Combination Chemotherapy for Adrenal Carcinoma: Response in a 51/2-Year-Old Male
Patricia A. Crock, MBBS, FRACP, and A.C.L. Clark, MD, FRACP
Adrenocortical carcinoma is an uncommon tumor of childhood, and systematic studies of therapeutic options are not available. Chil- dren with very large tumours have a poor outlook with surgery alone, so that other treatment should be considered, but the lit- erature is unhelpful in suggesting what this
should be. In the case reported here, combi- nation chemotherapy, including cisplatinum, gave a well-documented good partial re- sponse, suggesting a possible role for adju- vant chemotherapy using such a drug com- bination.
Key words: childhood, adrenal cortex neoplasms, drug therapy
INTRODUCTION
Adrenocortical carcinoma is a rare tumour of child- hood [1]. Primary surgical resection may be curative [2], but prognosis is dependent on tumour size and location [3-5]. Although current reports in the paediatric litera- ture on outcome are more optimistic [6], occurrence of metastatic disease still carries on almost uniformly fatal outcome.
This paper reports on the good partial response to combination chemotherapy of recurrent metastatic adren- ocortical carcinoma in a 5-year-old boy, and discusses its possible role in adjuvant therapy.
CASE REPORT
A 51/2-year-old boy came to our centre on November 7, 1984 with lethargy of about 2 weeks’ duration, increas- ing appetite, swelling of the abdomen for 4 days, and abdominal pain on the day of admission. Past and family histories were unremarkable. Examination showed that the child had mild Cushingoid facies, height 107 cm (< 25th percentile), weight 20 kg (> 50th percentile), and blood pressure (BP) 120/90. There was a mass in the left hypochondrium extending 8 cm below the costal margin, with distended veins on the abdominal wall. He had stage-2 pubic hair and some penile enlargement.
Clinical Findings
Full blood examination, serum electrolytes, and he- patic and renal function were normal. Bone age was 6.5 years (Greulich and Pyle). Plasma and urinary steroids were elevated (Tables I and II), and 24-hour urinary MHMA, noradrenaline, and adrenaline were normal. Dopamine excretion was 2.06 umol/day (normal 0.55-
1.08 umol/day). Chest X-ray, liver ultrasound, and bone scan were normal. Abdominal ultrasound showed a well- defined mass displacing the left kidney downward. Bi- opsy showed adrenal carcinoma, and the tumor was re- moved, together with the left kidney, the spleen, and the tail of the pancreas, on November 20, 1984.
The tumour measured 15.0 x 11.5 x 10.5 cm. It was encapsulated, largely necrotic, and haemorrhagic, and the capsule was breached. Tumour weight (+kidney) was 1,248 g. (Average kidney weight for height [107 cm] is 72 g [7]). Histology confirmed the diagnosis of adrenal carcinoma with microscopic spread to the left kidney but no lymph node involvement.
Urinary and plasma steroids fell to normal within 3 weeks (Tables I and II and Fig. 1), but 8 weeks postop- eratively he again developed abdominal pain, lethargy, fever, and vomiting, and BP was 130/90. CT scan showed enlarged retroperitoneal lymph nodes, with multiple sec- ondary deposits in both lobes of the liver and in the lungs. Urinary and plasma androgens were again ele- vated (Table 1 and II and Fig. 1).
Treatment
A single course of 5-fluorouracil 600 mg/m2, actino- mycin D 1.5 mg/m2 and cyclophosphamide 600 mg/m2 was given, but the tumour continued to progress, and 3 weeks later he had hypertensive encephalopathy (BP 170/
From the Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
Address reprint requests to Patricia A. Crock, Department of Paediat- rics, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, 3168, Victoria, Australia.
| 17 OH-progesterone (nmol/l) | 44 Androstenedione (nmol/l) | DHEASª (umol/l) | Testosterone (nmol/l) | |
|---|---|---|---|---|
| Normal range | <5 | 0.4-1.8 | <1.5 | <1 |
| At diagnosis (November 19, 1984) | 15 | >18 | 46 | 4.6 |
| Postoperative (November 30, 1984) | <2 | <0.5 | <0.3 | 0.2 |
| Metastatic disease (January 18, 1985) | 9.2 | 9.7 | 20.1 | 2.1 |
| Postchemotherapy FACb (February 6, 1985) | 107 | >5 | - | 6.1 |
| OPEC started Feb 13, 1985 (March 6, 1985) | 34 | >25 | - | 5.0 |
| OPEC ceased June 14, 1985 (July 3, 1985) | <2 | 0.6 | 0.8 | 0.4 |
| Recurrence | 7.6 | |||
| (August 26, 1985) |
ªDHEAS, dihydroepiandrosterone sulphate.
bFAC, Tt-fluorouracil, actinomycin D, cyclophosphamide.
| Androsterone | Etiocholanolone | Pregnantriol | THSª | |
|---|---|---|---|---|
| Normal range | <1.5 | <1.5 | <0.6 | <1.0 |
| At diagnosis (November 18, 1984) | 14 | 19 | 6.9 | 2.5 |
| Postoperative (November 30, 1984) | <0.1 | 0.1 | 0.6 | <0.1 |
| Metastastic disease (January 18, 1985) | 4.6 | 7.4 | 9.8 | 1.4 |
| Postchemotherapy FACb (February 6, 1985) | 7.0 | 8.4 | 16 | 1.4 |
| OPEC started Feb. 13, 1985 (March 13, 1985) | 20 | 20 | 6.5 | 2.7 |
| OPEC cease June 14, 1985 (July 3, 1985) | 0.3 | 0.2 | <0.3 | 0.2 |
| Recurrence (August 26, 1985) | 11 | 15 | 26 | 1.4 |
ªTHS, tetrahydro-11 deoxycortisol.
bFAC, 5-fluorouracil, actinomycin D, cyclophosphamide.
110) requiring intravenous hypotensive therapy. Chemo- therapy was changed to the following regimen (OPEC, Oncovin, cisPlatinum, Epipodophyllotoxin, Cyclophos- phamide) on February 13, 1985: Day 1) cyclophospha- mide 600 mg/m2, vincristine 1.5 mg/m2; day 2) cisplatinum 100 mg/m2; day 4) VM26 (teniposide) 150 mg/m2.
He had six courses over a period of 18 weeks; while on OPEC, all urinary and plasma steroids fell to normal (Tables I and II and Fig. 1). Hypertension and hepato- megaly resolved as seen by clinical examination, as did ultrasound evidence of liver secondary tumours. Pulmo- nary metastases regressed radiologically, except for sev- eral small opacities in the left lung on June 5, 1985.
He regained normal activity for almost 3 months, and then in August, 1985 the tumour recurred, 2 months after
completion of chemotherapy. He died at home on Octo- ber 11, 1985.
DISCUSSION
Prognosis in adrenal cortical carcinoma is poor in tumours over 170 g and > 7 cm [3-5, 8-11]. Despite the large mass of the present tumour, the decision was made not to give adjuvant chemotherapy because all steroid markers returned to normal postoperatively. Further- more, a review of the literature provided little evidence of responsiveness to any chemotherapeutic regime in childhood [12-14]. Rarity of the disease has precluded controlled trials.
When metastatic disease was detected, a single dose of 5-fluorouracil (5-FU), actinomycin D, and cyclophos- phamide was given on the basis of equivocal evidence of
OPEC
Surgery
50
24 hr Urinary Androsterone
20
40
(umol/d)
Plasma DHEAS
30
( pmol / L )
10
20
10
N
N
N
D
J
F
M
A
M
J
J
A
‘84
‘85
response in a case report [12]. It proved ineffective. 5- FU in combination with o, p’-DDD [1, 1-dichloro-2-(-0- chlorophenyl)-2-(p-chlorophenyl)-ethane] had resulted in complete cure in one patient [15], but other reports of response to 5-FU in adults showed variable success [4, 13, 16-18].
Although its use had not been reported in children, cisplatinum has proved beneficial in metastatic disease [19-22]. On that basis, a drug combination (OPEC-see case record) containing cisplatinum was chosen. The other agents in the OPEC combination had also been associated with partial tumour response in a child [23] and in adults [14].
The role of adjuvant therapy has not been determined. Stewart et al. used postoperative irradiation in four chil- dren with large adrenal carcinomata (some with vena caval and nodal extension), three of whom survived 1 to 6 years [24]. Lefevre et al., on the other hand, saw measurable response to radiotherapy in only 1 of 11 cases [3].
Although there have been isolated reports of long- term survivors with o, p’-DDD for recurrent or meta- static disease [3, 15], this agent has not been used system- atically as adjuvant therapy in childhood. Likewise, experience with single agent [13, 14] and combination chemotherapy [12, 23] in childhood is limited.
This report illustrates the propensity for large adreno- cortical carcinomata to recur and metastasize. It also shows that combination chemotherapy containing cisplat- inum can be effective in causing regression of metastatic disease and so may have a role as adjuvant treatment in high-risk patients.
ACKNOWLEDGMENTS
We would like to thank Mrs. P. Hood for secretarial assistance.
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