Treatment of Adrenocortical Cancer with O,P’-DDD
ANTONIO DA SILVA COELHO NETTO, M.D., BERNARDO LÉO WAJCHENBERG, M.D., CASSIO RAVAGLIA, M.D., VIRGILIO GONÇALVES PEREIRA, M.D., JOSÉ SHNAIDER, M.D., ARMANDO AGUIAR PUPO, M.D., and ANTONIO BARROS DE ULHOA CINTRA, M.D., PH.D. São Paulo, Brazil
T HE INITIAL OBSERVATIONS of Nelson and Woodward (1, 2) that the feeding of the insecticide, 1,1-dichloro-2,2-bis (p-chloro- phenyl) ethane (DDD) to dogs results in necrosis and atrophy of ‘the adrenal cortex opened a new research field for adreno- corticolytic drugs. Brown et al. (3-5) ob- served that necrosis of the adrenal cortex was followed by a decrease in urinary ex- cretion of 17-hydroxycorticosteroids. In these animals a picture compatible with adrenocortical insufficiency developed which was not modified by the simulta- neous administration of adrenocortico- tropic hormone (ACTH) but which could be prevented by cortisone.
Other authors (6-8) confirmed these ini- tial data and the technical grade DDD was then characterized as a drug able to act specifically on the reticularis and fascicu- lata layers of the adrenal cortex, in a re- versible way, producing a hypofunctional status which could no longer be corrected by administration of ACTH.
The evident toxic effects of the drug limited its usefulness in man but stimu- lated research toward isolation from the insecticide of a more active, less toxic frac- tion. Through systematic fractionation of
From the First Medical Clinics, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil.
Requests for reprints should be addressed to Bernardo Léo Wajchenberg, Unidade de Diabetes e Suprarrenal, 1.a Clinica Medica, Hospital das Clínicas da Universidade de São Paulo, Brazil.
the technical DDD, Cueto and Brown (9) identified a strongly active isomer, with little toxicity, known as o,p’-DDD,* which, in animal experiments, produced significant histological, biochemical, and secretory changes of the adrenal cortex. Vilar and Tullner (10) observed that this drug caused focal degenerative lesions in the reticularis and fasciculata layers, associated with a de- crease in the rate of secretion of 17-hydroxy- corticoids and in the response of the adrenal cortex to corticotropin, indicating that it acts directly on the adrenals and not through the pituitary.
Bergenstal, Lipsett, Moy, and Hertz (11, 12), administering o,p’-DDD to 18 patients with metastatic functioning adrenal corti- cal cancer, observed a uniform decrease in steroid hormone excretion in the urine. In 7 of these patients there was also significant objective regression of measurable meta- static lesions. Toxic manifestations, highly variable in degree and unrelated to the dosage, were observed in the gastrointes- tinal tract, skin, and nervous system. These authors concluded that o,p’-DDD was cap- able of producing regression of metastatic adrenal cancer in man and inhibition of its hormonal secretion, both appearing to be reversible.
Recently, Gallagher, Fukushima, and Hellman (13) observed that the drug caused a greater decrease in cortisol than in andro- gen metabolites, which varied somewhat
. 2,2-bis (4-chlorophenyl, 2-chlorophenyl)-1,1-di- chloroethane.
| Patient | Sex | Age in Years and Months | Clinical Diagnosis | Major Clinical Signs | Bone Age | Metastasis | Urinary | |
|---|---|---|---|---|---|---|---|---|
| 17- OHCS | 17- KS | |||||||
| Adrenogenital syndrome | yr | mg/24 | hr | |||||
| S. A. A. (Case 1) | M | 4 yr | Acne, hypertrich- osis | 12 | - | 2.08 | 310.0 | |
| A. R. (Case 2) | M | 2 yr, 8 months | Cushing's and adrenogenital syndrome | Moon face, hy- pertrichosis | 1 | Pulmonary, abdominal | 14.0 | 15.6 |
| M. T. P. S. (Case 3) | F | 5 yr | Adrenogenital syndrome | Hypertrichosis, enlarged clitoris | 11} | Pulmonary, abdominal | 0.7 | 66.0 |
| C. F. S. (Case 4) | F | 4 yr | Adrenogenital syndrome | Hypertrichosis, enlarged clitoris | 6 | - | 990.0 | |
| F. F. (Case 5) | F | 7 yr | Adrenogenital syndrome | Hypertrichosis, enlarged clitoris | 10 | Pulmonary | 385.0 | |
with each of the 3 patients studied and with the particular metabolites. Pregnane -3a, 17, 20a-triol (pregnanetriol) was the most sensitive indicator of the action of the drug, declining very rapidly, in con- trast to the much longer time required by the 17-ketosteroids and 17-hydroxycorticos- teroids to reach normal levels, as first re- ported by Verdon, Bruton, Herman, and Beisel (14).
In patients with Cushing’s syndrome due to nontumorous hyperfunction, Southren,
Weisenfeld, Laufer, and Goldner (15) and Geyer (16) noticed complete regression of the clinical picture in association with a rapid and significant decrease in urinary 17-ketosteroids and 17-hydroxycorticoste- roids, after the use of o,p’-DDD. With- drawal of the drug was followed by a rise in the concentration of urinary steroids and recurrence of the stigmata of Cushing’s syndrome, re-institution of therapy causing a prompt return to normal.
These reports on the effectiveness of the
| Patient | Therapy | O,p- DDD Dosage | Dura- tion of Treat- ment | Therapeutic Results | Toxic Effects | Final Outcome |
|---|---|---|---|---|---|---|
| S. A. A. (Case 1) | Surgery, o,p-DDD | g/day 4- 8 | days 90 | Absence of metastasis | - | 1-yr follow-up |
| A. R. (Case 2) | Surgery o,p-DDD | 2-10 | 40 | - | Anorexia, mental depression | Died |
| M. T. P. S. (Case 3) | o,p-DDD, surgery, o,p-DDD | 2-10 | 70 | Tumor regression, disap- pearance of pulmonary metastasis | Nausea, mental depression, pig- mentation | Died (respiratory standstill) |
| C. F. S. (Case 4) | Surgery, o,p-DDD | 2- 4 | 210 | Absence of metastasis | Anorexia | 7-month follow-up |
| F. F. (Case 5) | Surgery, o,p-DDD | 2-10 | 545 | Disappearance of pul- monary metastasis, re- currence with therapy | Nausea, vomiting, diarrhea | 18-month follow-up, death |
drug led us to use o,p’-DDD in 5 patients with adrenocortical carcinoma.
MATERIALS AND METHODS
Five patients with adrenocortical cancer re- ceived 2,2-bis (4-chlorophenyl, 2-chlorophenyl)- 1,1-dichloroethane (o,p’-DDD). The patients presented clinical signs of virilization (adreno- genital syndrome), associated in case 2 with Cushing’s syndrome.
The clinical findings and urinary excretions are summarized in Table 1. O,p’-DDD was ad- ministered orally in daily doses of 2 g to a maxi- mum of 10 g. The period of administration was quite variable, from 40 days to 18 months. The drug was given to one of the patients (case 2) before surgery, to decrease tumor size, and after surgery for regression of metastasis; in 2 cases (1 and 4), after surgery, for possible prevention of metastasis development; and in the remain- ing patients (cases 3 and 5) because of meta- stasis that appeared after surgical extirpation of the primary adrenal tumor.
The results of treatment are summarized in Table 2.
Urinary 17-ketosteroids (17-KS) were deter- mined by the method of Drekter et al. (17) and the 17-hydroxycorticosteroids (17-OHCS) by the method of Butt, Kornel, and Morris (18).
COMMENTS
Administration of 2,2-bis (4-chlorophenyl, 2-chlorophenyl)-1,1-dichloroethane (o,p’- DDD) caused a significant decrease in uri- nary steroid excretion. At the same time, a striking regression of the clinical picture
was observed, despite initial response to surgery, except in case 2. When pulmonary and abdominal metastasis, or either, was noticeable, an objective regression in size (case 3, Figure 1) or complete disappear- ance (case 5, Figure 2) was observed.
In patient A. R. (case 2) with Cushing’s syndrome, who was found at laparotomy to have a large inoperable right adrenal carcinoma, the administration of the drug was ineffective, and the patient died shortly afterward. In 2 patients in whom o.p’-DDD was administered for the prevention of me- tastasis, no carcinoma appeared to have de- veloped during the follow-up periods of 7 months and 1 year, respectively.
Some toxic side effect was always present, particularly anorexia, diarrhea, vomiting, and mental depression. In case 3, death probably resulted from drug administra- tion, which caused depression of bulbar centers and respiratory standstill.
Results of the present study indicate that o,p’-DDD acts selectively on the adrenal cortex, its effects being related to the dose and time of administration of the drug.
Prolonged therapy with large amounts of o,p’-DDD could result in adrenal insuffici- ency and the need for specific treatment, as happened in one of our patients (case 5). The toxic side effects did not limit the usefulness of the therapeutic agent. The
90
70
50
URINARY 17-KS mg/24 h
30
10
EXPIRED 4
5/13
6/1
6/21
7/11
8/20
METASTASIS LOCALIZATION
0.9.000
Gm/24 h
#
MM 56 24.56
tendency for symptoms to recur when ad- ministration of the drug was stopped in- dicated that its effects were not definitive (Figure 3).
We were able to verify that in one of the patients (case 5), the tumor that was initially sensitive to the drug became re- sistant to it, with continued metastatic growth despite progressive increase in dos- age. Similar observations were made by Bergenstal et al. (12), by Verdon et al. (14), and by Gallagher and associates (13) who noted a steroid response without tumor
regression. These findings clearly indicate, then, that the neoplastic process was inde- pendent of the steroid production of these adrenal carcinomas.
Our experience with 5 cases of function- ing adrenal cortical carcinoma indicates that o,p’-DDD is a useful agent in the therapy of this type of cancer and its me- tastases. However, our data do not permit us to establish any therapeutic orientation about the initial period of administration of the drug, its dosage, and the duration of the treatment.
1000
900
C.F.S. Q, ADRENAL Co
800
50
URINARY 17-KS mg/24 h
25
20
15
10-
5
0
O-D’DDD
20
40
60
80
100
120
160
180 200 220 240260 300
4
DAYS
Gm /24 h
SUMMARY
Five cases of functioning adrenal car- cinoma treated with 2,2-bis (4-chlorophenyl, 2-chlorophenyl)-1,1-dichloroethane (o,p’- DDD) are described. This compound was employed to prevent and treat metastasis. Objective tumor regression was observed in 2 patients for 70 and 575 days, respec- tively. Three of the patients died during therapy, 2 from tumor progression and one probably from drug toxicity. The practical therapeutic usefulness of this agent was not restricted by the multiple side effects, which include gastrointestinal intolerance, mental depression, and somnolence.
Resistance to the drug was observed in one of the patients.
ACKNOWLEDGMENT
A portion of the o.p’-DDD used in this study was supplied by the Endocrinology Branch, Cancer Chemotherapy National Service Center, National Institutes of Health, Bethesda, Mary- land.
SUMMARIO IN INTERLINGUA
Es describite 5 casos de functionante carci- noma adrenal, tractate con 1,1-dichloro-2,2-bis- (p-chlorophenyl)-ethano. Iste composito esseva empleate pro prevenir e pro tractar metastases. Un objective regression del tumor esseva ob- servate in 2 patientes durante 70, respective- mente 575 dies. Tres del patientes moriva du- rante le therapia, 2 ab progression del tumor e le tertie probabilemente ab toxicitate del phar- maco. Le utilitate de iste agente in le practica therapeutic non esseva restringite per le multi- ple effectos secundari de character adverse le quales include intolerantia gastrointestinal, de- pression mental, e somnolentia.
Resistentia contra le droga esseva observate in un del patientes.
REFERENCES
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2. NELSON, A. A., WOODWARD, G .: Severe cortical atrophy (cytotoxic) and hepatic damage pro- duced in dogs by feeding 2,2-bis (parachloro- phenyl) 1,1-dichloroethane, DDD or TDE. Arch. Path. 48: 387, 1949.
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9. CUETO, C., BROWN, J. H. U .: Biological studies on an adrenocorticolytic agent and the iso- lation of the active components. Endocrin- ology 62: 334, 1958.
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12. BERGENSTAL, D. M., HERTZ, R., LIPSETT, M. B., MoY, R. H .: Chemotherapy of adrenocortical cancer with o,p’-DDD. Ann. Intern. Med. 53: 672, 1960.
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14. VERDON, T. A., JR., BRUTON, J., HERMAN, R. H., BEISEL, W. R .: Clinical and chemical re- sponse of functioning adrenal cortical car- cinoma to o.p’-DDD. Ibid., 226.
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16. GEYER, G .: Erfolgreiche behandlung eines falles von Cushing-syndrom mit o.p’-DDD. Acta Endocr. (Kobenhavn) 40: 332, 1962.
17. DREKTER, I. J., HEISLER, A., SCISM, G. R., STERN, S., PEARSON, S., MCGAVACK, T. H .: The de- termination of urinary steroids. I. The prepa- ration of pigment-free extracts and a simpli- fied procedure for the estimation of total 17-ketosteroids. J. Clin. Endocr. 12: 55, 1952.
18. BUTT, W. R., KORNEL, L., MORRIS, R .: The de- termination of 17-OH corticosteroids in urine. Acta Endocr. (Kobenhavn) 26: 65, 1957.