1. DiGiulio, Sarah

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Adrenocortical carcinoma (ACC) is a rare type of cancer, especially in children. But when it does occur, tumors are often aggressive and carry germline TP53 mutations. And because of their low prevalence, treatment protocols specific to children have not been well-investigated. This is what led Carlos Rodriguez-Galindo, MD, Chair of Global Pediatric Medicine and Director of St. Jude Global at St. Jude Children's Research Hospital, and his colleagues to conduct a recent trial investigating the use of adrenalectomy and retroperitoneal lymph node dissection with or without chemotherapy and mitotane for children with various stages of ACC. The results were published in the Journal of Clinical Oncology online ahead of print (2021; doi: 10.1200/JCO.20.02871).

Carlos Rodriguez-Gal... - Click to enlarge in new windowCarlos Rodriguez-Galindo, MD. Carlos Rodriguez-Galindo, MD

In conclusion, the authors noted: "Treatment of pediatric ACC can follow a risk-adapted approach, with surgery alone for patients with small tumors. Retroperitoneal lymph node dissection as conducted in this study failed to improve outcomes for patients with larger tumors, and thus its role as a standalone treatment strategy is uncertain. Patients with stage III demonstrate an excellent outcome combining surgery and chemotherapy, whereas the outcome for patients with metastatic disease remains poor."


The researchers called for more investigation of therapy options for people with metastatic ACC and more international collaboration in future research efforts (given the low prevalence of the cancer in any one country). In an interview with Oncology Times, Rodriguez-Galindo shared his thoughts about the research.


What led you and your coauthors to conduct this research now?

"The rarity of pediatric ACC has limited our ability to develop prospective clinical trials that could inform evidence-based treatment decisions. ACC is one of the rarest cancers in children; only about 30 cases are diagnosed every year in the United States. This gives you an idea of how difficult it is to organize a clinical trial with enough numbers to answer specific questions.


"Our study enrolled 78 patients over a 7-year period, and about one-third of these patients were enrolled in two institutions in Brazil, where the incidence of ACC is much higher, owing to a high prevalence of a germline mutation in the TP53 gene amongst its population.


"This trial was designed to answer three major questions:


1. Can we cure patients with small localized tumors with surgery only?


2. What is the role of retroperitoneal lymph node dissection in the treatment of children with localized resectable larger tumors?


3. What is the role of intensive chemotherapy and mitotane for children with more advanced disease?



"In addition to these three major treatment questions, we included several biology questions to estimate the prevalence of germline TP53 mutations and to understand the genomic landscape of this malignancy."


What were the most significant lessons learned from this trial?

"First, the outcome of patients with localized small tumors is excellent with surgery only (5-year overall survival estimates were 95 percent). For patients with larger tumors, the addition of a retroperitoneal lymph node dissection did not improve outcomes. Patients with locally advanced disease did very well with chemotherapy and surgery; this group includes patients with intraoperative tumor spillage.


"However, patients with metastatic disease did very poorly, even with the use of intensive chemotherapy. We also found that the use of the chemotherapy included in this protocol was very toxic. In terms of TP53 mutations, we found that about close to two-thirds of children with ACC carry a germline mutation."


So, what's the bottom-line message for practicing oncologists and cancer care providers? Should clinical practice change because of these findings?

"We can develop risk-adapted therapies for children with ACC, and this study is the first step towards better treatments.


"The results of the study help consolidate some existing practices, such as surgery only for small resectable tumors, and support the use of chemotherapy in cases of advanced localized disease. We were not able to demonstrate any beneficial impact to the use of retroperitoneal lymph node dissection; however, in a significant proportion of cases, this procedure was not done as prescribed, thus limiting our interpretation of the findings.


"Several questions remain, particularly the development of a better molecular-based risk stratification system that would allow us to understand better who can be treated with surgery only or who needs chemotherapy among patients with large tumors. We also need to find better treatments for patients with metastatic disease, who currently have very poor outcomes. Recent developments in the field of immunotherapy are promising, and some future efforts will be focused on understanding better the role of this approach."