CASE REPORT
Sustained remission of metastatic adrenal carcinoma during long-term administration of low-dose mitotane
I. Ilias, M. Alevizaki, G. Philippou, E. Anastasiou, and A. Souvatzoglou First Endocrine Section, “Alexandra” University Hospital, Athens, Greece
ABSTRACT. We present our experience with two female patients suffering from metastatic, recur- rent adrenocortical carcinomas, to whom o,p’-DDD (mitotane) was administered for unusually long du- ration. The first patient received mitotane as mono- therapy after relapse (in doses ranging from 3 to 6 g/day initially and 1 g/day thereafter, for 13 yr). The second patient presented with metastatic dis- ease and underwent radical surgical excision of the adrenal. Mitotane was administered initially at 2.5 g/day, and the dose was gradually lowered over 8 yr to 1 g/day, without interruption. Both patients tolerated the medication well, regardless of the daily dosage, with complaints limited to epigastric
INTRODUCTION
Reports in the past have shown a beneficial effect of high-dose o,p’-DDD (mitotane) administration (6-10 g/day) in patients with inoperable adrenal carcino- mas (1-4). A recent report of four cases has also sug- gested the beneficial effect of even low doses (1.5-2 g/day) (5). Although mitotane has been in clinical use for almost 40 yr (3), there is still no consensus as to its role as main or adjuvant treatment for adrenocor- tical carcinomas, either diagnosed for the first time or after relapse; recent reports have shown no long- term benefit in patients who had been administered mitotane for such carcinomas (6-8). On the other hand, no consensus exists for the optimal duration of administration of this medication. In the cases pre- sented in the literature, mitotane has been adminis- tered for a maximum duration of approximately 10
pain and nausea, while their disease has been kept under control for 14 and 16 yr, respectively. The blockade of steroid synthesis with mitotane re- sulted in hypercholesterolemia in both patients and in premature menopause in the second patient; however, these abnormalities were taken care of with the appropriate therapy. The excellent fol- low-up of these patients suggests that even in hopeless cases with metastatic adrenocortical car- cinoma, mitotane should be administered for very long periods of time as it can be well-tolerated and may be beneficial in the long run.
(J. Endocrinol. Invest. 24: 532-535, 2001) @2001, Editrice Kurtis
yr. We would like to add our experience with two pa- tients who were administered mitotane for a longer period with satisfactory results.
CASE 1
A 39-yr-old woman presented to another hospital with weakness in the extremities; during the pre- ceding 2 yr she had also observed signs of viriliza- tion, such as hirsutism. Past medical history includ- ed 3 cesarian sections. Physical examination was suggestive of Cushing’s syndrome. Morning cortisol levels were 694 nmol/l (normal values: 118-618 nmol/l) and did not decrease after the overnight administration of 1-mg dexamethasone. Further di- agnostic work-up showed serum DHEAS levels at 30.9 mol/l (normal values: 0.95-11.7 umol/l), while cortisol levels showed no daily variations with a me- dian level of 744 nmol/l. Computed tomography (CT) of the abdomen showed a large mass over the left kidney with a maximum diameter of approxi- mately 8 cm (Fig. 1). A left adrenalectomy was per- formed and a large adrenal mass (9x8x6 cm) was removed. Histology showed capsular invasion, nu- clear polymorphisms and vascular invasion, features diagnostic of an adrenal carcinoma, originating
Key-words: Adrenal cortex neoplasms, adult, human, mitotane, metasta- sis, recurrence.
Correspondence: Dr. I. Ilias, c/o Dr. A. Souvatzoglou, First Endocrine Section, “Alexandra” University Hospital, 80 Vassilisis Sofias Avenue, GR-11528 Athens, Greece
E-mail: ilias@compulink.gr
Accepted January 5, 2001.
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from the adrenal cortex. No local or distant metas- tases were found either before, during or after the operation, following which Cushing’s syndrome re- gressed. The patient received no further treatment and for the following 2 yr she was symptom-free. After these 2 yr her symptoms recurred and she was admitted to our hospital. A recurrence of the dis- ease was established: both low- and high-dose dex- amethasone suppresion tests were positive and a CT of the abdomen showed multiple nodules (1 to 4.5 cm) in the left suprarenal region (Fig. 2). A local recurrence was diagnosed, since no distant hepat- ic or other metastases were found. Treatment with mitotane was started at 4 g/day and this was sub- sequently increased to 6 g/day. Although the pa-
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tient initially complained of gastrointestinal symp- toms (epigastric discomfort and nausea), she grad- ually improved and the clinical signs of Cushing’s syndrome disappeared. One month later hydro- cortisone and mineralocorticoid replacement were added. One year later a new CT of the abdomen showed regression of the neoplastic masses except for a small residual nodule. The mitotane daily dose was lowered to 3 g/day and gradually after two years to 1 g/day, which was maintained up to 14 years after the initiation of treatment. During this period repeated hormonal and imaging diagnostic work-ups did not disclose any relapses (Fig. 3). It is of interest to note that five years after the initiation of treatment hypercholesterolemia and hyper- triglyceridemia ensued and necessitated the ad- ministration of statins. Recently she moved to an- other country and was lost to follow-up.
CASE 2
A 24-yr-old woman was admitted to our hospital for the evaluation of elevated blood pressure (220 over 150 mmHg), discovered during an episode of left renal colic in the 6 preceding months. More- over, she complained of amenorrhea which had been lasting for one year. One year earlier she had undergone a subtotal thyroidectomy for a benign functioning thyroid nodule. Physical examination was unremarkable. The diagnostic work-up disclo- sed elevated testosterone (16 nmol/l, normal val-
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ues: 0.48-2.64 nmol/l) and basal cortisol (1283 nmol/l) levels, plus elevated and unsuppressable cortisol levels either with 2 or 8 mg of dexametha- sone per 6 h for 48 h (1145 and 1237 nmol/l, re- spectively). The abdominal CT indicated the pres- ence of a tumor in the left adrenal, with hepatic metastases and possible infiltration of the spleen and the pancreatic tail. She was operated prompt- ly and a tumor, with a diameter of 19 cm, wedged between a normal left adrenal remnant and the kid- ney was excised and removed, as well as the spleen and the pancreatic tail. The tumor weighed 1400 g and on histologic examination an adrenal carcino- ma with capsular and vascular infiltration was diag- nosed. The spleen and pancreatic tail were free of disease. The patient received adjuvant chemother- apy with cisplatin and dexamethasone. The menses appeared again shortly after the cessation of che- motherapy. Replacement therapy with fludrocorti- sone and hydrocortisone was initiated. One year after the operation an abdominal CT disclosed mul- tiple lesions (0.5-2cm) in the right hepatic lobe, im- plying metastatic disease. Mitotane was started at 2.5 g/day. The patient complained of slight epi- gastric pain. Mitotane treatment was continued and on yearly abdominal CT scans the hepatic lesions gradually regressed. The mitotane dose was re- duced to 1.5 g/day after 4 yr and to 1 g/day after another 4 yr. Seven years after the initiation of mi- totane treatment hypercholesterolemia ensued, ac- companied by menopause. These conditions ne- cessitated the administration of a statin and of hor- mone replacement, respectively. The patient has received mitotane for 16 yr and her disease has not relapsed. She is still under replacement therapy with hydrocortisone and fludrocortisone. There are no signs of virilization or hypercortisolemia and her liver biochemistry is normal.
DISCUSSION
Adrenocortical carcinomas are uncommon neo- plasms, presenting in most cases with Cushing’s syndrome and/or virilizing features, with a rather ominous prognosis (6). Surgery is the treatment of choice, with adjuvant mitotane chemotherapy re- served for residual and unresectable tumors (7). In the two cases presented here mitotane was effica- cious in slowing/stopping regression of the disease, despite the fact that it was administered 2 yr and 1 yr after surgery, respectively. Recently it has been proposed that low-dose mitotane should be ad- ministered immediately after surgery for adreno- cortical carcinoma (5, 7). There are reports show- ing remission of metastatic adrenocortical carcino-
mas with continuous administration of mitotane for many years (9). A beneficial long-lasting effect of mitotane on such metastases has been document- ed in few subjects, where adrenocortical neoplasms did not relapse even after discontinuation of mi- totane for 2 years (10).
The effectiveness of treatment with mitotane has recently come under scrutiny because of the dis- appointing long term survival results reported in some of the largest studies, despite a beneficial ef- fect on the control of endocrine abnormalities and symptoms (6, 8, 11-13). Moreover, disturbances in lipid metabolism caused by mitotane can be pro- found (6) and, if untreated can lead to vascular com- plications.
In our two cases both patients tolerated their med- ication well, regardless of the daily dosage, with complaints limited to epigastric pain and nausea, while their disease was kept under control for 14 and 16 yr each. The blockade of steroid synthesis by mitotane resulted in hypercholesterolemia in both patients and in premature menopause in the second patient, however, these abnormalities were taken care of with the appropriate therapy.
Based on the results of these two cases, we may suggest that in otherwise hopeless cases, given no other choice of available therapy, this medication (both at high and low doses) can be well-tolerated for very long duration and may be beneficial to the patients.
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