Experimental and Clinical Endocrinology @ 1994 Johann Ambrosius Barth
Complete remission of metatasized adrenocortical carcinoma under o,p’-DDD
E. Kornely, R. Schlaghecke
Medizinische Klinik und Poliklinik, Abteilung für Endokrinologie und Rheumatologie, Heinrich Heine Universität, Düsseldorf, Germany
Key words: Adrenocortical carcinoma, o,p’-DDD, sys- temic chemotherapy, complete remission
Summary: The case of a 53 year old female patient with metastasized androgen producing adrenocortical carci- noma is presented. After initial adrenalectomy a local relapse had been treated by surgery and external ir- radiation. Solitary liver metastases had been resected re- peatedly. Subsequently multiple liver metastases required
systemic chemotherapy. Treatment with o,p’-DDD (in- itially 12 g/d, long term treatment 1.5-3 g/d) has re- sulted in a complete remission for nearly 4 years. Gastro- intestinal side effects occurred initially but subsided with dose reduction of o,p’-DDD.
Abbreviations: o,p’-DDD: 1,1 dichloro-2(0-chloro- phenyl)-2-(p-chlorophenyl)ethane DHEAS: Dehydroepi- androsterone sulfate
Introduction
Adrenocortical carcinoma is a rare malignancy with an incidence of approximately 1-2:1 000 000 a year (Copeland, 1983). Patients predominantly present with abdominal pain, an abdominal mass or endocrine symptoms such as virilization or Cu- shing’s syndrome (Hutter and Kayoe, 1966, Lubitz et al., 1973). Patients with clinically apparent signs of hormonal excess are usually diagnosed not ear- lier than those with non-functional tumors and have no better prognosis (Bertagna and Orth, 1981, King and Lack, 1979). The prognosis is poor with a median survival time of 2.5 months in un- treated patients (MacFarlane, 1958). Since 1960 o,p’-DDD (mitotane) has been clinically used es- pecially in not resectable and metastasized tumors. The results have been conflicting.
This paper discusses the case of a 53 year old woman with complete remission of metastatic adre- nocortical carcinoma under therapy with mitotane.
Materials and methods
In the early 1980’s, a 40 year old female patient developed slowly progressive hirsutism and acne.
In November 1983, serum testosterone was found to be elevated and computed tomography revealed a tumor of 4 cm in diameter of the left adrenal gland. She was admitted to her local hospital where a 150 g tumor was removed by adrenalec- tomy in January 1984. The histological examin- ation gave no proof of malignancy. After surgery, testosterone levels returned to normal but rose again by July 1986. CT scan showed a tumor of 2.5 cm in diameter in the region of the left adrenal gland. During laparatomy two tumors, 6 and 4 cm in diameter were found which enclosed parts of the aorta abdominalis and the left A. renalis and in- vaded the hilus region of the left kidney. The tumor mass was reduced, but could not be resected completely. Histologic examination again showed a highly differentiated adrenal cortical tissue which, in context with the finding of invasive growth, was classified as adrenocortical carci- noma. From September to November 1986 the left kidney region was irradiated externally with 50 Gy.
In November 1987 the testosterone level again rose to 1.4 ng/ml and CT scans revealed a hypo- dense lesion in the right lobe of the liver while the
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| normale range (postmeno- pausal) | |||
|---|---|---|---|
| Testosterone | ng/ml | 1.31 | <0.8 |
| 17-OH-Progesterone | ng/ml | 5.8 | <2.5 |
| DHEAS | µg/dl | 202 | <400 |
| Cortisol | ng/ml | 141 | 50-250 |
| ACTH | pg/ml | 33 | 10-60 |
| Estriol | pg/ml | 120 | <150 |
| Estradiol | pg/ml | 41 | <50 |
| LH | mU/ml | 53.3 | >20 |
| FSH | mU/ml | 56.2 | >20 |
adrenal regions were free of tumor. Exstirpation of the liver tumor in January 1988 resulted in nor- malization of androgen excess and revealed a met- astasis of the adrenocortical carcinoma.
Testosterone level rose to 1.4 ng/ml again in May 1988, and a metastasis to the left lobe of the liver was detected by CT scan. In June 1988, a part of the quadrate lobe of the liver and the left sided metastasis were resected. A CT scan in May 1989 identified another 2 metastases to the right lobe of the liver. The following laparatomy in June 1989 revealed an additional metastasis to the left lobe so that resection was impossible.
The patient was referred to the University of Düsseldorf hospital in October 1989. We saw a 50 year old female patient in a good general condition (173 cm, 72 kg). Apart from multiple abdominal scars after five laparatomies, physical examination was without pathologic findings. There were no signs of hirsutism or acne: blood pressure without medication was 130/70 mm Hg. Routine laboratory tests (ESR, complete blood count, blood glucose, electrolytes, creatinine, BUN, transaminases, alka- line phosphatase, LDH, electrophoresis, coagu- lation analysis) showed normal values. The chest radiograph was normal as well, more specifically without signs of pulmonary metastases. Abdomi- nal CT revealed three metastases to the liver, the largest 3 cm in diameter (Fig. 1). Analysis of hor- monal parameters showed elevated levels for nearly all adrenal androgens and a postmenopausal con- stellation with elevated gonadotropins and low es- trogens (for details see Table 1).
Results
In November 1989, we started oral therapy with o,p’-DDD (mitotane) at a daily dosage of 1.5 g. This was gradually increased to 12 g mitotane per day over a 15 day period. Because of sickness, vo- miting and concomitant weight loss of 6 kg, the
dose was reduced to 9 g/d for one week, 6 g/d for one week, 4.5 g/d for 2 weeks and 3 g/d for 9 months. Since November 1990 (=35 months) the patient has been taking 1.5 g/d mitotane without reporting side effects or further weight loss. To off- set mitotane side effects substitution therapy with 15-10-5 mg hydrocortisone and 0.1 mg fludro- cortisone was used. As high dose or prolonged treatment with o,p’-DDD can increase the need of cortisol replacement the patient was carefully monitored for clinical or laboratory signs of cor- tisol deficiency (Table 2).
Table 2 shows the normalization or suppression of adrenal androgens; all elevated androgens re- turned to normal regardless of the daily dosage of mitotane. The metastases showed a marked re- gression on the first posttreatment CT in March 1990 and completely disappeared in June 1990 (Fig. 2). To date (September 1993) there has been nor further progress of the tumor. Apart from the dose dependent gastrointestinal side effects we ob- served only a moderate elevation of the gamma- glutamyl transferase activity (Table 2). Neither neurologic disturbances nor adrenal insufficiency did occur.
Discussion
Complete resection is the treatment of choice in adrenocortical carcinoma [Bodie et al., 1989, Hutter and Kayoe, 1966, Nader et al., 1983]. The 5-year survival rate of patients after total tumor removal is only 45% [Bodie et al., 1989, Grondal et al., 1990]. However, only approximately half of the patients are resectable by the time the diagnosis is made; the others have distant metastases or re- gional tumor spread is too extensive [Bodie et al., 1989, Hajjar et al., 1975, King and Lack, 1979, Nader et al., 1983]. The need of an effective sys- temic therapy is obvious.
As the tumor is extremely rare controlled studies on chemotherapy for adrenocortical carcinoma do not exist. There is anecdotic evidence of tumor re- gression under cisplatin, etoposide, doxorubicin or 5-fluorouracil [Chun et al., 1983, Johnson and Greco, 1986, Schlumberger et al., 1988, van Slooten et al., 1983, Tattersall et al., 1980].
The most extensively studied drug is mitotane which was introduced in the treatment of adreno- cortical carcinoma in 1960 by Bergenstal and co- workers. They reported a reduction of tumor size or urinary steroid excretion in 14 out of 18 patients. In multicenter studies Hutter [1966] and Lubitz [1973] demonstrated palliative effects of mi- totane. Compared to the 2.5 months survival per- iod for untreated patients reported by MacFarlane in 1958 the median survival improved to 7-170
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| 9/89 | 1/90 | 3/90 | 2/91 | 1/92 | 1/93 | 7/93 | ||
|---|---|---|---|---|---|---|---|---|
| Mitotane | g/d | 0 | 4.5 | 3 | 1.5 | 1.5 | 1.5 | 1.5 |
| Testosterone | ng/ml | 1.31 | 0.44 | 0.38 | 0.21 | 0.18 | 0.15 | 0.12 |
| DHEAS | ug/dl | 202 | 21 | 6 | <1 | <1 | 7 | 8 |
| 17 OH-progesterone | ng/ml | 5.8 | 0.46 | 1.61 | 0.49 | 0.42 | 0.28 | 0.37 |
| Androstendione | ng/ml | 2.5 | 1.54 | 0.49 | 0.1 | 0.1 | 0.1 | 0.1 |
| gamma-GT | U/1 | 20 | 69 | 128 | 85 | 51 | 65 | 44 |
| ACTH | pg/ml | 33 | 77 | 22 | 35 | 41 | 47 | 29 |
months. However, later studies failed to demon- strate an effect of mitotane on survival. Long term observation after tumor resection showed no dif- ference in survival periods whether patients were treated with mitotane or not [Hajjar et al., 1975]. Similar results with a 5-year survival both for patients with and without mitotane around 20% were reported by Bertagna et al., 1981 and Luton et al., 1990. Nevertheless, there have been several reports of prolonged remissions under mitotane
even by authors who found no statistically signifi- cant effect on survival [Becker and Schumacher, 1975, Bodie et al., 1989, Holl et al., 1983, Jarabak and Rice, 1981, Luton et al., 1990]. In one case the combination of 5-fluorouracil and mitotane even cured a 17 year old girl with lung and liver metast- ases after resection of an adrenocortical carcinoma (Ostuni and Roginski, 1975).
In our case, a left sided adrenocortical carci- noma was removed surgically but relapsed after 2.5 years. As a second radical resection was impossible the left adrenal region was irradiated. This success- fully controlled local tumor rests but failed to pre- vent metastatic spread. Solitary liver metastases were removed consecutively. Multiple liver metast- ases were successfully treated with moderate doses of mitotane and resulted in a complete remission that has now lasted for nearly four years. Gastroin- testinal side effects occured only under higher daily doses of mitotane and subsided with dose re- duction.
To date there is no parameter known to be pre- dictive of a positive response to mitotane in adre- nocorticol carcinoma. Although there is no proof of a statistically significant effect on survival, this report shows that the individual patient may ben- efit considerably from this therapy, thus encourag- ing the use of mitotane in not resectable adreno- cortical carcinoma.
Literature
Becker D, Schumacher OP: o,p’-DDD therapy in invas- ive adrenocortical carcinoma. Ann Intern Med 82: 677-679, 1975.
Bergenstal DM, Hertz R, Lipsett MB, Moy RH: Chemotherapy of adrenocortical cancer with o,p’- DDD. Ann Intern Med 53: 672-682, 1960
Bertagna C, Orth DN: Clinical and laboratory findings and results of therapy in 58 patients with adrenocor- tical tumors admitted to a single medical center (1951 to 1978). Am J Med 71: 855-875, 1981.
Bodie B, Novick AC, Pontes JE, Straffon RA, Montie JE, Babiak T, Sheeler L, Schumacher P: The Cleve- land clinic experience with adrenal cortical carcinoma. J Urol 141: 257-260, 1989.
Chun HG, Yagoda A, Kemeny N: Cisplatin for adrenal cortical carcinoma. Cancer Treat Rep 67: 513-514, 1983
Copeland PM: The incidentally discovered adrenal mass. Ann Intern Med 98: 940-945, 1983
Grondal S, Cedermark B, Eriksson B, Grimelius L, Har- ach R, Kristofferson A, Rastad J, Uden P, Akerstrom G: Adrenocortical carcinoma. A retrospective study of a rare tumor with a poor prognosis. Eur J Surg Oncol 16: 500-506, 1990
Hajjar RA, Hickey RC, Samaan NA: Adrenal cortical carcinoma. A study of 32 patients. Cancer 35: 549-554, 1975.
Holl WR, Fehm HL, Heymer B, Homoki J, Pfeiffer EF: Nebennierenrinden-Karzinom seit neun Jahren - heute beschwerdefrei. Klinikarzt 12: 336-339, 1983
Hutter AM, Kayhoe DE: Adrenal cortical carcinoma. Clinical features of 138 patients. Am J Med 41: 572-580, 1966.
Hutter AM, Kayhoe DE: Adrenal cortical carcinoma. Results of treatment with o,p’-DDD in 138 patients. Am J Med 41: 581-592, 1966
Jarabak J, Rice K: Metastatic adrenal cortical carci- noma. Prolonged regression with mitotane therapy. JAMA 246: 1706-1707, 1981
Johnson DH, Greco FA: Treatment of metastatic adre- nal cortical carcinoma with cisplatin and etoposide (VP-16). Cancer 58: 2198-2202, 1986
King DR, Lack EE: Adrenal cortical carcinoma. A clinical and pathologic study of 49 cases. Cancer 44: 239-244, 1979
Lubitz JA, Freeman L, Okun R: Mitotane use in inoper- able adrenal cortical carcinoma. JAMA 223: 1109-1112, 1973
Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, Laudat MH, Louvel A, Chapuis Y, Blondeau P, Bonnin A, Bricaire H: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 322: 1195-1201, 1990
Mac Farlane DA: Cancer of the adrenal cortex. Ann R Coll Surg Engl 23: 155-164, 1958
Nader S, Hickey RC, Sellin RV, Samaan NA: Adrenal cortical carcinoma. A study of 77 cases. Cancer 52: 707-711, 1983
Ostuni JA, Roginsky MS: Metastatic adrenal cortical carcinoma. Documented cure with combined chemo- therapy. Arch Intern Med 135: 1257-1258, 1975
Schlumberger M, Ostronoff M, Bellaiche M, Rougier P, Droz JP, Parmentier, C: 5-fluorouracil, doxorubicin, and cisplatin regimen in adrenal cortical carcinoma. Cancer 61: 1492-1494, 1988
van Slooten H, van Oosterom AT: CAP (Cyclophos- phamide, Doxorubicin, and Cisplatin) regimen in ad- renal cortical carcinoma. Cancer Treat Rep 67: 377-379, 1983
Tattersall MHN, Lander H, Bain B, Stocks AE, Woods RL, Fox RM, Byrne E, Trotten JR, Roos I: Cis-plati- num treatment of metastatic adrenal carcinoma. Med J Aust 1: 419-421, 1980
Author’s address: Dr. Elisabeth Kornely, Medizinische Klinik und Poliklinik, Abteilung für Endokrinologie und Rheumatologie, Heinrich Heine Universität Düssel- dorf, Postfach 10 10 07, D-40001 Düsseldorf, Tel. 0211/ 311 7810
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