NOTE
A Case of Adrenocortical Cancer Treated with O,P’-DDD
NOBORU SAKAUCHI, SOICHI KUMAOKA, TSUGUO NARUKE,
OSAHIKO ABE, MITSUTOSHI KUSAMA AND OSAMU TAKATANI
National Cancer Center Hospital, and National Cancer Center Research Institute, Division of Endocrinology, Chuo-ku, Tokyo
Synopsis
O,P’-DDD was given to a 41-year-old Japanese woman with metastatic ad- renocortical carcinoma with dosage of 8 g a day orally. The treatment resulted in objective regression of all metastases for 237 days. Significant decrease was seen in 17-ketosteroid, 17-hydroxycorticosteroid, 17-ketogenic steroids, estrogen in the urine, and 17-hydroxycorticosteroid, cortisol in plasma during the course of treatment.
O,P’-DDD, (2,2-bis-[2-Chlorophenyl-4- Chlorophenyl] 1,1-Dichlorethane), which is a ortho prime isomer of DDT, induces a selective necrosis of the zona fasciculata and zona reticularis of the adrenal cortex in animals and humans. Efforts of its use to the treatment of patients with advanced adrenocortical cancer stemed from Bergenstal et al. (1960). The clinical experience with the use of O,P’-DDD on 138 patients with adrenocortical cancer was summarized by Hutter and Kayhoe 1966 and compared with that in the forty-eight previously published cases. It was seen that 34% of the patients had objective tumor regression, pro- longation of life and invariable accompaniment of steroid response.
We describe here our experience with O,P’- DDD in the treatment of metastatic adreno- cortical cancer.
Case History
A Japanese female patient aged 41 years was
admitted to National Cancer Center Hospital, Tokyo, Japan, on October 1, 1965 with a history or lumbal pain and a large mass in the upper left abdomen which had developed since spring of the same year. The mass in the upper left abdomen was removed on October 25. The tumor was 1,800 g in weight and 21 x 17 x 11 cm in size. Histological examination revealed a well differentiated carcinoma of the adrenal cortex.
She had no complaint until when a small round shadow was discovered radiographically in the lower region of the left lung. She was readmitted to the hospital on May 29, 1967. At the second admission, she had no symptom of hyperadrenocorticism except for slight hirstism in the lower extremities. There were spastic paralysis and hypesthesia in the lower half of the body, disturbance of gait, liver enlargement and a large mass in the left hypochondrium.
Fluoroskopic examination of the chest showed multiple coin lesions of pulmonary metastasis bilaterally (Fig. 2). X-ray exami- nation of the thoracic spines revealed osteolysis and osteosclerosis in 7 - 9th, which were thought to be due to metastasis. Angiography of the aorta showed a large mass in the upper
0,P’-DDD
9
0-
PREDNISOLONE
15mg
0
9
a
HYPESTHESIA PARALYSIS
VOLUNTAR MOVEMENT IN LOWER EXTREMITIES
GAIT POSSIBLE
DISCHARGE
80
STEROIDS EXCRETION
1
1
1
60
mg/24hrs 40
20
17-OHCS
0
17-KS
1
JUN.
1967
JUL.
AUG.
SEP.
OCT.
left abdomen. Laboratory examination revealed slight anemia, normal electrolytes, normal liver function, and slightly elevated lactic de- hydrogenase activity in serum. Alkaline phosphatase was 1.9 unit in serum (Bessey- Lawry).
Urinary 17-ketosteroid excretion was 54.8 - 155.4 mg/24 hrs .; urinary 17-hydroxycorticoste- roid 11.4 - 36.0 mg/24 hrs .; urinary 17-keto- genic steroid 40.1 - 59.6 mg/24 hrs. (deoxy 31.3 - 47.7, oxy 8.8 - 11.9 mg/24 hrs.); es- trogen 9.0 - 28.5 µg/24 hrs .; gonadotropin 16 units/24 hrs .; plasma 17-hydroxycorticosteroid 11.6 - 57.6 ug/100 ml; plasma cortisol 16.8 - 36.0 µg/100 ml. Fractions of urinary steroids; are shown in Table 1. It was remarkable that dehydroepiandrosterone increased much more than other fractions of 17-ketosteroid.
Treatment with O,P’-DDD
Treatment with O,P’-DDD was started orally on June 17 in a daily dose of 4 g which was increased to 8 g three weeks later. The subsequent progress and response to O,P’-DDD is shown in Figure 1. One month later, signifi-
| HORMONES | BEFORE O,P'-DDD | DURING O,P'-DDD | NORMAL VALUE |
|---|---|---|---|
| 17-KS in Urine mg/24 hrs. | 54.8 - 155.4 | 4.4 - 31.9 | 3.7 ± 9.6 |
| DHA | 55.0 | 8.1 | 0.7 ± 0.5 |
| AND | 17.8 | 1.3 | 1.7 ± 0.6 |
| ETIO | 41.3 | 3.0 | 1.7± 0.7 |
| 11-OXY-17KS | 9.2 | 4.6 | 1.5 ± 0.7 |
| 17-OHCS | 11.4 - 36.0 | 6.0 - 31.2 | 3.9 ± 8.6 |
| Cortols | 3.0 | 1.4 | 0.6 ± 0.3 |
| Cortolones | 2.1 | 0.8 | 1.0 ± 0.5 |
| THF | 5.6 | 5.3 | 1.1 ± 0.6 |
| THE | 4.9 | 4.2 | 1.8 ± 1.0 |
| Cortisol | 1.9 | 0.7 | 0.2 ± 0.1 |
| Cortisone | 2.6 | 0.4 | 0.2 ± 0.1 |
| 17-KGS | 40.1 - 59.6 | 17.9 | 7.4-10.2 |
| DEOXY | 31.3 - 47.7 | 14.5 | 1.2 - 1.9 |
| OXY | 8.8 - 11.9 | 3.4 | 6.2 - 8.3 |
| Pregnanediol | 11.2 - 11.8 | 5.1 - 11.2 | 0.6 - 3.6 |
| Pregnanetriol | 0.1 - 4.2 | 0.1 - 0.1 | 0.4 - 2.8 |
| Total Estogen ug/24 hrs. | 9.0 - 28.5 | 5.0 - 7.0 | 2 -30 |
| Gonadotropin u/24 hrs. | 16 | 16 | 4 -16 |
| 17-OHCS in Plasma ug/100 ml | 11.6 - 57.6 | 12.4 - 34.0 | 8.0 -21.0 |
| Cortisol in Plasma | 16.8 - 36.0 | 2.1 - 18.0 | 6.6-15.8 |
cant decrease in the size of the liver and of upper left abdominal mass and improvement of paralysis and hypesthesia in the lower half of the body were noted. After two and a half months she could walk by herself. X-rays of the chest and thoracic spines which were taken three months after the initiation of treatment, showed considerable regression in the pulmo- nary metastasis (Fig. 3) and moderate calcifi- cation in the 7 - 9th thoracic spines. Remark- able decrease was recognized in 17-ketosteroid and its fractions, 17-hydroxycorticosteroid, 17- ketogenic steroids and their metabolites, urinary estrogen, plasma 17-hydroxycorticosteroid and cortisol. Urinary dehydroepiandrosterone ex- cretion was considerably higher than other fractions of 17-ketosteroid through the whole course of the treatment.
The drug was fairly well tolerated and no
definite toxic effects on the hemopoietic system nor change in the results of the liver function test were noticed. There were occasional bouts of nausea and vomiting, but it was not clear whether they were due to the O,P’-DDD or the disease. There were, however, a significant rise in the level of serum cholesterol and decrease of PBI. When the liver size decreased, lactic dehydrogenase and isocitric dehydrogenase were reduced.
The patient was discharged from the hospital on October 14 and took up her household routine again. There was a marked regression of all the metastatic lesions for 237 days. Urinary 17-ketosteroid excretion showed an almost normal level during the course of treat- ment, until she suddenly died at home of asphyxiation due to vomiting on January 29, 1968. Autopsy could not be performed.
Discussion
A post mortem examination could not be done. It was, however, clear that O,P’-DDD caused a considerable regression of metastases of the adrenocortical carcinoma which in this case involved the liver, lung, thoracic spines and upper left quadrant of the abdomen.
As seen in Figure 1, a marked reduction of both 17-hydroxycorticosteroid and 17- ketosteroid in urine was seen within only a few days of the therapy, as reported previously
(Southren et al., 1966). Tumor regression was observed clinically later. A similar finding was stated earlier by Hutter and Kayhoe (1966). The results of steroids excretion seen in Table 1 suggest that O,P’-DDD has a direct effect on the pathway from cholesterol to pregnenolone in adrenocortical cancer.
Toxicity reactions due to O,P’-DDD was reported by Hutter and Kayhoe (1966) as consisted of nausea, vomiting, diarrhea, neuro- muscular disturbance, depression, skin rash and others. Patients who showed no toxicity reactions were reported to be only 11% of 132 cases. Fortunately, no obvious toxic sign except for temporary nausea and vomiting was recognized in this case. However, decreased PBI and hypercholesterolemia were seen during the course of treatment, as reported by Donowski et al. (1964).
Acknowledgement
Our thanks are due to Miss N. Kato, Mrs. T. Yamada, Miss Y. Kanai, Miss E. Fujita and Miss M. Kato for making steroid analysis.
References
Bergenstal, D. M., R. Hertz, M. B. Lipsett and R. H. Moy (1960). Ann. intern. Med. 53, 672. Donowski, T. S., M. E. Sarver, C. Moses and J. V. Bonessi (1964). Am. J. Med. 37, 235. Hutter, A. M. and D. E. Kayhoe (1966). Ibid. 41,581.
Southren, A. L., S. Tochimoto, L. Strom, A. Ratuschni, H. Ross and G. Gordon (1966). J. Clin. Endocrinol. 26, 268.