Is There a Role for Low Doses of Mitotane (o,p’-DDD) as Adjuvant Therapy in Adrenocortical Carcinoma?
GABRIEL DICKSTEIN, CARMELA SHECHNER, ELDAD ARAD, LAEL-ANSON BEST, AND OFER NATIV
Division of Endocrinology (G.D., C.S., E.A.) and Department of Urology (O.N.), Bnai Zion Medical Center, Haifa, Israel, and Department of Chest Surgery, Rambam Medical Center (L .- A. B.), Haifa, Israel
ABSTRACT
Four patients suffering from adrenocortical carcinoma were treated with low doses (1.5-2.0 g) of mitotane (o,p’-DDD) for the complete follow-up time following surgery (21-68 months). Treat- ment with mitotane was started shortly after surgical removal of the tumor (three patients) or the tumor and multiple lung metastasis (one patient). No significant side effects or complications from the medi- cation were noted. Two patients remain disease free after 57 and 21 months on treatment. A third patient died of an unrelated reason (varicose vein bleeding) after 68 months on mitotane without evidence
of tumor recurrence or metastasis. In the fourth patient, two lung metastasis were successfully removed after 48 months of follow-up. The patient is doing well and is disease free 6 months later. Though our series is too small to draw final conclusions, we suggest that low doses of mitotane, which are well tolerated, might offer prolonged disease-free survival in adrenocortical carcinoma. To be beneficial treatment has to be started early after surgical removal of the tumor and metastasis, and be continued for long periods of time. (J Clin Endocrinol Metab 83: 3100-3103, 1998)
A DRENOCORTICAL carcinoma is a rare tumor that gen- erally carries a poor prognosis (1). The differentiation between adrenocortical adenoma and carcinoma is difficult in the absence of metastasis (2). It is widely accepted that adrenal tumors larger than 5.0 cm in diameter should be resected surgically. Recent studies suggest that tumor size is a reliable preoperative indicator of adrenal adenoma vs. ad- renocortical carcinoma (3). The above-mentioned cutoff size had a sensitivity of 93% and specificity of 64% in separating between benign and malignant adrenocortical lesions (4).
It is also accepted that radical excision with en bloc resec- tion of any local invasion offers the best chance for cure, and prolongs life significantly (5). Little is, however, agreed on about other means of treatment to improve survival and cure in this grave disease. The most accepted chemotherapic agent used is o,p’-DDD (mitotane), a specific adrenolytic agent (6). Its common mode of use is in high doses of 6-10 g/day, which cause severe side effects, and besides some encour- aging results, there are many disappointing ones. These are well summarized in a review article by Barzilai and Pazianos (7).
There are suggestions in the literature that administering much lower, well-tolerated doses of o,p’-DDD, as adjuvant treatment to surgery after the primary tumor and metastasis were resected, may offer much greater advantages regarding survival and remission (8, 9). We treated four patients with adrenocortical carcinoma this way, and herein report our results, adding some information about this challenging disease.
Patients and Treatments
Low-dose adjuvant treatment with mitotane in adrenocortical carci- noma was approved by the hospital ethics board, and informed consent form was obtained from all participants.
Patient 1
A 57-yr-old woman was evaluated in another hospital for severe new-onset hirsutism. Elevated levels of testosterone were found (6.5 nmol/L; normal, <5.0), and on abdominal computerized tomography (CT) scan a left adrenal tumor of 8.0 cm in size was demonstrated. The tumor was resected and was described as a benign adrenal adenoma, because it demonstrated no features suggestive of malignancy. One year later, hirsutism recurred. The patient was reevaluated by us. Elevated testosterone levels were found (7.8 nmol/L). On CT scan was found a recurrence of the left adrenal tumor, and multiple lung lesions were found. In two surgical procedures an adrenal tumor of 7.0 cm in size and 13 lung metastases were removed from both lungs. The histology of the tumors resected from both lungs was consistent with adrenocortical carcinoma. Repeated CT scan (3 months later) showed no evidence of residual tumor tissue. Testosterone levels returned to normal (2.0-2.5 nmol/L), as did dehydroepiandrosterone sulfate levels (0.2-0.3 pmol/ L). The patient was put on o,p’-DDD treatment of up to 5.0 g, which she could not tolerate because of nausea and weakness. Within 2 months the dose was tapered down to 1.5 g, and she remained on this dose, which was well tolerated, for 48 months. Her follow-up included testosterone and cortisol measurements, as well as liver function tests and complete blood counts. CT scans were repeated every 6 months. All these tests were negative for 4 yr. After that time, a repeat CT showed two lesions in the left lung. These were resected and were found to be consistent with adrenocortical carcinoma. Three months later a repeat chest CT was normal (Fig. 1B) and has remained so after 6 months.
Patient 2
A 67-yr-old man was evaluated for microhematuria and weight loss of 5 kg in 2 months. On CT scan a left adrenal tumor of about 12 cm in size was demonstrated. Urinary free cortisol level was elevated to 253 ug/24 h. No further endocrine evaluation was done before resection of the tumor. On surgery, the tumor was found to be very friable and ruptured in situ, spilling a large quantity of fluid. The tumor was found to be an adrenal tumor, 9.0 × 9.0 cm in size (Fig. 2). In two places the
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surface was cut, and it seemed that much of the internal contents was lacking. The tumor weighed 190 g (without the fluid spilled on surgery). It showed invasion of anaplastic cells with significant pleomorphism. Many cells had multiple nuclei with bizarre shapes. There were areas of bleeding in the tumor. The fibrotic capsule included hemosiderine pig- ment. The tumor’s capsule was invaded by tumor cells. There was a large number of mitosis, partially pathological.
The patient was put on mitotane, 2.0 g/day, and the dose was reduced after 1 yr to 1.5 g/day. He tolerated this dose well, with no side effects. Repeat CT scans every 6 months showed no recurrence of tumor and no metastases. After approximately 1 year of treatment, cortisol levels dropped and signs of hypoadrenalism developed. He was put on 0.5 mg of dexamethasone and did well. After 68 months of follow-up, the patient developed severe hematemesis and died of rupture of esopha- geal varicose veins secondary to chronic active hepatitis, from which he
was known to suffer. There was no evidence of adrenal tumor recurrence when he died based on chest and abdominal CT scans done about a month before to the esophageal bleeding.
Patient 3
A 29-yr-old man was found to have a right adrenal tumor on CT scan performed as part of workup for abdominal pain, diarrhea, and weight loss of 6 kg in 3 months. The tumor was resected and found to be 11.0 x 8.0 × 6.0 cm in size and weighed 320 g (Fig. 3). The tumor cells showed pleomorphism and anaplsticity (grade 3-4). About one third of the tumor grew in a diffuse manner without any organization.
The patient was put on mitotane 1.5 g/day and has now been fol- lowed for 57 months. No recurrence of tumor or development of me- tastasis was noted. The only side effect he suffers is the development of
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bilateral gynecomastia. Of interest may be the fact that while on o,p’- DDD treatment, his wife conceived and delivered a normal baby, which is now 9 months old.
Patient 4
A 45-yr-old woman was evaluated for new-onset hirsutism. Elevated testosterone levels (8.2 nmol/L) were found, whereas dehydroepiandro- sterone sulfate was in the normal range (9.7 umol/L). On CT a large right adrenal tumor was demonstrated. The tumor was resected and found to be 7.5 × 5.0 × 4.0 cm in size. It weighed 53 g. Some tumor zones were composed of large cells with eosinophilic cytoplasm and large hyper- chromatic nuclei separated by fibrovascular septa. Occasional mitotic divisions were seen, as was focal tumor necrosis. There was evidence of focal vascular and capsular invasion. In one place, the tumor was not totally resected.
The patient was put on o,p’-DDD 1.5 g/day, a dose that she tolerates well. Testosterone levels dropped post surgery to normal, and remained so since (0.5-0.7 nmol/L). Cortisol levels became low on o,p’-DDD treatment, and replacement therapy with dexamethasone was started. The patient is doing well with no side effects, complications, recurrence of the tumor, or development of metastases for the past 21 months.
Results and Discussion
We present herein the results of adjuvant treatment with low doses of o,p’-DDD in four patients suffering from ad- renocortical carcinoma, after resection of the primary tumor in three, and of the primary tumor and multiple lung me- tastasis in the fourth. None of the patients who had stage 2 carcinoma (tumors >5.0 cm in diameter, confined to the adrenal gland) (5) developed local recurrence or distant me- tastasis in a follow-up period of 18-68 months. The patient who had multiple lung metastasis had two more lung le-
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sions, which were successfully resected, 48 months after ini- tiating o,p’-DDD therapy.
One may question the diagnosis of adrenal carcinoma in our patients. This diagnosis is indeed difficult to make, and the literature on this subject is controversial. It is well known that histology may be misleading. A recent review (5) summarized the histological features suggestive of carcinoma. Among these are frequent mitoses (patient 2), marked cellular pleomorphism (patients 2 and 3), nuclear atypia (patient 2), and invasion of the capsule (patients 2 and 4) or vascular invasion (patient 4). Using the criteria for size as predictor of malignancy in adrenocortical tumors, our patients fulfill the criterion of tumors larger than 5 cm and of volume greater than 200 cm3 (2). Patients 1 and 4 had virilizing-only tumors without clinical or biological Cushing’s syndrome. This feature was found in the widely quoted study by Bertaga and Orth (1) to be relatively common in adreno- cortical carcinoma (7 out of 32 patients or 22%) but very un- common in adrenocortical adenoma (1 out of 26 patients or 4%).
Patient 1 exhibited a very unusual course. Despite multiple lung metastasis, she experienced 4 yr of remission. It is our belief that the combination of careful removal of all tumorous lesions together with prophylactic use of low doses of o,p’- DDD allowed this long remission period. After recurrence of the two lung lesions, which were successfully and unevent- fully removed, the o,p’-DDD dose was raised to 3.0 g, and thus far no recurrences were observed. We were able to find one similar case in the literature (10). That patient started out with an even worse situation (the primary tumor being much more widespread), but did well on a combination of repeated surgeries and 3.0 g of o,p’-DDD. In that case the authors contributed the success to the repeated surgical procedures, and, in our view, underscored the possible effect of the ad- juvant medical treatment.
The role of mitotane in treatment of adrenocortical carci- noma is controversial (1, 5-8). Besides the problem of diag-
| Patient no. | Age, Sex | Clinical presentation | Tumor size | Tumor stage | Mitotane dose (g) | Survival time (mo) |
|---|---|---|---|---|---|---|
| 1 | 57, F | Virilization | 7.0 times 7.0 | T4N0M1 | 1.5-3.0ª | >54 |
| 2 | 67, M | Hematuria, wt. loss | 9.0 times 9.0 | T2N0M0 | 1.5-2.0 | 68 |
| 3 | 29, M | Abdominal pain, wt. loss | 11.0 times 8.0 | T2N0M0 | 1.5 | >57 |
| 4 | 45, F | Hirsutism | 7.5 times 5.0 | T2N0M0 | 1.5 | 21 |
” For first 2 months up to 5.0 g.
nosing adrenal carcinoma and separating it from adenoma, there is also a lack of controlled studies. In most cases mi- totane was added in high doses, at different stages of the disease, with or without tumor removal. Schtiengart et al. (8) were the first to suggest the beneficial effects of low doses of mitotane given immediately after tumor resection. Their re- sults were also supported by a later study (9). One study that may suggest a clear benefit from use of adjuvant treatment with mitotane appeared recently (11). It showed that out of 26 patients who were treated with surgery + mitotane, the survival rate was 46% (12 patients), whereas in those who only were operated on, only 28% survived. In the group that received mitotane adjuvantly, 13 were started immediately post operatively, whereas in 13 the treatment was delayed for 3-15 months. Comparing these two groups, survival rate in the first was 10 out of 13 (77%), whereas in the second it was only 2 out of 13 (15%). These data strongly suggest that there is a positive role for treatment with low doses of mitotane only when started shortly after tumor resection. Schtiengart et al. (8) data showed that patients who received mitotane as adjuvant therapy before evidence of metastases was noted, and in those who were treated with mitotane and underwent subsequent surgery for recurrent tumor, had a significantly longer survival (74 + 33 months) than those who got no mitotane treatment (10.3 ± 8.7 months). Other studies con- cerning this subject are in process (2).
The number of patients we present is too small to draw final conclusions. However, the results are very encouraging and suggest the importance of further study into this matter. Thus far there is no better mode of treatment other than surgery only to offer to patients. Mitotane in doses of 1.5-3.0 g causes very little and well-tolerated side effects (some nausea and dizziness) without any complications. There is a need for cortisol and, later on, mineralocorticoid replacement therapy. The fact that three of our patients (grade 2) show no tumor recurrence after 68, 54, and 18 months of treatment, and one (grade 4) patient developed treatable recurrence at
48 months, strongly suggests a positive role of mitotane under these circumstances.
Despite the limitations mentioned above, we feel that low- dose mitotane treatment adjuvantly to surgical resection of- fers clear benefits in an otherwise grave disease. Unlike what is typically employed, mitotane treatment has to be started very shortly after surgery, and be continued for a very long time; how long is as yet undetermined. These low doses of mitotane are well tolerated and do not influence patients’ daily routine. This in contrast to the high doses needed, with very limited effect if treatment is started only when the tumor recurs. Further studies are needed to define the exact positive role of this mode of treatment.
References
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