Case Reports
Addison’s Disease Following Combined Chemotherapy for Hyperfunctioning Adrenocortical Carcinoma
MARTIN S. ROGINSKY, MD, AND MARTIN SCHICK, MD, EAST MEADOW, NY
CARCINOMA of the adrenal cortex is extremely malignant. The neoplastic and endocrine behavior of the tumor both de- termine the course of the disease in the patient.1 Success in producing a remission of both of these manifestations in a patient by use of a combination of chemothera- peutic agents, forms the basis of the present report. In addition, this is the first docu- mentation of Addison’s disease resulting from chemotherapy of a hyperfunctioning adrenal carcinoma.
Report of Case
A 17-year-old woman was first seen in Meadow- brook Hospital in December 1964 because of ab- dominal pain of several days duration. In May 1963 the patient had rapidly developed Cushing’s syndrome. At another hospital the diagnosis was confirmed by urinary steroid determinations. An intravenous pyelogram revealed a large mass above the left kidney but there was no evidence of metastases, and results of liver-function studies were normal. On June 19, 1963, an adrenocortical carcinoma weighing 1,520 gm was surgically re- moved. Postoperatively, cortisone and corticotropin (ACTH) injections were administered for several weeks. Over the ensuing months all clinical signs
Received for publication Sept 14, 1965; accepted Dec 7.
From the Department of Medicine, Meadowbrook Hospital, East Meadow, NY.
Reprint requests to PO Box 175, East Meadow, NY 11554 (Dr. Roginsky).
of the disease disappeared and the patient re- mained entirely well. In December 1964, when the patient was first seen at Meadowbrook Hos- pital, only a suggestion of return of Cushing’s syndrome was present, with mild hirsutism and a gain of 5 lb (2.3 kg).
The results of laboratory investigations were as follows: hemoglobin 11.0 gm/100 ml and a white blood cell count of 17,400/cu mm. Urinalysis showed bacteriuria and pyuria. The fasting blood sugar level was 138 mg/100 ml; blood urea nitro- gen, 7 mg/100 ml; serum sodium, 136 mEq/liter ; potassium, 4.7 mEq/liter; chlorides, 100 mEq/ liter; and serum bicarbonate, 24 mEq/liter. The alkaline phosphatase value was 4.5 King-Arm- strong units. Biochemical confirmation of in- creased production of adrenocortical steroids was made (Table). The 24-hour urinary excretion of 17-ketosteroids was 22 mg and of 17-ketogenic steroids, 45 mg. The daily cortical production rate was 82.5 mg (normal 10 to 20 mg). The plasma cortisol level was high (26.5ug/100 ml) and a four-hour infusion of 25 units of cortico- tropin produced a moderate rise to 51.9ug/100 ml. Dexamethasone (2 mg/day for two days) had no suppressive effect on the urinary steroids. The chest x-ray film showed at least two distinctly outlined rounded densities in the lung fields (Fig 1, left). A liver scan with rose bengal I 125 re- vealed several concentric areas of inactivity in- terpreted as metastatic lesions (Fig 2, left). An intravenous pyelogram showed that the right kid- ney was displaced downward by a large suprarenal mass (Fig 3, left).
In January 1965, chemotherapy was instituted with op’-dichlorodiphenyl dichloroethane (op’-
Arch Intern Med-Vol 117, May 1966
DDD) daily and fluorouracil intermittently every three to four weeks. At this time the features of Cushing’s syndrome were manifest and an abdominal mass, thought to be liver metastasis and extending 5 cm below the right costal margin, was easily palpable. The first three months of treatment did not result in any hormonal or clinical improvement. In April 1965 (the fourth month of treatment) dramatic clinical response and tumor regression occurred (Fig 1, right, 2, right, and 3, right). Following the fifth course of fluorouracil, in May 1965, severe weakness, nausea, vomiting, and emotional depression developed. These symptoms were first attributed to drug toxicity but the development of hyponatremia and hyperkalemia suggested hypocortisolism. The
clinical response to the administration of corti- costeroids was dramatic. When the patient’s clinical status had stabilized confirmation of the diagnosis of Addison’s disease was made by the absence of any detectable urinary 17-ketogenic steroids, and by the failure of the adrenal to re- spond to exogenous corticotropin (Table). A cortisol production rate could not be calculated because of the inability to detect by paper chromatography any metabolites of cortisol in the hydrolyzed urine. Bledsoe et alª recently de- scribed an effect of op’-DDD on cortisol metabolism resulting in excretion of appreciable quantities of 6-ß-hydroxycortisol. This may have contributed to the diminished urinary steroid values in this patient since the procedure for urinary steroid determination does not efficiently extract this polar
| Date | 17 Ketosteroids (Mg/24 Hr) | 17 Ketogenic Steroids (Mg/24 Hr) | Plasma 17, 21-dihydroxy- 20-ketosteroids (ug/100 Ml) | Cortisol Secretion Rate (Mg/24 Hr) | Serum Electrolytes Na K | (mEq/Liter) CI CO2 | |||
|---|---|---|---|---|---|---|---|---|---|
| Before | After | ||||||||
| Dec 1964 | 22.0 | 50.4 | 26.5 | 51.9 | 82.5 | 138 | 4.3 | 98 | 27 |
| Dec 1964 | 29.8 * | 45.5 * | |||||||
| Jan 1965 | 35.0 | 65.3 | 140 | 4.3 | 102 | 25 | |||
| Feb 1965 | 30.5 | 76.5 | 43.0 | 132 | 4.5 | 102 | 20 | ||
| March 1965 | 22.0 | 80.5 | 41.0 | 140 | 4.2 | 100 | 27 | ||
| April 1965 | 4.5 | 0.0 | 129 | 5.1 | 96 | 19 | |||
| May 3, 1965 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 + | 110 | 6.8 | 86 | 13 |
| May 10, 1965 | 0.3 | 16.5 + | 137 | 4.6 | 101 | 20 | |||
| August 1965 | 0.0 | 0.0 § | 140 | 4.4 | 99 | 22 | |||
* The 24-hour urinary excretion following administration of dexamethasone 2 mg/day for 2 days.
t There was no detectable tetrahydrocortisone or tetrahydrohydrocortisone detectable on the paper chromatogram with tetra- zolium blue reagent.
# The patient was receiving 20 mg of prednisone during this urinary collection period. § The patient was receiving 1.5 mg of dexamethasone during this urinary collection period. Arch Intern Med-Vol 117, May 1966
metabolite. However, the plasma cortisol determi- nation and the production rate study would re- main essentially unaffected.
A total of 469 gm of op’-DDD and 22.4 gm of fluorouracil was administered. Since April 1965 no chemotherapy has been given, At the present time there is no evidence of the malig- nancy both functionally and morphologically. She is being maintained on a regimen of 10 mg prednisone and 0.1 mg fludrocortisone acetate (Florinef Acetate).
Comment
In 1960 Nelson and Woodward,3 demon- strated in dogs selective destruction of the adrenal cortex as a result of prolonged ad- ministration of DDD. Subsequently, op’- DDD was identified as the adrenolytic agent.4 The mechanism for this effect has never clearly been understood, although studies by Fennigan on the tissue distribu- tion of this agent suggests that the affinity for the adrenal cortex is due to the drug’s marked lipid solubility.4 Animal studies have also demonstrated an inhibitory effect on glucocorticoid production by op’-DDD.6 Studies on humans have been inconclusive. Zimmerman et al,7 reporting on ten patients, found no affect on steroidogenesis and no adrenal necrosis. On the other hand, reports from The National Institutes of Health 8,9 have demonstrated regression of metastases and profound histologic damage to the car-
Arch Intern Med-Vol 117, May 1966
cinoma and even on normal human adrenal cortical tissue. All reports unfortunately have emphasized the often intolerable side effects of this drug which have seriously hampered therapeutic efforts. The major toxicities reported have included gastrointes- tinal reactions, skin rashes, central depres- sion, and muscular tremors.
Fluorouracil, a pyrimidine analog which interferes with the synthesis of nucleic acid, has demonstrated oncolytic activity in a wide variety of neoplasms, including carci- noma of the breast, colon, stomach, cervix, and ovary.10 Effectiveness in adrenal car- cinoma has not been reported but the prim- itive cytology and rapid growth of this malignancy suggested its application. An- other possible mechanism for the action of fluorouracil is furnished by a report of the effect of this agent in blocking adrenal response to corticotropin.11 That this may be significant is suggested in the present case by the apparent stimulatory effect of corticotropin on the tumor.12 In addition, the enhanced therapeutic effect of a combi- nation of drugs, each at a lower dose, is a desirable goal.13
Recently another compound (7-12-di- methylbenzanthracene) has been found to
have a selective destructive effect on the adrenal cortex. Clinical application has not yet been described but this drug may also prove to be an effective agent in the treat- ment of adrenocortical carcinoma.
Summary
A patient with disseminated carcinoma of the adrenal cortex was treated with a com- bination of op’-dichlorodiphenyl dichloro- ethane (op’ DDD) and fluorouacil. This is the first case in which chemotherapy has been shown to cause both tumor regression and complete inhibition of hormonal pro- duction. Our experience suggest that com- bined chemotherapy may be more effective than a single agent in the treatment of this disease.
Generic and Trade Names of Drugs
Cortisone acetate-Cortogen Acetate, Cortone Acetate.
Corticotropin-Acthar, Actrope, Solacthyl, El- Acorto, Cortrophin.
Dexamethasone-Decadron, Deronil, Gamma- corten, Hexadrol, Dexameth.
Rose Bengal I 125-Radio-Rose-Bengal-I-125, Robengatrope.
Fludrocortisone-Alflorone Acetate, F Cortef Acetate.
Fluorouracil-Stoxil, Herplex, Dendrid. Prednisone-Deltasone, Deltra, Meticorten, Paracort, Cotone, Lisacort, Metasone.
REFERENCES
1. Lipsett, M.B .; Hertz, R .; and Ross, G.T .: Clin- ical and Pathophysiologic Aspects of Adrenocortical Carcinoma, Amer J Med 35:374-382, 1963.
2. Bledsoe, T, et al: An Effect of OP’ DDD on the Extra-Adrenal Metabolism of Cortisol in Man, J Clin Endocr 24:1303-1309, 1964.
3. Nelson, A., and Woodward, G .: Severe Adrenal Cortical Atrophy and Hepatic Damage Produced in Dogs by Feeding 2,2 Bis- (parachlorophenyl) - 1,1 Dichloroethane, Arch Path 48:387-393, 1949.
4. Nichols, J., and Hennigan, G.R .: Studies on DDD, 2,2 Bis- (parachlorophenyl)-1,1 Dichloro- ethane, Exp Med Surg 15:310-315, 1957.
5. Fennigan, J.R .; Hang, H.B .; and Larson, P.S .: Tissue Distribution and Elimination of DDD and DDT Following Oral Administration to Dogs and Rats, Proc Soc Exper Biol Med 72:357-360, 1949.
6. Villar, O., and Tullner, W.W .: Effects of OP’ DDD in Histology and 17-Hydroxycorticosteroid Output of the Dog Adrenal Cortex, Endocrinology 65:80-86, 1959.
7. Zimmerman, R., et al: The Effect of DDD on the Human Adrenal, Cancer 9:940-946, 1965.
8. Bergenstal, D.M., et al: Chemotherapy of Ad- renocortical Cancer With OP’ DDD, Ann Intern Med 53:672-682, 1960.
9. Hertz, R .: “Pharmacological Alteration of Ad- renal Function and Neoplasia in Man,” in Currie, A. R. (ed.) : Human Cortex, London : E & S. Living- stone Ltd., 1962, pp 469-473.
10. Ansfield, F.J .; Schroder, J.M .; and Curreri, A.R .: Five Years Experience With 5-Fluorouracil, JAMA 181:295-299, 1962.
11. Staehelin, M .: Action of Puromycin and 5 FU on the Adrenal Responsiveness to ACTH, Ex- perimentia 21:229-234, 1965.
12. Martin, F.I.R .: Evidence of a Hormonal In- fluence on the Steroid Output of Adrenal Carci- noma, Amer J Med 32:795-798, 1962.
13. Li, Min C., et al: Effects of Combined Drug Therapy in Metastatic Cancer of Testes, JAMA 174:1291-1299, 1960.
14. Huggins, C., and Morii, S .: Selective Adrenal Necrosis Induced by 7. 12-Dimethylbenzanthracene, J Exp Med 114:714-747, 1961.