o,p’DDD Therapy in Invasive Adrenocortical Carcinoma
DENIS BECKER, M.D., and O. PETER SCHUMACHER, M.D., Ph.D., F.A.C.P., Cleveland, Ohio
Invasive adrenocortical carcinoma was diagnosed in two patients, 31/2 and 69 years of age, respectively. Therapy with o,p’DDD was begun immediately, and the patients have survived 4 1/12 and 7 9/12 years, respectively. The prolonged survival represents possible “cure” of inoperable disease following early initiation of therapy.
IN 1960 BERGENSTAL and co-workers (1) reported on the effectiveness of 1-dichloro-2-(o-chlorophenyl)-2-(p-chloro- phenyl)-ethane (o,p’DDD) in inducing a regression in metastatic adrenal cortical carcinoma, both in measurable size and function, as based on urinary steroid excretion.
In 1966 Hutter and Kayhoe (2, 3) reviewed case his- tories of 138 patients treated with o,p’DDD by 105 investi- gators, establishing an expectation for the mean duration of steroid response (inhibition of pretreatment elevated urinary steroid levels) to be 5 months and the mean dura- tion of measurable disease response (continued inhibition of tumor growth) to be 10 months.
In 1973 Lubitz, Freeman, and Okun (4) reported that in 115 patients treated at the National Institutes of Health since Hutter and Kayhoe’s report, the duration of life from the onset of treatment ranged from 21 days to 411/3 months (mean, 8.4 months; median, 5 months). The data of Lubitz, Freeman, and Okun (4) seemed to indicate that there was some improvement in survival after treat- ment, comparing their results with the data of Macfar- lane (5) who found that, without treatment, mean sur- vival after diagnosis of inoperable adrenal carcinoma was 2.9 months, and median was 2.5 months. Further, they concluded that there were no patients cured of the dis- ease. We report the cases of two patients who began treatment immediately upon diagnosis of adrenal cortical carcinoma; there is no evidence of recurrence 4 1/12 and 7 9/12 years after initial o,p’DDD administration.
Patient 1
A 31/2-year-old boy was just recovering from a “cold” of 4 days’ duration. Further, his mother thought his genitalia were getting larger.
On physical examination pertinent findings included a mildly distended, nontender abdomen with the large, hard, smooth liver palpable 10 cm below the right costal margin. His testicles were 2 and 1.5 cm in size, his penis was enlarged to 8 cm, and scant pubic hair was present. He had a well- developed musculature. Significant abnormal findings were serum glutamic oxalacetic acid, 108 Karmen units; serum lactic dehydrogenase, 890 Wacker units; cephalin flocculation,
From the Department of Endocrinology, The Cleveland Clinic Founda- tion and The Cleveland Clinic Educational Foundation, Cleveland, Ohio.
2+ (48 h); serum calcium, 11.4 mg/100 ml; and serum phos- phorus, 8.1 mg/100 ml. Alkaline phosphatase, creatinine phos- phokinase, serum glutamic pyruvic transaminase, and total bilirubin were normal. The urogram showed the right kidney displaced downward with a suggestion of a retroperitoneal mass suprarenally. The liver scan showed decreased uptake of the right lobe of the liver compatible with metastatic neo- plasm. The urinary 17-hydroxycorticosteroids were not mea- surable; urinary 17-ketosteroids were 1351.8 mg/24 h (normal, 6 to 21 mg/24 h). Gonadotrophins were less than 13 mouse uterine units/24 h (normal, 13-105 mouse uterine units/24 h).
On 24 April 1970, a right nephrectomy was done, with a wide excision of a right-sided adrenal cortical carcinoma mea- suring 8 cm × 11 cm × 11 cm and weighing 805 g. Grossly, the tumor was invading the capsule of the liver and appeared to be infiltrating the inferior vena cava and hepatic veins.
On 8 May 1970, o,p’DDD therapy was started, 0.5 mg twice daily. Decadron® was administered, 0.25 mg twice daily, and fludrocortisone acetate (Florinef®) was added, 0.1 mg twice a week. In August 1970 his breasts seemed to be enlarging bilaterally. Bone age on 21 August 1970 was 41/2 years (chron- ologic age, 3 10/12 years). In September he was at the 25th percentile in both height and weight (versus, preoperatively, 45th percentile in height and 90 percentile in weight).
In January 1971 a follow-up note recorded increased brown pigmentation of his areolae and his breasts further enlarged. In January 1972 Decadron® therapy was changed to hydrocor- tisone, 10 mg three times a day, to determine if the gyneco- mastia could be reversed. In April, however, the gynecomastia was worse. In July 1972 a follow-up laparotomy was suggested, but the patient’s father refused to give permission. Bone age was 7 years (chronologic age, 51/2 years).
On 18 January 1973, 2 years and 7 months after initiation of treatment, the o,p’DDD therapy was discontinued. In July 1973 the dosage of hydrocortisone was decreased to 10 mg twice daily. In January 1974 his response to ACTH infusion was interpreted as suggestive of a functioning adrenal gland (Table 1). The hydrocortisone dosage was decreased to 5 mg twice daily. In June 1974 there was no evidence of tumor recurrence.
Patient 2
A 69-year-old man was seen at his local hospital emer- gency room with a chief complaint of “a pressure sensation” of sudden onset in his left upper abdomen. The pressure was described as a vague “discomfort,” unrelieved by bowel move- ments, associated with nausea and vomiting, and relieved by belching or vomiting “yellow bile.” He was febrile and com- plained that the abdominal pain radiated to his left shoulder, chest, and also left lower abdomen. There was no history or evidence of recent gastrointestinal bleeding, although he ap- peared anemic. After a physical examination, he was trans- ferred to the Cleveland Clinic to determine the possibility of a dissecting abdominal aortic aneurysm.
On admission physical examination showed a well-devel- oped, cooperative man, alert and in no distress. His blood pressure was 140/72 mm Hg, temperature 38.9 ℃; his skin was pale, dry, warm, and of normal turgor. His conjunctiva were pale, and there was an ecchymosis noted on his left flank. His lungs had some dullness to percussion and decreased breath sounds in the bases bilaterally with tubular breath
| Date | Urinary Assays | Other Tests | |
|---|---|---|---|
| 17-Hydroxycorticosteroids (Normal, 3 to 12 mg/24 h) | 17-Ketosteroids (Normal, 6 to 21 mg/24 h) | ||
| mg/24 h | |||
| Patient 1 | |||
| 23 April 70 | Not measurable | 1351.8 | |
| 5 May 70 | 0.5 | 1 | Plasma cortisol (normal, |
| 6 to 26 ug/100 ml; baseline, 3.1 µg/100 ml), 25 µg/100 ml | |||
| 14 December 70 | 4.2 | 2.6 | at 3 h after ACTH gel, 100 U |
| 29 March 72 | 1.5 | 1.3 | |
| 8 January 73 | 1.6 | 1.8 | |
| 27 January 74 | 1.4 | 3,9 | Plasma cortisol (baseline, |
| Start of 48-h ACTH infusion | 1.9 =g/100 ml) | ||
| at 3 h 2.4 4g/100 ml | |||
| at 12 h 3.0 µg/100 ml | |||
| at 24 h 10.7 µg/100 ml | |||
| at 48 h 16.5 µg/100 ml | |||
| 29 January 74 | 1.9 | 2.9 | |
| 17 June 74 | 2.9 | 3.7 | |
| Patient 2 | |||
| 19 August 66 | 5 | 5.6 | |
| 28 February 67 | 4 | 5.2 | |
| 8 June 67 | 11 | 7.6 | |
| After ACTH gel, 100 U | |||
| 9 February 68 | 2 | 5 | |
| 3 June 69 | 4.4 | 3.2 | |
| 17 June 70 | 6.1 | 7 | |
| 12 December 72 | 6.8 | 4.1 | |
| 21 March 73 | Plasma cortisol (normal, | ||
| 6 to 26 µg/100 ml), | |||
| 2.5 µg/100 ml; 1 h after | |||
| Cortrosyn®, 0.25 mg, 16.8 µg/100 ml | |||
| 12 May 74 | 2.2 | 7.2 | Free cortisol (normal, 80 to 370 µg/24 h), 67.7 µg/24 h |
sounds noted in the left lower lobe posteriorly. Occasional premature beats and a grade II/VI holosystolic murmur were noted at the lower left sternal border on cardiac auscultation. His abdomen was soft, slightly distended, and there was some left upper quadrant tenderness. No rebound, abnormal masses, or organomegaly were noted. Bowel sounds were slightly de- creased. The remainder of the physical examination was un- remarkable.
Hemoglobin value on admission was 9.2 g/100 ml; hemato- crit, 28%; leukocyte count, 14 000/mmª with a left shift noted on the differential count. Chest roentgenograms showed blunt- ing of both costophrenic angles. Atelectasis was noted in both bases with an effusion present in the left costophrenic angle. An abdominal roentgenogram showed a distended colon with a fluid level noted in the ascending colon, and the splenic flexure was displaced medially. An arteriogram showed the spleen to be pushed down by a left subdiaphragmatic mass or abscess, and the left kidney seemed inferiorly displaced. The urogram, superior mesenteric arteriogram, and aortogram were normal with no evidence of aneurysm, leakage, or mass.
At laparotomy a left adrenal tumor was found with evidence of a retroperitoneal hemorrhage and a subscapular hematoma of the spleen posteriorly. The pathologic diagnosis was ad- renocortical carcinoma with metastatic spread evidenced in the periadrenal fatty tissues.
Because the patient had pathologic evidence of metastasis, o,p’DDD therapy, 4 g/day, was started on 21 August 1966, with dosage increasing over 5 days to 10 g/day as tolerated.
For baseline values, urinary 17-ketosteroids were 5.6 mg/24 h and 17-hydroxycorticoids were 5.0 mg/24 h.
In another 6 months the patient found that doses of more than 1 g/day upset his stomach, and he tapered his dose ac- cordingly, from 10 g/day. In June 1967 he had an adequate elevation in 17-hydroxycorticosteroids in response to ACTH gel, 100 U.
In December 1972, 6 years and 4 months after initiation of therapy, there was still no evidence of recurrence and o,p’DDD was stopped. Urinary 17-ketosteroids and 17-hy- droxycorticosteroids remained unchanged (Table 1). Through- out the course of therapy he was receiving Decadron®, 0.25 mg to 0.5 mg twice daily, and Florinef®, 0.1 mg once a day. On 21 March 1973, he was noted to have a normal response to Cortrosyn® stimulation (Table 1). Physical examination at this time showed no nodes or abnormal masses. His chest roentgenogram was normal. In May 1974 there was no evi- dence of tumor recurrence.
Discussion
Both patients have survived for a long time after the diagnosis of invasive adrenal carcinoma and prompt initiation of o,p’DDD therapy. The surgical approach was to excise all visible tumor mass, and the successful extensive dissection may well be partially responsible for both cases surviving to date. The addition of o,p’DDD
nevertheless must be credited with the notable distinction in survival between our cases and Macfarlane’s inoperable patients not treated with o,p’DDD (Patients 1 and 2 having survived 41/2 and 7 9/12 years since initiation of treatment, as opposed to Macfarlane’s report of 2.9 months mean survival after diagnosis, without treatment).
There have been few reports of o,p’DDD treatment in children with proved metastatic adrenal carcinoma (6). Patient 1, first examined at 31/2 years of age, and mani- festing no evidence of recurrence 41/2 years later, must certainly be the youngest “cured” patient. Since tumor excision, both have shown adequate ACTH responsiveness (of the remaining adrenal gland, and not of possible metastatic functional tumor) (7). Although the cause of gynecomastia in Patient 1 could never be definitely identi- fied, it was felt that this was due to Decadron®, the re- maining functioning tumor, or even the o,p’DDD.
In contradistinction to the conclusion of Hoffman and Mattox (8), who considered o.p’DDD to be ineffective therapy for 19 patients with adrenocortical carcinoma, our two cases represent exceptional responsiveness to o,p’DDD. To date neither patient has shown evidence of either resumed steroid secretion or tumor growth. Both have had prolonged survival and possible “cure” of proved
adrenocortical carcinoma following extensive excision of the tumor mass and early postoperative initiation of o,p’DDD therapy.
ACKNOWLEDGMENTS: Received 22 August 1974; revision accepted 15 January 1975.
Requests for reprints should be addressed to O. Peter Schumacher, M.D., The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44106.
References
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3. HUTTER AM JR, KAYHOE DE: Adrenal cortical carcinoma; re- sults of treatment with o,p’DDD in 138 patients. Am J Med 41:581-590, 1966
4. LUBITZ JA, FREEMAN L, OKUN R: Mitotane use in inoperable adrenal cortical carcinoma. JAMA 223:1109-1112, 1973
5. MACFARLANE DA: Cancer of the adrenal cortex. Ann R Coll Surg Engl 23:155-164, 1958
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7. MARTIN FIR: Evidence of an hormonal influence on the steroid output of adrenal carcinoma. Am J Med 32:795-798, 1962
8. HOFFMAN DL, MATTOX VR: Treatment of adrenocortical carci- noma with o,p’DDD. Med Clin North Am 56:999-1012, 1972