent on treatment day 1 with mitotane, was maximal by day 4, and was pres- ent from seven to ten months after mitotane withdrawal. In contrast with the urinary 17-OHCS, plasma 17-OHCS concentrations and cortisol secretion did not change during the first two weeks of treatment with mitotane. The decrease in urinary 17-OHCS was caused by a decrease in the cortisol metabolites tetrahydrocor- tisol and tetrahydrocortisone, which was measured by the Porter-Silber reaction for urinary 17-OHCS.25 Mito- tane causes an increase in the metabolite 6-hydroxycortisol, which is too polar a compound to be measured in the test for urinary 17-OHCS.
PHARMACOLOGY AND PHARMACOKINETICS
There are only a few studies of the pharmacology and metabolism of mitotane in humans.23.26-29 Mitotane in tablet form is ~ 40 percent absorbed from the gastroin- testinal tract. Sixty percent of the oral dose is excreted unchanged in the stool and ~ ten percent is excreted as a metabolite in the urine. Measurable concentrations of the oxidative metabolites are also found in the bile and cerebrospinal fluid. The urinary metabolites can be measured for up to one month after discontinuing ther- apy. Apparently 20 to 30 percent of the oral dose administered each day is retained and stored in tissue. Mitotane is fat-soluble and deposits in subcutaneous fat, liver, brain, and both normal and malignant adrenal tis- sue. It does not usually affect hepatic, renal, bone mar- row, or ovarian function.23,29 The maximum plasma concentration after an initial dose is reached in three to five hours and equilibration between plasma and the tissue occurs within 12 hours.27 The serum half-life after
a single dose is two to three hours. With prolonged mito- tane therapy, the serum half-life after drug withdrawal was 18 to 159 days.15,30
Although a number of metabolites of mitotane have been identified in the urine, only one metabolite [2,2-bis (2-chlorophenyl,4’-chlorophenyl) 1,1-dichloroethylene] or o,p’-DDE has been found in plasma and in tissue. 27-29 During treatment, the ratio of o,p’-ODD to o,p’DDE in serum and tissues decreases. It is not known if o,p’DDE has any adrenolytic activity or if the appar- ent increase in metabolism of mitotane to o,p’-DDE has any effect on the therapeutic results of treatment.27
CLINICAL USE
In 1960, Bergenstal and associates reported the results of mitotane treatment in 18 patients with adrenocorti- cal carcinoma. Objective remission of metastases occurred in seven patients and lasted between 11/2 and 26 months. Seven additional patients had significant steroid suppression. Four patients had no response. The average dose of mitotane was 8-10 g/d for six to eight weeks.22
Subsequently, the National Cancer Institute spon- sored the production and distribution of mitotane to individual investigators to treat patients with histologi- cally proven adrenocortical carcinoma. Each investiga- tor was requested to file complete case reports and periodic studies of the drug’s efficacy and safety. In 1966, Hutter and Kayhoe reported the findings of 105 investigators with 138 patients treated with mitotane between 1960 and 1965.9 An additional 115 patients were treated by 95 investigators between 1965 and 1969. These patients are the subject of a report by Lubitz and associates in 1973.12
Hutter and Kayhoe reported that ~ 70 percent of the 138 patients with adrenocortical carcinoma achieved a 50 percent or greater decrease in hormone excretion with mitotane. A minimum of four weeks of treatment was required to ensure an adequate therapeutic trial. The median duration of steroid response was nine months. Thirty-four percent of the patients had an objective reduction in tumor mass. The median time to response was six weeks with a mean duration of 10.2 months. The average dose of mitotane required for a response was 8.5 g/d.9
Of the 115 patients reported by Lubitz and associ- ates, 89 percent had a steroid response and 61 percent had a measurable disease response. The maximum dose of mitotane for most patients was 5-10 g/d. The mean time between mitotane initiation and decreased steroid excretion was 17 days. The median time of onset of tumor regression was four weeks.12 The improved response rate as compared with Hutter and Kayhoe’s9 series is attributed to a shorter length of time between diagnosis and institution of mitotane therapy in these patients.
Lubitz and associates also determined the effect of mitotane treatment on survival. The mean duration of patient life was 8.4 months (range 21 d-41 mo). 12 This compares with a mean survival from the time of diag- nosis of 2.9 months (range a few days to one year) reported by Macfarlane in 20 cases of untreated inoper- able adrenocortical carcinoma.2
Since 1970, a number of reports on the treatment of adrenocortical carcinoma have been pub- lished.3-7.13,16,31-34 Because of the rarity of the disease, most investigators report the experience of an institu- tion or institutions over a period of years. Many of the patients in these independent publications have already been included in the results of Hutter and Kayhoe9 or Lubitz and associates.12
Hogan and associates treated four adrenocortical car- cinoma patients with mitotane 5-10 g/d. Two of three patients had an objective tumor response. Severe drug toxicity occurred in all four patients and signs of adre- nal insufficiency occurred in three. No patient tolerated more than 6 g/d of mitotane for longer than two months.23
Bulger and Correa treated five patients with adreno- cortical carcinoma with mitotane 2-10 g/d for periods of from five days to six weeks. In all but one patient, the drug was discontinued in less than one month because of side effects. Two patients had a decrease in urinary steroid concentrations but no objective tumor regression occurred in any patient.15 This probably was not an adequate therapeutic trial of mitotane. Hutter and Kayhoe9 and Lubitz and associates12 reported a median onset of tumor response of six and four weeks, respectively.
The studies by Hogan and associates23 and Bulger and Correa15 illustrate the difficulty in evaluating the efficacy of mitotane in adrenocortical carcinoma. There are no randomized, controlled, double-blinded studies. No single investigator has treated more than a few adrenocortical carcinoma patients. The dosage of mito- tane and the duration of therapy are not standardized because of poor patient tolerance of the drug’s consider- able side effects. Drug intolerance often leads to decreas- ing the dosage or discontinuing therapy.
There have been patients who have survived for long periods apparently disease-free after surgical resection of the tumor and treatment with mitotane.17.30.35.36 Whether these cases should be considered as cures or long-term remissions is debatable. Although recurrences or metastasis generally occur four months to four years postoperatively, an interval of 12 years before recur- rence has been reported.37 In the presented case, the dis- ease recurred six months after surgery and the patient died ten months after surgery.
Most studies have found no relationship between tumor histology, hormone production, and response to therapy and prognosis.5,6,15,16.34 Recently, Hogan and associates reported that patients with differentiated adrenocortical carcinoma survive longer than patients with anaplastic adrenocortical carcinoma. Most of these data came from retrospective case analyses.33
DOSAGE AND ADMINISTRATION
The usual recommended dose of mitotane for the treatment of adrenocortical carcinoma is 8-10 g/d administered in three or four divided doses.1.9.11.12.23 However, there are no phase II or phase III studies indicating that this dosage is necessary to achieve tumor response, and some patients have responded at lower dosages.23 Reported maintenance doses in the literature range from 0.5-20 g/d.12.38 The manufacturer recom-
mends that therapy be initiated at 8-10 g/d and main- tained at the highest tolerated dosage for at least three months to ensure an adequate trial. Some clinicians have used 1-6 g/d to initiate therapy and then rapidly increased the dosage until intolerable side effects devel- oped.9,12.23 It has been suggested that because serum con- centrations of mitotane increase rapidly and the drug persists in serum for months, rapidly escalating doses to the point of toxicity is clinically counterproductive. 23 Although there are reports of pediatric patients with adrenocortical carcinoma treated with mitotane, the dosage has varied widely.35,36.38 There is a two- to four- week lag time in reduction in steroid levels and often a 12-week onset before measurable tumor regression is observed.9,12
SUPPLEMENTAL STEROID THERAPY
Therapy with dexamethasone should be initiated at the time mitotane therapy begins. Mitotane’s effect on the extraadrenal metabolism of cortisol invalidates uri- nary 17-OHCS as an indicator of adrenocortical produc- tion of cortisol. Plasma cortisol concentrations may be used to assess mitotane’s effect on cortisol production, mitigating the use of cortisone or hydrocortisone as replacement therapy. The decrease in urinary 17-OHCS (Table 1) in our patient reflects both mitotane’s effect on the extraadrenal metabolism of cortisol and a decrease in production of cortisol, as supported by the fall in serum cortisol concentrations.
Concomitant therapy with a mineralocorticoid may be required with prolonged therapy.23 It is possible that some of the side effects experienced early in treatment could be caused by the onset of Addison’s syndrome and failure to initiate steroid replacement promptly. Mitotane should be discontinued following shock or severe trauma, and exogenous steroids should be administered.
There is one report of recovery of adrenal function after treatment of adrenocortical carcinoma with mito- tane. A two-year-old child was treated with mitotane 0.5-2.0 g/d for 20 months. Mineralocorticoid and glucocorticoid supplements were continued for seven years. Adrenal function gradually recovered and was normal 18 months after steroids were discontinued. The dose of mitotane in this case was less than the dose required for a direct adrenolytic effect.38
SIDE EFFECTS
The common toxic effects of mitotane primarily involve the gastrointestinal and neurological systems. Gastrointestinal toxicity is manifested by anorexia, nau- sea, vomiting, and diarrhea, and occurs in 50 to 80 per- cent of patients.9,12 Phenothiazines are moderately effective in controlling the nausea and vomiting associated with mitotane.31 Cellulose acetylphthalate, present in some mitotane tablets, prevents the absorp- tion of mitotane from the stomach and appears to decrease the gastrointestinal side effects.39 A recent study by Mollenaar and associates suggests that mito- tane is better absorbed and produces fewer gastrointes- tinal side effects when administered as a milk-powder mixture. 26
There is a 37 to 60 percent incidence of neurological toxicity associated with the drug, including lethargy, weakness, dizziness, confusion, and headache.9,12 It is not known if there is any relationship between either the dose or serum concentration of mitotane and ther- apeutic response or toxicity. Some investigators have suggested that serum concentrations >10 µg/ml are associated with tumor response and serum levels >20 ug/ml are associated with central nervous system tox- icity.27,30,40 Further study is needed to confirm these observations.
Toxicity involving the skin, eye, and genitourinary and cardiovascular systems is less frequent.9.12.41 Genitourinary toxicity consists of hematuria, hemor- rhagic cystitis, and albuminuria and occurs in two per- cent of patients treated with mitotane.41 No mechanism for this side effect has been suggested.
Mitotane has been reported to decrease total thyrox- ine concentrations without altering free thyroxine levels. This occurs without evidence of hypothyroidism and probably results from competition for protein binding sites. 42
Side effects often necessitate a decrease in dosage or interruption of therapy. Many patients do not tolerate more than 6.0 g/d of mitotane for longer than two months. 15.23 Mitotane therapy can be very debilitating, resulting in patient intolerance and discontinuation of treatment.5.15,31
DRUG INTERACTIONS
There is one case report of spironolactone apparently antagonizing the adrenolytic effect of mitotane.43 There was no evidence of this interaction in the patient dis- cussed here, but spironolactone and mitotane were used concomitantly for only five days.
Mitotane stimulates hepatic microsomal oxidases. 44,45 Although no drug interactions with mitotane have been reported, it could affect the metabolism of concomi- tantly administered drugs.
Aminoglutethimide
Aminoglutethimide, 2-(p-aminophenyl)-2-ethylglutar- imide is an amino derivative of the hypnotic agent glutethimide. It was introduced as an anticonvulsant in 1960, but was withdrawn from the market because of reports of adrenal insufficiency and goiterous hypothyroidism. Today, it is used as an alternative to surgical adrenalectomy in metastatic carcinoma of the breast, and most of the information on its mechanism of action, pharmacology, and toxicity is derived from this literature.46 Aminoglutethimide is effective in revers- ing the signs and symptoms of Cushing’s syndrome, especially those that occur with functional adrenocor- tical tumors.19 It has no antitumor effect in adrenocor- tical carcinoma and is used only as palliative therapy.
MECHANISM OF ACTION
Aminoglutethimide blocks the synthesis of adrenocor- tical hormones by inhibiting cytochrome P-450-mediated steroid hydroxylation (Figure 1). Aminoglutethimide blocks the conversion of cholesterol to pregnenolone by inhibiting 20 a-hydroxylation or 22 a-hydroxylation (the
AMINOGLUTETHIMIDE
Cholesterol
Mineralocorticoids
As Steroids
20( OH, 22 @ OH Cholesterol
18 OH
Steroids
Corticosterone
Pregnenolone
Progesterone
Desoxycorticosterone
17 @ OH
Progesterone
11 Desoxycortisol
Glucocorticoids
Androstenedione
Testosterone
1
Dihydrotestosterone
Androgens
Estrogens
specific step has not been determined) (site 1).47-50 Steroids that escape this blockade are preferentially con- verted to 44 compounds through acceleration of 30-ol- dehydrogenase, 45 to 44 isomerase enzyme system (site 7). By blocking the C21, C18, and C11 hydroxylation enzymes (sites 3-5), these 44 steroids cannot be converted to cortisol or aldosterone and are excreted as 44 andro- gens. Aminoglutethimide also blocks the peripheral aromatization of these androgens to estrogens (site 6). In summary, aminoglutethimide inhibits glucocorticoid, mineralocorticoid, and estrogen production but andro- gen and progesterone secretion are preserved. As a result of decreased cortisol production, the hypothalamic- pituitary-adrenal negative feedback axis is interrupted and adrenocorticotrophic hormone (ACTH) levels increase until the aminoglutethimide blockade is over- come (Figure 2-A). 49-51
In postmenopausal women, the aromatization of the major androgens androstenedione and testosterone to estrogens takes place in extraadrenal sites. Therefore, aminoglutethimide effectively blocks estrogen produc- tion. In contrast with this effect, aminoglutethimide only minimally inhibits estrogen production by the ovar- ian follicle. The administration of aminoglutethimide to premenopausal women does not inhibit estrogen production or interfere with menses.49
PHARMACOLOGY AND PHARMACOKINETICS
The extent of oral absorption of aminoglutethimide is not known. Peak serum concentrations occur within two to four hours after oral administration. The initial mean half-life of aminoglutethimide is 13.3 hours, decreasing to 7.3 hours with continued treatment. It is proposed that the decrease in half-life is caused by aminoglutethimide’s induction of its own metabolism. 52 Aminoglutethimide appears to be polymorphically acetylated, but a response relationship has not been established as yet in fast or slow acetylator phenotypes. 53 Four metabolites have been identified. Thirty-nine to 54 percent of the drug is excreted unchanged in the urine over eight hours.52,54 Twenty to 50 percent is excreted in the urine as the metabolite aceto-aminoglutethimide, which is a very weak inhibitor of cortisol synthesis. 49
A
B
Q
ACTH
0
O
DEXAMETHASONE 1 mg q.d.
O
CHOLESTEROL 0
0
AMINO-GLU TETHIMIDE
PREGNENOLONE
AMINO- GLUTETHIMIDE 1000 mg q.d.
CORTISOL
ESTROGENS
SITE OF ADRENAL BLOCKADE REFLEX ACTH RISE OVERCOMES BLOCKADE
ADD REPLACEMENT GLUCOCORTICOID REFLEX ACTH RISE PERSISTS
O
0
O POSTULATED DRUG INTERACTION
C
D
50
.
Control
O-O Amino glutethimide
Hatt cafe, 264 min
O
%. Dose /Lrier
D
a
DEXAMETHASONE 3 mg q.d.
Half Life, 120 min
O
p< 001
O
O
0
300 360
AMINO· GLUTETHIMIDE 1000 mg q.d.
0
60
120
30 240
Minutes
-
PROOF OF DRUG INTERACTION
EFFECTIVE MEDICAL ADRENALECTOMY REGIMEN
U
AMINOGLUTETHIMIDE ACCELERATES DEXAMETHASONE METABOLISM
INCREASE DEXAMETHASONE DOSAGE
CLINICAL USE
Schteingart and associates in 1966 were the first to report on the successful use of aminoglutethimide in a patient with Cushing’s syndrome caused by adrenocor- tical carcinoma.55
After aminoglutethimide was withdrawn from general use in 1966, 168 patients with Cushing’s syndrome were treated with it on an investigational basis between 1966 and 1976. Misbin and associates compiled the data and reported the results of this series. Of the 168 patients, 21 had Cushing’s syndrome caused by adrenocortical carcinoma and were not receiving concurrent adrenal- blocking agents such as mitotane and metyrapone. Treatment with aminoglutethimide was continued unin- terrupted for at least 14 days. The usual dose of aminoglutethimide was 250 mg qid. A biochemical response was defined as at least a 50 percent reduction in steroid concentrations or a return to normal limits after initiation of aminoglutethimide. A clinical response was defined as an improvement in the signs and symp- toms of Cushing’s syndrome such as muscle weakness, hypokalemia, and hyperglycemia. Of the 21 patients, 62 percent had a biochemical and clinical response, 14 percent had a biochemical response only, and 24 per- cent had no response to aminoglutethimide.19
As with mitotane, there are no randomized, con- trolled, double-blinded studies of the use of amino-
glutethimide in adrenocortical carcinoma. In addition to the series of Misbin and associates, 19 the case reported by Schteingart and associates55 appears to be the only other published report on the use of aminoglutethimide in adrenocortical carcinoma.
There is little information on the combined use of aminoglutethimide and mitotane in the treatment of adrenocortical carcinoma. Two case reports suggested that combined therapy offered no benefit over mitotane alone, 56,57 and two other case reports showed dramatic biochemical and clinical responses with the addition of aminoglutethimide to mitotane therapy.55.58
Although it has no antitumor activity, aminoglutethi- mide can effectively relieve the biochemical and clini- cal signs and symptoms of Cushing’s syndrome caused by metastatic adrenocortical carcinoma. By relieving the signs and symptoms of excess steroid production, aminoglutethimide can improve the quality of life for patients with functioning adrenocortical tumors.
DOSAGE AND ADMINISTRATION
The usual doses of aminoglutethimide for the treat- ment of Cushing’s syndrome is 750 mg-2.0 g/d in three or four divided doses. The onset of action is within days, as evidenced by a decrease in steroid levels and reversal of Cushingoid signs and symptoms.11.19
SUPPLEMENTAL STEROID THERAPY
To prevent the compensatory rise in ACTH and override of aminoglutethimide’s blockade of cortisol synthesis, dexamethasone or hydrocortisone can be administered (Figure 2-B).49,59,60 Because aminoglutethi- mide alters the extraadrenal metabolism of steroids, measurement of urinary 17-OHCS and 17-ketosteroids (17-KS) are not accurate indicators of drug response. Measurement of plasma cortisol or dehydroepiandoster- one sulfate (DHEA-S) is preferred.11.50 Therefore, dex- amethasone is the preferred steroid to prevent the override of aminoglutethimide’s blockade (Figure 2-D).
The recommended dose of dexamethasone (2.0 mg/d) exceeds the doses required for physiologic replacement since aminoglutethimide has been shown to induce the metabolism of dexamethasone, decreasing its half-life by ~ 50 percent (Figure 2-C).49 This larger than physi- ologic dose of dexamethasone has not resulted in signs of steroid excess.49,50.59.61 Aminoglutethimide accelerates dexamethasone metabolism by inducing the liver micro- somal enzyme 6-6-hydroxylase. This is the same mech- anism by which phenobarbital and phenytoin induce dexamethasone metabolism. 6-6-hydroxylation is a major site of inactivation of several synthetic glucocor- ticoids, including dexamethasone, prednisone, and pred- nisolone. Hydrocortisone is metabolized by another pathway and is not affected by the administration of aminoglutethimide.49 Therefore, hydrocortisone may be the optimal steroid for replacement when plasma DHEA-S levels are used to monitor aminoglutethimide’s efficacy, as in the treatment of breast cancer.5º Fludro- hydrocortisone 0.1 mg/d may be required to prevent mineralocorticoid deficiency.59,60
SIDE EFFECTS
Most of the side effects occurring during aminoglute- thimide therapy are dose related. In most instances, the drug is well tolerated in dosages up to 1 g/d.60,61 Leth- argy occurs in 41.5 percent of patients, other central ner- vous system symptoms such as dizziness and ataxia are less common.60 Approximately one-third of patients develop a cutaneous rash that clears spontaneously on continued treatment.60,61 Hematologic toxicity occurs infrequently. Pancytopenia, leukopenia, and thrombo- cytopenia all have been reported to occur during amino- glutethimide therapy.62-65 Although at least one patient with leukopenia has been rechallenged successfully and treated with aminoglutethimide, it is not advisable to rechallenge patients with hematological side effects until further data become available.65 Two cases of amino- glutethimide hypersensitivity associated with cholestatic jaundice have been reported.66,67
Aminoglutethimide has an antithyroid effect similar to that of propylthiouracil, causing a diminished uptake and organification of iodine.68 Serum thyroxine concen- trations will fall during the first eight weeks of treat- ment. Thyroid-stimulating hormone levels increase and thyroxine synthesis recovers. Fewer than five percent of patients develop clinical hypothyroidism.60
DRUG INTERACTIONS
In addition to its effects on dexamethasone metabo- lism, of particular significance is the effect of aminoglu- tethimide on warfarin metabolism. Aminoglutethimide decreases the anticoagulant effect of warfarin, requir- ing an increase in the warfarin dose to maintain ther- apeutic anticoagulation. This effect has persisted for two weeks after the discontinuation of aminoglutethimide. A three- to fivefold increase in warfarin clearance was shown in two patients after initiation of aminoglutethi- mide. The increase in clearance was probably caused by the induction of hepatic microsomal enzymes, acceler- ating warfarin metabolism.69 This interaction has also been reported to occur with acenocoumarin, another coumarin derivative.7º Therapy with warfarin must be monitored carefully when aminoglutethimide therapy is started or discontinued.
Discussion
Surgery and chemotherapy with mitotane are the accepted treatments for adrenocortical carcinoma. In this case, surgical excision of the tumor was followed by treatment with mitotane and aminoglutethimide when increased cortisol production recurred six months after surgery. The patient in the presented case showed a biochemical response to aminoglutethimide and mito- tane, with a reduction in plasma cortisol and urinary 17-OHCS (Table 1). The fall in steroid concentrations was associated with an improvement in hypertension, hypokalemia, and edema, as evidenced by weight loss. There was no evidence of tumor regression and the patient died ten months after diagnosis.
Both aminoglutethimide and mitotane have complex mechanisms of action and side effects that are exten- sions of their pharmacologic properties. Although they have different mechanisms of action, both drugs halt
cortisol production and interfere with the extraadrenal metabolism of cortisol. Because of the effect on extraadrenal metabolism of cortisol, serum cortisol con- centrations must be used to evaluate response to ther- apy. Replacement therapy with cortisol would invalidate serum cortisol concentrations. Replacement therapy with dexamethasone is required for both drugs but, because of aminoglutethimide’s induction of dexameth- asone metabolism, the dose must be increased if amino- glutethimide is used.
Drug interactions caused by the pharmacological properties of aminoglutethimide and mitotane must also be considered. An example of this type of interaction occurred in our patient. Prior to the initiation of aminoglutethimide, the patient was receiving potassium supplementation (80 mEq KCl/d) for persistent hypokalemia (K + on admission 2.3 mEq/L). Serum potassium increased from 2.9 mEq/L to 4.1 mEq/L four days after the start of aminoglutethimide therapy (Table 1). The patient was also receiving spironolactone at this time. The rapid decrease in steroid production and reversal of hypokalemia caused by aminoglutethi- mide, added to the potassium-sparing effects of spironolactone, were anticipated and scheduled potas- sium supplementation was stopped on aminoglutethi- mide initiation.
Both drugs have a high incidence of central nervous system side effects and both affect thyroid function tests. The patient in this case developed biochemical hypothyroidism when lost to follow-up. L-thyroxine was begun prematurely before the results of her TSH levels were available. Thyroid replacement therapy during treatment with aminoglutethimide is not indicated unless the compensatory rise in TSH does not occur, which would result in clinical hypothyroidism.
The incidence of genitourinary side effects with these drugs is low. However, this patient developed hemor- rhagic cystitis that cleared when mitotane was discon- tinued. Therefore, the cystitis was presumed to be secondary to the mitotane.
The combined use of these drugs requires a complete understanding of their individual actions and awareness of the potential for additive therapeutic and toxic effects. Precision monitoring can minimize drug toxic- ity and enable the patient to tolerate an unpleasant course of therapy, which is the only treatment availa- ble for this rare malignant disease. ~
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EXTRACTO
Se presenta en este artículo el reporte de un caso de carcinoma adrenocortical y se discuten el tratamiento y la historia natural de la enfermedad. El carcinoma adrenocortical es una malignidad rara con un promedio de sobrevivencia menor de tres meses si el paciente no recibe tratamiento. Se clasifica en funcional y no-funcional depen- diendo de la evidencia clínica y bioquímica de sobreproducción de esteroides.
El tratamiento primario es la resección quirúrgica del tumor, con quimioterapia indicada para efectos antitumoral y antihormonal. La única droga disponible ahora que prolonga la vida de los pacientes con esta enfermedad es mitotano, un adrenolítico directo. Su uso clínico está limitado por su toxicidad gastrointestinal y neurológica. La aminoglutetimida inhibe la síntesis de esteroides bloqueando la conversión de colesterol a pregnenolona. No tiene efecto antitumoral en carcinoma adrenocortical, pero es efectiva en aliviar los signos y síntomas de exceso de producción de hormonas en tumores fun- cionales.
Ambos, mitotano y aminoglutetimida, tienen mecanismos de acción complejos. El uso combinado de estas drogas para el tratamiento de carcinoma adrenocortical requiere un entendimiento completo de sus acciones individuales y un conocimiento del potencial de efectos aditivos terapéuticos y tóxicos.
AMPARO IZQUIERDO
RESUME
Dans cet article est rapporté un cas de carcinome corticosurrénalien. L’histoire naturelle de la maladie et son traitement y sont présentés. Ce carcinome est une tumeur maligne rare; le taux de survie moyen des patients non traités est moins de 3 mois. La tumeur est classifiée comme étant sécrétrice ou non sécrétrice dépendant de l’évidence cli- nique et biochimique de la surproduction hormonale. La résection chirurgicale de la tumeur est le traitement primaire. La chimiothéra pie est indiquée pour ses effets antihormonaux et antitumoraux. Le mitotane est un adrénolytique direct et est le seul médicament présente- ment disponible qui a amélioré la survie des patients atteints. Son utili- sation clinique est limitée par sa toxicité gastrointestinale et neurologique. L’aminoglutéthimide inhibe la synthèse stéroidienne en bloquant la conversion du cholestérol en pregnenolone; cette substance ne possède pas d’effet antitumoral dans ce carcinome mais contrôle les signes et symptômes de production excessive d’hormones dans les tumeurs sécrétrices.
Les mécanismes d’action de ces deux médicaments sont complexes. Leur utilisation concomitante dans le traitement du carcinome cor- ticosurrénalien doit être accompagnée d’une compréhension totale de leurs actions individuelles et d’une surveillance étroite du potentiel synergétique des effets thérapeutiques et toxiques.
DENYSE DEMERS
Call for Papers FIFTEENTH EUROPEAN SYMPOSIUM ON CLINICAL PHARMACY
EUROPEAN SOCIETY OF CLINICAL PHARMACY Estoril Coast, Lisbon, Portugal October 23-25, 1986
The European Society of Clinical Pharmacy (ESCP) was founded in October 1979 at the Eighth European Symposium on Clinical Pharmacy in Lyon, France. The main theme for the 15th symposium is undergraduate and postgraduate edu- cation in clinical pharmacy. Secondary themes are the phar- macist and clinical trials, clinical pharmacokinetics, clinical nutrition, and drug information. The deadline for paper abstracts is May 15, 1986. Official languages are English and Portuguese, with simultaneous translation.
The ESCP is governed by a general committee with represen- tatives from 11 countries. The meeting provides an excellent opportunity to learn of international clinical pharmacy prac- tice and research. Those interested in submitting papers or obtaining further information should write:
J.A. Aranda da Silva Simpósio Europeu de Farmácia Clínica R. Sociedade Farmacêutica, 18 1199 Lisboa Codex Portugal
The 1st Annual Finland Medical and Pharmaceutical Conference Helsinki, Haikko, and Finnish Lapland February 1-March 30, 1986 (from New York) February 12-March 23, 1986 (from Seattle)
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1986 JAN