From the Journals

Intensive AT/RT regimen sets new efficacy benchmark


 

FROM THE JOURNAL OF CLINICAL ONCOLOGY

Intensive postoperative chemotherapy and focal radiation may improve event-free survival (EFS) among patients with atypical teratoid/rhabdoid tumors (AT/RT), results of the phase 3 ACNS0333 trial suggest.

Compared with historical therapies, the treatment protocol reduced the risk of EFS events by 57%, reported lead author Alyssa T. Reddy, MD, of the University of California San Francisco Benioff Children’s Hospital, and colleagues, who also noted that this is the first AT/RT-specific cooperative group trial.

“Case series and retrospective data suggested high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue, early radiation therapy, and methotrexate had activity against AT/RT,” the investigators wrote in the Journal of Clinical Oncology.

Based on these findings, the investigators designed the ACNS0333 treatment protocol. Following surgery, all patients received two cycles of induction with methotrexate, vincristine, etoposide, cyclophosphamide, and cisplatin. They then underwent PBSC harvest.

Next, patients were divided into two groups based on age, disease location, and extent. Conformal radiotherapy was given between induction and consolidation to patients who were at least 6 months of age with tumor localized to the infratentorial brain or at least 12 months of age with tumor localized to the supratentorial brain. For younger patients or those with metastatic disease, radiotherapy was administered after consolidation was complete. Consolidation consisted of three cycles of thiotepa and carboplatin with PBSC support.

In addition to efficacy and safety analyses, molecular testing was performed on frozen tumor tissue and blood. This enabled a retrospective exploratory analysis of methylation profiles, which were used to subtype disease into three molecular classes: 2A/TYR, 2B/MYC, or 1/SHH-NOTCH.

Patient characteristics and results

The evaluable cohort included 65 patients, most of whom (83%) were younger than 36 months of age at baseline. About half of patients (51%) had infratentorial tumors, slightly fewer (40%) had supratentorial tumors, and 7.5% had a contiguous tumor in both locations. About one-third of patients (37%) had metastatic disease, and almost two-thirds (62%) had residual disease after surgery.

The median follow-up was 4.7 years. At 4 years, patients had an EFS rate of 35%. For patients aged 36 months or older, the 4-year EFS rate was higher still, at 48%.

These EFS rates compared favorably with the 6.4% EFS rate observed in a historical cohort of patients from the CCG-9921 trial (J Clin Oncol. 2005 Oct 20;23[30]:7621-31) and the POG-9233/4 trial (Neuro Oncol. 2014 Mar;16[3]:457-65). Overall, there was a 57% reduction in risk of EFS events in the ACNS0333 cohort compared with the historical controls (hazard ratio, 0.43; P less than .0005).

The 4-year overall survival rate was 43% for the entire ACNS0333 cohort and 57% for patients aged 36 months or older. Looking at molecular subtypes, patients with 1/SHH-NOTCH tumors had the best 4-year overall survival rate, at 56%, compared with 41% for 2A/TYR and 27% for 2B/MYC.

Adverse events were predominantly hematologic or infectious events reported during the induction and consolidation phases. Grade 4 or higher adverse events that occurred in at least 5% of patients were hypokalemia, hypotension, hypoxia, sepsis, ALT increase, and decreases in lymphocyte, neutrophil, platelet, and white blood cell counts.

Eight deaths were reported, four of which were associated with treatment. Causes of treatment-related death were sepsis after prolonged myelosuppression, respiratory failure from pulmonary fibrosis, and central nervous system necrosis (n = 2). One patient with central nervous system necrosis had viral encephalitis and sepsis at the time of death.

“ACNS0333 has shown that intensive multimodal therapy significantly improves survival for patients with AT/RT,” the investigators concluded. “However, further intensification using cytotoxic agents is likely not feasible. There are increasing data suggesting that AT/RT may be a good candidate for pathway-specific targeted therapies.”

The study was funded by the Children’s Oncology Group, the National Institutes of Health, the St. Baldrick’s Foundation, the Canadian Cancer Society, and the Children’s of Alabama Kaul Pediatric Research Institute. The investigators disclosed relationships with Novartis, AstraZeneca, and Merck Sharp & Dohme.

SOURCE: Reddy AT et al. J Clin Oncol. 2020 Feb 27. doi: 10.1200/JCO.19.01776.

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