Pediatric Adrenocortical Carcinoma: Different Treatment Strategies by Disease Stage

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Carlos Rodriguez-Galindo, MD

Carlos Rodriguez-Galindo, MD

As reported in the Journal of Clinical Oncology by Carlos Rodriguez-Galindo, MD, and colleagues, the Children’s Oncology Group ARAR0332 Protocol has identified outcomes associated with different treatment strategies according to disease stage in patients with pediatric adrenocortical carcinoma.

Study Details

The study included 77 patients, enrolled between September 2006 and May 2013, who received different treatments according to adrenocortical carcinoma stage:

  • 24 with stage I disease (median age = 1.5 years) received adrenalectomy alone
  • 15 with stage II (completely resected > 200 cc or > 100 g) disease (median age = 2 years) received adrenalectomy and retroperitoneal lymph node dissection
  • 24 with stage III (median age = 3 years) and 14 with stage IV disease (median age = 13 years) were treated with mitotane and chemotherapy.

Treatment for patients with stage III or IV disease consisted of eight cycles of chemotherapy with cisplatin, etoposide, and doxorubicin and daily mitotane (adjusted to plasma concentrations of 14–20 µg/mL) for 8 months, with surgery of primary tumor and metastases as clinically indicated. Any patient who had mitotane stopped due to toxicity was considered to have a mitotane feasibility event; any patient who had a component of chemotherapy stopped due to toxicity was considered to have a chemotherapy feasibility event.

Key Findings

The 5-year event-free survival estimates were 86.2%, 53.3%, 81%, and 7.1%, for stages I, II, III, and IV, respectively; the corresponding 5-year overall survival estimates were 95.2%, 78.8%, 94.7%, and 15.6%, respectively.

On univariate analysis, age, stage, presence of virilization, Cushing syndrome, hypertension, germline TP53 status, and presence of a somatic ATRX mutation were associated with event-free survival. On multivariate analysis, only stage (P < .001) and age (P = .003) remained significant factors. Compared with stage I, hazard ratios were 4.3 (95% CI = 1.1–17) for stage II, 0.92 (95% CI = 0.20–4.3) for stage III, and 9.4 (95% CI = 2.5–37) for stage IV. Compared with median age ≤ 38 months, the hazard ratio was 3.8 (95% CI = 1.5–9.8) for median age ≥ 39 months.

The probabilities of mitotane and chemotherapy feasibility events were 10.5% (95% CI = 2.9%–24.8%) and 31.6% (95% CI = 17.5%–48.7%), indicating that the regimen was not feasible and that further modifications are required to improve tolerance.

The investigators concluded: “Outcome for children with stage I adrenocortical carcinoma is excellent with surgery. Outcome for patients with stage II disease is inferior despite retroperitoneal lymph node dissection. Patients with stage III adrenocortical carcinoma have an excellent outcome combining surgery and chemotherapy. Patients with stage IV adrenocortical carcinoma are older and have a poor outcome; new treatments should be explored for this high-risk group. The combination of mitotane and chemotherapy as prescribed in ARAR0332 resulted in significant toxicity; one-third of patients with advanced disease could not complete the scheduled treatment.”

Dr. Rodriguez-Galindo, of the Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by National Cancer Institute grants, Canadian Institutes for Health Research, American Lebanese Syrian Associated Charities, and St. Baldrick’s Foundation. For full disclosures of the study authors, visit

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