Clinical results of the use of mitotane for adrenocortical carcinoma
A.A. Kasperlik-Zaluska
Department of Endocrinology, Center for Postgraduate Medical Education, Warsaw, Poland
Abstract
| Correspondence | Mitotane (o,p'-DDD) acts mainly as an inhibitor of intramitochondrial pregnenolone and cortisol synthesis. Its adrenolytic effect depends on metabolic activation due to conversion to o,p'-DDA and o,p'-DDE. The drug has been used for 40 years in the treatment of adrenocortical | Key words · Mitotane · Adrenocortical carcinoma · Cushing's syndrome |
|---|---|---|
| A.A. Kasperlik-Zaluska | ||
| Department of Endocrinology Bielañski Hospital | ||
| ul. Ceglowska 80 01-809 Warsaw Poland | carcinoma, mainly its regional and metastatic stage, as an adjuvant to surgical resection of the tumor. In the medical literature there are | |
| Fax: +48-22-834-3131 | controversial opinions about its efficacy for the treatment of adreno- | |
| E-mail: | cortical carcinoma. In our experience, mitotane administered imme- diately after surgery appeared to be much more efficient than when administered later. We have administered this drug in all cases of | |
| anna.8463401@pharmanet.com.pl | ||
| Presented at the First | microscopically confirmed adrenocortical carcinoma, irrespectively of stage at the time of surgery, for fear of a false too optimistic classification. In our series of 82 patients with adrenocortical carcino- ma, 59 patients have been treated with mitotane, 32 of them immedi- ately after surgery, and 27 with a delay of 2 to 24 months. Today there are 18 survivors in the group of patients treated with mitotane soon after the operation and only 6 survivors in the group receiving mitotane with a delay. All patients were simultaneously given replacement therapy. Undesired effects of mitotane administration included in- creased aminotransferase and alkaline phosphatase activity, decreased white cell, platelet or red cell number, and myasthenia. Furthermore, we used mitotane with good results in Cushing's syndrome of non- malignant origin as pre-treatment before surgery or in long-term treatment for patients with poor tolerance of other adrenal inhibitors. | |
| International Meeting on Adrenal Disease: Basic and Clinical Aspects, Ribeirão Preto, SP, Brazil, August 31-September 2, 1999. | ||
| Research supported by a CMKP grant | ||
| (No. 501-1-2-07-27/98). Received December 20, 1999 Accepted March 10, 2000 |
Introduction
Forty years ago Bergenstal et al. (1) pub- lished their first report on the beneficial ef- fects of o,p’-DDD (1,1-(dichlorodiphenyl)- 2,2-dichloroethane; mitotane) in adrenocor- tical carcinoma.
Mitotane inhibits the intramitochondrial conversion of cholesterol to pregnenolone and the conversion of 11-deoxycortisol to cortisol (2,3). It is also capable of producing
selective adrenocortical necrosis, both in the adrenal tumor and in metastases. Addition- ally, it reverses gene-expressed chemotherapy resistance by reducing cellular drug efflux (4). The adrenolytic effect of mitotane de- pends on metabolic activation, o,p’-DDA and o,p’-DDE being the end products of the presumed metabolic activating pathway (5,6).
The annual incidence of adrenocortical carcinoma has been estimated at 0.5-2 per million (7). The introduction of new imaging
procedures may modify the data on the fre- quency of these tumors, because a signifi- cant number of clinically silent carcinomas are found in ultrasound scans. It is possible that the poor prognosis characteristic of adre- nocortical carcinoma may change into a bet- ter one due to earlier detectability.
It is obvious that prognosis depends mainly on the rate of tumor expansion. The staging, according to the Surveillance, Epi- demiology and End Result Classification (8), distinguishes localized, regional and meta- static (distant) forms of adrenocortical carci- noma. The staging system proposed by MacFarlane (9) distinguishes four stages: stage I (tumor less than 5 cm in diameter) and stage II (tumor more than 5 cm, not spreading into neighboring tissues), corre- sponding to a localized stage, stage III - corresponding to regional disease, and stage IV - corresponding to metastatic disease.
Surgery, sometimes aggressive (in stages III and IV), remains the basis of therapy. For many years mitotane has been considered to be the drug of choice for patients with inoper- able, recurrent or metastatic adrenal carcino- ma and has been administered mainly to treat these conditions. In recent years it has been advocated as a therapy following the resection of a localized tumor. In 1992 Wooten and King (10) cited 51 reports con- cerning tumor responses to mitotane, with the number of patients ranging from 1 to 75, and a total number of 551. Partial or total responses were noted in 194 of them (35.2%), and the best results (61%) were observed in the Lubitz series (11). Luton et al. (12) in 1990 used mitotane as adjuvant therapy after surgery in 59 patients; however, only eight had partial tumor regression. In our own 1995 report (13), mitotane administration resulted in remission in 12 out of 32 patients (37.5%).
The present study aimed at evaluating the results of mitotane therapy in the Depart- ment of Endocrinology (Center for Post- graduate Medical Education, Warsaw, Po-
land) during the last 33 years.
Material and Methods
Two groups of patients have been treated with mitotane in our department: group I consisting of patients with adrenocortical carcinoma, and group II consisting of pa- tients with Cushing’s syndrome of non-ma- lignant origin.
Group I. Since 1966, 82 patients with adrenocortical carcinoma were referred to our department. There were 63 women and 19 men aged 13-70 years (mean 43.4). In 29 of them the adrenal tumor was found inci- dentally by ultrasound scan. In most patients in both groups, the tumor was diagnosed in the metastatic stage of the disease (Table 1). The size of the tumor ranged from 3.2 to 23.0 cm in the group of incidentally found masses and between 3.5 and 17.0 in the non-inci- dental group. Clinically silent adrenal tu- mors were diagnosed in 30 patients. Cushing’s syndrome and virilization, often associated with hypertension, occurred most frequently in patients with hormonally ac- tive adrenal tumors (13). Four patients died just before surgery and two others immedi- ately after the operation. Seventy-six other patients have been treated with surgery and/ or with mitotane or cytostatic agents (Table 2).
Seventy-four patients were treated with surgery; four of them were submitted to partial hepatectomy and two to nephrectomy. Two patients with inoperable tumors only received mitotane in daily doses of 4.0-15.0 g. Sixty-one surgically treated patients re- ceived mitotane, which was the only adju- vant therapy in 55 of them. A method con- sisting of quickly increasing mitotane doses, beginning with 1.5-2.0 g daily, was used. For patients with localized disease the daily doses did not exceed 4.0 g. For patients with re- gional and metastatic disease the daily mitotane doses were increased every 5-7 days up to 8.0-10.0 g for two weeks and were
then gradually reduced. For long-term treat- ment a daily dose of 4.0 to 5.0 g was given during the first year, 3.0-4.0 g during the 2nd and 3rd year and 1.5-3.0 g during the next two years. In cases misdiagnosed at the time of surgery, the dose of mitotane was in- creased to 8.0-10.0 g daily, with the appear- ance of metastases or regional recurrence. Thirty-two patients received mitotane im- mediately after surgery, and 27 patients 2 to 15 months after the operation. One male patient referred to our department two years after removal of the carcinoma, with a recur- rent tumor progressing during gamma-inter- feron administration and six cycles of che- motherapy, received mitotane at doses of 8.0-10.0 g daily for 3 months. The subse- quent long-term doses ranged from 5.0 to 6.0 g a day. In another male patient, referred to our department five years after right adreno- cortical carcinoma and metastatic prostate gland resection, the hormonal signs of left adrenal carcinoma appeared six months later. Mitotane treatment was administered imme- diately after left adrenal carcinoma removal. Cytostatic drugs were administered to nine patients (see Table 2), simultaneously with mitotane therapy in six of them. All patients treated with mitotane simultaneously re- ceived replacement therapy, hydrocortisone (30 to 50 mg daily) + prednisolone (5 to 10 mg daily) and fludrocortisone (0.1 to 0.15 mg daily). The doses of hydrocortisone were gradually reduced after mitotane withdrawal.
Serum mitotane concentrations were measured in the laboratory of the Child Health Center, Warsaw (by M. Filipek), in patients with regional or distant disease. Values rang- ing from 15 to 25 µg/ml were considered as active mitotane levels. In the last year, the plasma levels of mitotane and its metabolites (o,p’-DDA and o,p’-DDE) were determined at the Norwegian Radium Hospital, Depart- ment of Clinical Pharmacology (Oslo, Nor- way) by A. Andersen and D.J. Warren (6).
Group II included 22 women, 22-57 years old, with adrenal hyperfunction of non-ma-
lignant etiology. Sixteen patients (12 pa- tients with Cushing’s syndrome, three with an adrenal adenoma and one with nodular hyperplasia) received mitotane in short cycles (3-6 weeks) as pre-treatment before surgery. Six patients (four patients with Cushing’s disease and two women with ectopic ACTH syndrome) have been treated with mitotane for much longer courses (ranging from three months to three years) because of poor toler- ance or ineffectiveness of other anti-adrenal drugs (14,15). The daily mitotane doses ranged from 2.0 to 4.0 g. During long-term therapy (1-3 years) the maintenance mitotane dose was 1.0-1.5 g daily. Only one patient with a concomitant severe Alternaria alter- nata (opportunistic) infection received higher doses of up to 6.0 g per day for five weeks (241 g, in total). No replacement therapy with hydrocortisone has been necessary in five patients. Hydrocortisone has been ad- ministered to one patient at the dose of 10 mg every morning, together with mitotane at the dose of 0.5 g daily, during the second year of treatment.
Results
The results of treatment of 76 patients with adrenocortical carcinoma are summa- rized in Table 2. There were 18 survivors in the group of 32 patients treated with mitotane immediately after surgery (56%). Three of them were classified as metastatic and three others as regional disease. One patient with regional disease survived nearly 10 years on mitotane therapy. Five patients in this group died because of diseases not related to adre- nal carcinoma. In the group of patients to whom mitotane was administered with a
| Localized | Regional | Metastatic | |
|---|---|---|---|
| Total | 23 | 12 | 47 |
| Incidental (29) | 8 | 7 | 14 |
| Non-incidental (53) | 15 | 5 | 33 |
delay there were six survivors at the time of summarizing the results (22%). Similarly, only one patient survived out of 8 who did not use mitotane. In the patient with carcino- ma recurring during gamma-interferon ad- ministration and chemotherapy, treatment with mitotane resulted in the reduction of tumor size from 12 to 6 cm on CT (16).
The side effects of mitotane therapy in- cluded an increase in aminotransferase and alkaline phosphatase activity (6 patients) and a fall in the number of leukocytes, platelets or erythrocytes (5 patients). A transient re- duction of mitotane dose with a simulta- neous increase of prednisolone dose was sufficient to obtain improvement of labora- tory results in most patients. Myasthenia due to a toxic influence on neuromuscular junc- tions was observed only in three women, requiring reduction of mitotane daily dose or even withdrawal of the drug (in one patient).
Pre-operative mitotane administration to patients with Cushing’s syndrome of non- malignant origin resulted in partial remis- sion of the disease with good tolerance of surgical treatment. During long-term mito- tane therapy in six patients with severe Cushing’s syndrome, complete remission was obtained. In one patient with Cushing’s syn- drome complicated by a systemic Alternaria alternata infection, general improvement has been achieved with fungal infection healing (17). No undesired effects of mitotane therapy
were observed in these patients.
Discussion
In our Department of Endocrinology, mitotane has been used for the treatment of adrenocortical carcinoma for 33 years (18). In our experience, surgery followed by im- mediate mitotane administration is the method of choice for adrenocortical carcino- ma therapy. We give this drug to all patients with microscopically proved adrenal carci- noma, irrespectively of staging at the time of surgery because we have found that false- positive classification (untrue diagnosis of localized disease) has not been infrequent. According to Folkman’s theory (19), we be- lieve that dormant micrometastases may rep- licate after tumor removal due to a switch to the angiogenic phenotype in response to a decrease in plasma angiostatin concentra- tions. Mitotane administered as early as pos- sible after the operation could prevent angio- genesis in the micrometastases and thus pre- vent carcinoma dissemination. The results of early mitotane administration for our se- ries (56 vs 22% survival in the group with delayed treatment) seem to confirm this sug- gestion. Unfortunately, mitotane is not uni- formly efficient in all cases of adrenocortical carcinoma, although it is possible that in most of them a delay in therapeutic inter- vention plays the most important role. What seems necessary in the interpretation of the results of therapy is analysis of the time when the therapy was introduced. In distant disease mitotane associated with cytostatic agents may be more effective (20).
Clinically silent adrenocortical carcino- mas usually are found incidentally, mainly in the ultrasound scan. The detectability of the incidentally found malignant adrenal tu- mors could be increased by obligatory ab- dominal ultrasound scans (every two or three years, for example). In our series, 29 adreno- cortical carcinomas were discovered inci- dentally (35.4% of 82 patients). In the group
| Method | No. of patients | Survival (months) | No. of survivors |
|---|---|---|---|
| Surgery | 8 (5*) | 1-314 | 1 |
| Surgery + adjuvant therapy | 66 (37*) | 4-118 | 26 |
| + mitotane | 55 (29*) | 4-118 | 24 |
| + mitotane, 5-FU | 4 (4*) | 4-24 | 0 |
| + mitotane, cisplatin, etoposide | 2 (2*) | 6-86 | 2 |
| + cisplatin, etoposide | 3 (3*) | 12-20 | 0 |
| + radiotherapy | 2 (1*) | 5, 12 | 0 |
| Mitotane | 2 (2*) | 6, 10 | 0 |
of 451 patients referred to our department because of incidentally found adrenal masses the carcinomas appeared to be present in 6.7%.
The second type of mitotane use, i.e., in hypercorticism of non-malignant etiology, appeared to be beneficial to all treated pa- tients. Mitotane seems to be the drug of choice in Cushing’s disease associated with polycystic ovary syndrome because it does not stimulate androgen production as other inhibitors of steroidogenesis do.
The side effects of mitotane were rare in our material; only in one patient did we observe severe myasthenia, which forced us to withdraw the drug after one year of therapy. In our patients there were no features of neurotoxicity after long-term administration of high doses of mitotane exceeding 8.0 g per day (21). Nobody in our group of pa- tients had vomiting or nausea, even with doses up to 10.0 g daily. We have adminis- tered slightly increased doses of hydrocorti- sone and prednisolone to prevent hypo- adrenalism because both the above-men- tioned symptoms may have been due to cor- tisol deficiency. In our experience, hydro- cortisone associated with prednisolone and fludrocortisone seems to be better suited for replacement therapy than dexamethasone or prednisolone alone during mitotane admini- stration. The determination of serum cortisol levels in our patients showed that mitotane did not change hydrocortisone absorption,
although Robinson et al. (22) observed that the corticosteroids were cleared more rap- idly from the circulation during mitotane administration.
Both high (23) and low (24) doses of mitotane have been recommended in the literature. It seems that the best method is to measure plasma mitotane concentration to choose the optimal mitotane dose.
It is not certain how long mitotane must be administered to patients without evident regional or distant invasion by adrenocorti- cal carcinoma. I have adopted a period of four to five years and this period seems to be sufficient in most cases. However, the fact that one patient, not treated with mitotane, developed a left adrenocortical carcinoma in the sixth year after removal of a right adrenal carcinoma makes the five-year period of treatment questionable. Further observations are necessary to gain more knowledge about this matter.
We may summarize by saying that sur- gery associated with early mitotane adminis- tration is a method of choice for adreno- cortical carcinoma treatment. In the distant stage simultaneous use of cisplatin and eto- poside may have beneficial effects. Replace- ment therapy with slightly increased doses of hydrocortisone, fludrocortisone and pred- nisolone is necessary during mitotane ad- ministration. The side effects of mitotane are infrequent when the daily doses do not ex- ceed 8.0-10.0 g.
References
1. Bergenstal DM, Lipsett MB, Moy RH & Hertz R (1959). Regression of adrenal can- cer and suppression of adrenal function in men by o,p’-DDD. Transactions of the As- sociation of American Physicians, 72: 341.
2. Hart MM & Straw JA (1971). Studies on the site of action of o,p’-DDD in the dog adrenal cortex. I. Inhibition of ACTH-medi- ated pregnenolone synthesis. Steroids, 17: 559-574.
3. Hart MM, Swackhammer ES & Straw JA (1971). Studies on the site of action of
o,p’-DDD in the dog adrenal cortex. Il. TPNH- and corticosteroid precursor-stim- ulation of o,p’-DDD inhibited steroidogen- esis. Steroids, 17: 575-586.
4. Bates SE, Shieh CY, Mickley LA, Dichek HL, Gazdar A, Loriaux DL & Fojo AT (1991). Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glyco- protein) which is also expressed by adrenocortical carcinomas. Journal of Clinical Endocrinology and Metabolism,
73: 18-29.
5. Andersen A, Warren DJ, Nome O, Vesterhus L & Slordal L (1995). A high- pressure liquid chromatographic method for measuring mitotane [1,1-(dichlorodi- phenyl)-2,2-dichloroethane] and its meta- bolite 1,1-(o,p’-dichlorodiphenyl)-2,2- dichloroethene in plasma. Therapeutic Drug Monitoring, 17: 526-531.
6. Andersen A, Kasperlik-Zaluska AA & War- ren DJ (1999). Determination of mitotane (o.p’-DDD) and its metabolites o,p’-DDA
and o,p’-DDE in plasma by high perfor- mance liquid chromatography. Therapeu- tic Drug Monitoring, 21: 355-359.
7. Brennan MF (1987). Adrenocortical carci- noma. Cancer Journal for Clinicians, 37: 348-365.
8. US Department of Health, Education and Welfare (1977). Summary Staging Guide for Cancer Surveillance, Epidemiology and End Result Reporting Program. April 1977, Public Health Service, National In- stitutes of Health, Bethesda, MD, 12-14.
9. MacFarlane DA (1958). Cancer of the ad- renal cortex: the natural history, progno- sis and treatment in a study of fifty-five cases. Annals of the Royal College of Sur- geons of England, 23: 155-186.
10. Wooten MD & King DK (1993). Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer, 72: 3145-3155.
11. Lubitz JA, Freeman L & Okun R (1973). Mitotane use in inoperable adrenal corti- cal carcinoma. Journal of the American Medical Association, 223: 1109-1112.
12. Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, Laudat MH, Louvel A, Chapuis Y & Blondeau H (1990). Clinical features of adrenocortical carcino- ma, prognostic factors, and the effect of mitotane therapy. New England Journal of Medicine, 322: 1195-1201.
13. Kasperlik-Zaluska AA, Migdalska BM,
Zgliczyński S & Makowska AM (1995). Adrenocortical carcinoma. A clinical study and treatment results of 52 patients. Can- cer, 75: 2587-2591.
14. Kasperlik-Zaluska A, Jeske W & Migdalska B (1986). Adrenal and pituitary effects of mitotane in Cushing’s syndrome. Endo- krynologia Polska, 37: 17-21.
15. Brzezińska A, Slowińska-Srzednicka J, Zgliczyński W, Kasperlik-Zaluska A, Gietka-Czernel M & Zgliczyński S (1994). Preoperative mitotane treatment of pa- tients with Cushing’s syndrome and ad- vanced hypertension. Endokrynologia Polska, 45: 7-12.
16. Kasperlik-Zaluska AA, Migdalska BM & Makowska AM (1998). Incidentally found adrenocortical carcinoma. A study of 21 patients. European Journal of Cancer, 34: 1721-1724.
17. Kasperlik-Zaluska AA & Bieluńska S (1991). Effect of mitotane on Alternaria alternata infection in Cushing’s syndrome. Lancet, 337: 53-54.
18. Hartwig W, Massalski W, Kasperlik- Zaluska A, Migdalska B, Szamatowicz M & Jakowicki J (1968). Hormonally active carcinoma of the adrenal cortex treated with o,p’-DDD. Polish Endocrinology, 19: 57-69.
19. Folkman J (1995). Clinical applications of research on angiogenesis. New England Journal of Medicine, 333: 1757-1763.
20. Berruti A, Terzolo M, Pia A, Angeli A & Dogliotti L (1998). Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocorti- cal carcinoma. Cancer, 83: 2194-2200.
21. Dolz M, Nunez S, Klein M, Prieto S, Leclere J & Weryha G (1999). Mitotane neurotoxicity mimicking dramatic worsen- ing of hypercortisolism during the treat- ment of metastatic corticosurrenaloma. 81st Annual Meeting of the Endocrino- logical Society, June 12-15, San Diego, California, Program and Abstracts, P1-578, 257.
22. Robinson BG, Hales IB, Henniker AJ, Ho K, Luttrell BM, Smee IR & Stiel JN (1987). The effect of o,p’-DDD on adrenal steroid replacement therapy requirements. Clini- cal Endocrinology, 27: 437-444.
23. Haak HR, Hermans J, van de Velde CJH, Lentjes EGWM, Goslings BM, Fleuren GJ & Krans HMJ (1994). Optimal treatment of adrenocortical carcinoma with mito- tane: results in a consecutive series of 96 patients. British Journal of Cancer, 69: 947-951.
24. Dickstein G, Shechner C, Arad E, Best L-A & Nativ O (1998). Is there a role for low doses of mitotane (o,p’-DDD) as adjuvant therapy in adrenocortical carcinoma? Jour- nal of Clinical Endocrinology and Metabo- lism, 83: 3100-3103.