Partial Response After Intensive Chemotherapy for Adrenal Cortical Carcinoma in a Child
Maurizio Aricò, MD, Grazia Bossi, MD, Chiara Livieri, MD, Emanuela Raiteri, MD, and Francesca Severi, MD
Adrenocortical carcinoma (ACC) in child- hood is a rare tumor with high fatality rate. Available reports provide event free survival rates ranging between 10 to 50%. Optimal treatment has not yet been established; sur- gery plays a major role, and the value of adjuvant chemotherapy needs to be evalu- ated further, especially in children who de- velop recurrent disease and those with me- tastases at diagnosis. Optimal therapy of ACC has not been established. Surgery has been curative after complete tumor resec- tion. Children with inoperable, recurrent and metastatic ACC have been treated with O,P’DDD, with response rates ranging from 10 to 60% in different series [7,11-20]. Radio-
therapy [21] and other anti-cancer drugs have been used [4-22] but their efficacy has not been established. Combination chemo- therapy containing oncovin, cisPlatinum, epipodophyllotoxin and cyclophosphamide (OPEC) produced regression of metastatic ACC in a 5-year-old male [23].
We report one girl with relapsed dissemi- nated ACC who showed good, even if tem- porary, control of the disease, with disap- pearance of lung, liver and spleen metastases, and marked reduction of the adrenal mass, following combined chemotherapy according to the “eight-drugs-in-one-day” protocol. C) 1992 Wiley-Liss, Inc.
Key words: childhood, adrenal cortical carcinoma, chemotherapy
INTRODUCTION
Adrenocortical carcinoma (ACC) is rare in childhood accounting for only 0.2% of all childhood malignancies [1,2] and about 5-6% of adrenal cancers [3]. Recently published data suggest an incidence of 0.5 cases per million per year [4]. Chromosome 11 alteration was re- cently reported in ACC in children but not in adults [5]. The diagnosis is often delayed and difficult because of its rarity and the deep retroperitoneal location of the adrenal glands. About 95% pediatric adreno-cortical tumors are hormonally active [6] compared to only 35% in adults [7]. The natural history of ACC was noted in 1958 by McFarlane when he stated that the mean survival of un- treated patients was 2.9 months [8]. Recent reports sug- gest event-free survival ranging between 23 to 45% at 5 years [7,9] but only 10% at 10 years [7]. A recent review suggests that older age, interval of > 6 months between the initial symptoms and diagnosis, increased urinary steroid levels, and a tumor size greater than 200 cm3 are associated with an increased risk of treatment failure
[9,10]. We report one girl with relapsed ACC who had good partial clinical response following combined che- motherapy according to the “eight-drugs-in-one-day” protocol [24].
CASE REPORT
A 2-year-old girl had been first seen for virilization. On admittance, examination showed height at the 90th centile and weight at the 50th centile (according to Tan- ner) for age without evidence of hypertension or moon facies. There was a palpable abdominal mass extending 6
From the Department of Pediatrics, IRCCS Policlinico San Matteo, the University of Pavia, Pavia, Italy.
Received July 18, 1991; accepted December 19, 1991.
Address reprint requests to Dr. Maurizio Aricò, Clinica Pediatrica dell’Università di Pavia, IRCCS Policlinico San Matteo, I-27100, Pa- via, Italy.
@ 1992 Wiley-Liss, Inc.
| Time | T ng/dl | C ng/dl | DHA ng/ml | DHA-S ng/ml | D4-A ng/ml | 17 OH-P ng/ml | 17-KS mg/24 h | 17 OHC mg/24 h |
|---|---|---|---|---|---|---|---|---|
| Normal range | <20 | 5-28 | <2.5 | <150 | <1.2 | 0.2-1.6 | <3.0 | <5.0 |
| Surgery | 200 | 16.2 | >30 | 3,850 | >6 | 2.4 | 5.6 | 1 |
| Day + 3 | 0.38 | ND | <0.5 | 176 | 1 | 0.2 | 1.06 | 5 |
| Day + 10 | <12 | 15.3 | <0.5 | 51 | ND | 0.28 | ND | ND |
| Day + 20 | <12 | ND | <0.5 | <50 | ND | ND | ND | ND |
| Month + 3 | 42 | ND | 2.2 | 1,190 | ND | ND | ND | ND |
| Month + 4 | 124 | ND | >30 | 4,711 | ND | 0.5 | ND | ND |
| (relapse) | ||||||||
| Month + 5 | 136 | ND | ND | 6,200 | ND | 1.8 | ND | ND |
| Month + 8 | 350 | ND | ND | 6,400 | ND | 1.8 | ND | ND |
| Month + 9 | 51 | ND | ND | 1,687 | ND | ND | ND | ND |
*Abbreviations: T = Testosterone; C = Cortisol; DHA = Dehydroepiandrosterone; DHA-S = Dehydroepiandrosterone sulphate; D4-A = Delta-4 Androstenedione; 17-OH-P = 17-OH Proges- terone; 17-KS = 17 Ketosteroid; 17-OH-C = 17 OH corticosteroid; ND = Not determined.
cm below the left costal margin. She had stage-2 pubic hair and clytorimegaly. Full blood examination revealed WBC 10,700/mm3, Hb 7.9 g/dl, MCV 54 fl, platelets 842,000/mm3. Serum and urinary steroids were increased (Table I). Urinary VMA and catecholamines were nor- mal. Serum CEA was 0.8 ng/ml, Ca 125 was 14.3 U/ml, Ca 50 was 4.9 U/ml. Bone age (according to Greulich and Pyle) was 2.5 years (+4 months). Chest X-ray was normal. Abdominal ultrasound and CT scan showed a large retroperitoneal mass displacing the left kidney downward.
The tumor was resected together with the left kidney, part of the diaphragm, and one large pararenal lymph node; it measured 14 x 6 cm, weighed 385 g, was encap- sulated and largely necrotic. Histology showed the diag- nosis of ACC. Perioperative steroid treatment had been given. One single dose of vincristine and cyclophospha- mide was administered, and the child was soon dis- charged. Eight weeks postoperatively she developed fe- ver, followed by sharp increase in the DHA-S level that had previously been normal (Table I). We first saw the child 4 months after surgery, when control ultrasound showed recurrent lesions in the primary tumor site and in the spleen. At that time she was in good condition. Clini- cal findings showed WBC 9,900/mm3, Hb 7.5 g/dl, fer- ritin 352 ng/ml, normal LDH and alfa-fetoprotein. CT scan confirmed progression of the disease due to large local relapse, multiple secondary lesions in both lungs, a transdiaphragmatic lesion displacing the colon down- ward, one mass invading the psoas muscle and multiple enlarged retroperitoneal lymph nodes. Combined poli- chemotherapy was started according to the “eight-drugs- in-one-day” protocol [11]; vincristine 1.5 mg/m2 i.v., methyl-prednisolone 600 mg/m2 i.v., carmustine (CCNU) 75 mg/m2 i.v., procarbazine 75 mg/m2 orally,
hydroxyurea 1500 mg/m2 orally, cisplatin 60 mg/m2 i.v., cytosine-arabinoside 300 mg/m2 i.v., cyclophosphamide 300 mg/m2 i.v. The treatment was well tolerated without relevant toxicity. Restaging after the first cycle showed marked reduction in the size of the pulmonary lesions. Additional courses were given monthly. After the third cycle, ultrasound re-evaluation showed marked reduction of all the intra-abdominal metastases. After the 5th cycle, restaging showed disappearance of all the pulmonary le- sions, marked reduction of the adrenal mass and of the intraabdominal lymph nodes, and disappearance of the liver and spleen metastases. Nevertheless, soon thereaf- ter, she developed a new lung metastasis with increase of the serum and urine steroid levels. Despite administration of a total of 10 cycles of chemotherapy, the child had progressive disease with massive involvement of lungs, liver and the primary site. O,P’DDD-mitotane 500 mg/ daily was administered for 2 months with no improve- ment. She died 18 months after surgery, 13 months after starting chemotherapy.
DISCUSSION
This child had a dismal prognosis according to her huge tumor burden. Nevertheless, following apparently complete resection of the primary mass and according to normalization of steroid levels, the decision had been made not to give adjuvant chemotherapy. She developed metastatic disease soon after surgery, however, presag- ing a dismal prognosis, so we decided to treat her with aggressive salvage chemotherapy.
The rationale for using multiple drugs administered simultaneously or in a close temporal sequence derived from an attempt to minimize the emergence of tumor cell lines resistant to chemotherapy, also addressing the prob-
lem of heterogeneity and variable permeability to drugs within these cells. Our experience with this combination therapy in children with brain tumor had demonstrated its feasibility and very low acute toxicity. The child obtained a good response. There was disappearance of the large local relapse and the multiple secondary lesions in the lungs and in the transdiaphragmatic region, albeit disease control was only transient, lasting about four months. It was followed by overt disease progression, refractory also to O,P’DDD-mitotane. The value of adjuvant che- motherapy in ACC remains to be further clarified. A cooperative approach could warrant a trial of O,P’DDD in patients with low tumor burden and with combined chemotherapy including cisplatin in children with unfa- vorable prognosis or in relapse.
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