Therapy of Adrenocortical Cancer with o,p’ DDD in Two Children
To the Editor: Several reports of the use of ortho para prime DDD’ in therapy of adrenocortical cancer have followed the early report in 1959 by Bergenstal et al. (1) that this agent had therapeutic po- tential in patients with metastatic ad- renocortical carcinoma. The present report adds two children to the four treated with this agent reported by Bergenstal et al. (2, 3).
Case 1-EC-UAMC #17 66 50
This white female child entered the Uni- versity of Arkansas Medical Center at the age of 29 months with the complaints of the appearance of pubic hair and enlarging genitalia over a 1-year period. She was the second of 2 siblings, the product of a normal pregnancy and delivery. Birth weight was 6 lb 2} oz. She appeared normal at birth and developed normally during the first 18 months of life. At 18 months of age hirsutism and pubic hair were noted by the parents. These symptoms progressed over the next 12 months, at the end of which time a physician was consulted and the child was referred to the University of Arkansas Medical Center.
Physical Examination. Height and weight were at the 50th percentile. The clitoris was 4 cm in length and there was marked pubic hair growth. A large mass difficult to dis- tinguish from liver was palpable 5 cm below the lateral right costal margin. Twenty-four hr 17-ketosteroid excretion on 2 occasions measured 27.6 and 61 mg. Urinary preg- nanetriol was not elevated. Buccal smear was positive. Gynogram revealed a normal
· Received August 25, 1962.
1 2,2-Bis (2-chlorophenyl-4 chlorophenyl)-1,1 dichloroethane. The o,p’ DDD was obtained through the courtesy of the Endocrinology Branch of the Cancer Chemotherapy National Service Center of the National Institutes of Health.
vagina and uterus. IVP revealed a mass dis- placing the right kidney inferiorly. Chest film was normal.
Operation was performed on the 16th hospital day. An encapsulated tumor 10 cm in diameter was removed without difficulty. There was no evidence of metastasis. The pa- tient was supported with Solu-Cortef for several days postoperatively.
The tumor was diagnosed as an adrenal adenocarcinoma on the basis of histologic evidence of capsular invasion. Twenty-four hr 17-ketosteroid excretion 6 days post- operatively was 12 mg. The patient was dis- charged without further therapy on the 23rd hospital day. Two months later, 24-hr 17-ketosteroid excretion was 1 mg.
The patient did well without evidence of metastases until 8 months postoperatively, when renewed growth of pubic hair was noted. Chest films at that time revealed 2 large, nodular pulmonary metastases. A 4×5} cm nodular mass was visible in the superior segment of the right lower lobe. In addition, a 1} X22 cm left paratracheal node was visible above the left hilus. A firm 6 ×6 cm mass was again palpable in the RUQ. Twenty-four hr 17-ketosteroid excretion was now 53 mg. There was a marked estrogen effect by vaginal smear. Bone age was read as 4 years by the standards of Gruelich and Pyle (CA 3 1/12 yr). Again the IVP re- vealed lateral and downward displacement of the right kidney by a presumably extrinsic mass.
The child was begun on 4 g ortho para’ DDD daily 9 months after her surgery and remained on 23-4 g for 151 days. Total dose was 519.5 g, as follows:
| Daily dose | Duration |
|---|---|
| 4 g | 10 days |
| 2} g | 20 days 44 days |
| 3 g | 21 days |
| 3} g | 56 days |
| 4 g |
Urinary 17-hydroxy and 17-ketosteroid values were:
Duration of Rx 17-OH Steroid 17-Ketosteroid
| mg/24 hr | mg/24 hr | |
|---|---|---|
| Before therapy | 2.6 | 53 |
| 7 days | 1.2 | 28.6 |
| 35 days | 0.4 | 8.3 |
| 44 days | 0.9 | 10.6 |
| 56 days | 4.5 | |
| 64 days | 13.8 | |
| 105 days | 19.4 |
A water-loading test was normal on the 45th day. No signs of adrenocortical de- ficiency appeared at any time. On the 105th day a 4-hr plasma 17-hydroxysteroid re- sponse to 40 units ACTH2 revealed:
Plasma cortisol3 before ACTH 18 µg/100 ml 29 µg/100 ml
After 4 hr of ACTH infusion
By 30 days of therapy a definite decrease was observed in the size of the pulmonary
metastases. By 79 days these lesions had al- most entirely disappeared. By 97 days of therapy, however, the pulmonary metastases were again observed to be increasing in size and new lesions were visible in the right middle lobe (see Fig. 1). Lung metastases had grown markedly in size by 146 days and the right flank mass was now 12-15 cm in diameter and the liver was palpated 6-7 cm below the costal margin and was displaced to the left. The drug was discontinued after 151 days of therapy. The child continued to deteriorate and died in her local hospital at the age of 46 months, 2 months after dis- continuing o, p’ DDD therapy.
Untoward symptoms observed during therapy consisted of mild transient anorexia during the first 7-10 days. Attempts to in- crease the dose beyond 4 g/day terminally were unsuccessful because of anorexia and nausea. Body weight remained 30-31} 1b throughout the therapy period. Urinalyses, hemoglobin, white blood counts, serum elec- trolytes and liver function tests (bromsul- phalein retention, thymol turbidity, cephalin
? All ACTH was Armour Acthar.
3 Plasma cortisol or 17-OH steroid refers to 17,21-dihydroxy-20-ketosteroids-determined by modification of the Porter-Silber method as reported by Peterson, R. E., A. Karrer and S. L. Guerra, Anal. Chem. 29: 144, 1957.
flocculation, alkaline phosphatase and serum glutamic oxaloacetic transaminase) were un- altered by the o,p’ DDD therapy.
Case 2-ES-UAMC #17 86 32
This white female child entered the Uni- versity of Arkansas Medical Center at the age of 23 months because of clitoral enlarge- ment and pubic hair growth of 6 months’ duration. She was an adopted child. Little in- formation was available regarding the par- ents. They were apparently healthy and the pregnancy and delivery uncomplicated. Growth and development were unremark- able. Height and weight were 50th percentile for her age.
Physical Examination. The liver was pal- pable 4-5 cm below the right costal margin, with the impression of a mass deep below the liver. A considerable growth of coarse pubic hair was noted and the clitoris was approxi- mately 1} cm in length.
Routine laboratory investigations, includ- ing urinalysis, blood counts and serum elec- trolytes, were normal. Twenty-four hr urinary 17-ketosteroid excretion was 62 mg. Urinary pregnanetriol was not elevated. IVP and presacral air study revealed the right kidney to be displaced inferiorly. Bone age and chest roentgenograms were normal.
Exploratory laparotomy was performed on the 7th hospital day, and a 380 g, 11×7×9 cm encapsulated right flank mass was re- moved without difficulty. No evidence of metastasis was noted. The mass was diag- nosed histologically as an adrenal adenoma after careful search revealed no evidence of capsular invasion. Histologically, the tumor was quite anaplastic.
Six days postoperatively 24-hr 17-keto- steroid excretion was 0.7 mg. However, one month after surgery 24-hr 17-ketosteroid ex- cretion was 22 mg. Examination failed to re- veal any evidence of recurrent tumor. An 84-day course of ortho para’ DDD was begun 32 days after surgery. Total dosage was 241 g, as follows:
| Daily dose | Duration |
|---|---|
| 3 g | 16 days |
| 2} g | 22 days |
| 3 g | 46 days |
Twenty-four hr 17-hydroxysteroid and 17- ketosteroid excretions on therapy were:
17-OH Steroid 17-Ketosteroid
| Duration of Rx | mg/24 hr | mg/24 hr |
|---|---|---|
| Before therapy | 3.3 | 22 |
| 15 days | 0.3 | |
| 28 days | 0.2 | 1.2 |
| 53 days | 0.9 | |
| 68 days | 1.4 | |
| 75 days | 0.5 |
On the 64th day a fainting spell associated with sweating and lethargy was noted. Serum Na was 131 mEq/liter and serum K 6.0 mEq/liter. BUN was 16 mg/100 ml. Weight was unchanged. Three g NaCl and 15 mg/day hydrocortisone were begun. After a 4-day interval off hydrocortisone, on the 76th day, the plasma 17-OH steroid response to a 4-hr infusion of 40 units ACTH was:
| Before ACTH | 4 ug/100 ml |
| After 4 hr ACTH | 0 µg/100 ml |
Five mg hydrocortisone t.i.d. was resumed and the patient was discharged on this medi- cation.
After 84 days the o,p’ DDD therapy was discontinued. The child remained asympto- matic on salt and 15 mg/day hydrocortisone for a period of 7 months. At that time, after 4 days off hydrocortisone, a repeat ACTH test was done with results as follows:
Plasma cortisol before ACTH 18 ug/100 ml After 4 hr ACTH infusion 38 ug/100 ml
The hydrocortisone and salt supplements were discontinued and the child has remained asymptomatic 14 months after discontinuing DDD. Physical examination and chest roentgenogram are normal.
No untoward symptoms were noted during o,p’ DDD therapy. Body weight was essen- tially constant throughout the therapy period. Serial urinalyses and serum proteins were normal. There was no evidence of bone marrow toxicity, as determined by serial peripheral blood counts.
Comments
As noted in previous reports, ortho para’ DDD will cause regression in size and function of metastases of adreno- cortical carcinoma as well as a decrease or ablation of adrenal capacity for 17- hydroxysteroid production (1-6). In the
first patient, as in 12 of the 18 patients of Bergenstal et al. (2, 3) and in the patient of Verdon et al. (4), the initial tumor regression was followed by further pro- gression of tumor growth and eventual death of the patient. Adrenal insuffi- ciency did not occur in spite of large and prolonged o,p’ DDD dosage.
In the second patient it was not felt possible to exclude malignant potential of the tumor. Histologically, the tissue was quite anaplastic but capsular inva- sion could not be demonstrated. Thus the present health of the patient may not be attributable to the o,p’ DDD therapy. The elevated 17-ketosteroid level one month after surgery, however, does suggest the existence of residual functional neoplastic tissue. This patient is also of interest in that her adrenal function was apparently completely ab- lated with the o,p’ DDD therapy. She developed clinical adrenal insufficiency and had no plasma cortisol response to ACTH. Normal adrenal function re-
turned within seven months of discon- tinuing o,p’ DDD.
D. A. FISHER, M.D. T. C. PANOS, M.D.
J. C. MELBY, M.D.4
University of Arkansas School of Medicine, Little Rock, Arkansas
References
1. Bergenstal, D. M., M. B. Lipsett, R. H. Moy and R. Hertz, Trans. Ass. Amer. Physicians 72: 341, 1959.
2. : In Pincus, G. and E. P. Vollmer (eds.): Biological Activities of Steroids in Re- lation to Cancer, Academic Press, Inc., New York, p. 463, 1960.
3. Bergenstal, D. M., R. Hertz, M. B. Lipsett and R. H. Moy, Ann. Intern. Med. 53: 672, 1960.
4. Verdon, T. A., Jr., J. Bruton, R. H. Herman and W. R. Beisel, Metabolism 11: 226, 1962.
5. Molnar, G. D., S. L. Nunn and W. N. Tauxe, Proc. Mayo Clin. 36: 618, 1961.
6. Southren, A. L., S. Weisenfeld, A. Laufer and M. G. Goldner, J. Clin. Endocrinol. & Metab. 21: 201, 1961.
4 Present address: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.