2011 Plenary Retrospective: New Standard of Care for High-Risk Neuroblastoma in Europe

2011 Plenary Retrospective: New Standard of Care for High-Risk Neuroblastoma in Europe

Dr. Ruth Ladenstein presented SIOPEN trial results during the 2011 Plenary Session.
Trial results presented during the 2011 ASCO Annual Meeting Plenary Session indicated that the myeloablative regimen of busulfan and melphalan (BuMel) was superior to the regimen of carboplatin, etoposide, and melphalan (CEM) for treatment of high-risk neuroblastoma. Ruth Ladenstein, MD, of St. Anna Children’s Cancer Research Institute, Austria, presented the phase III results of the HR-NLB1/SIOPEN trial, which was stopped early after an analysis showed 49% event-free survival (EFS) with the BuMel regimen compared with 33% for the CEM regimen.1

These trial results prompted pilot studies in North America but did not change clinical practice. BuMel, however, now is considered the “high-dose therapy benchmark” in patients with high-risk neuroblastoma treated in Europe, Dr. Ladenstein told the ASCO Daily News. “After COJEC [cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide] induction, BuMel significantly improved EFS in children with high-risk neuroblastoma with an adequate response to induction therapy and induced less severe toxicities,” she said. “Ongoing randomized SIOPEN studies will continue to optimize therapy for high-risk neuroblastoma.”

The multinational, cooperative group, randomized clinical SIOPEN trial enrolled patients with high-risk neuroblastoma on an open-label study that included 598 eligible patients who received rapid induction therapy with COJEC. After induction therapy, 296 patients received an oral BuMel regimen; after 2006, busulfan was administered intravenously in the regimen. The remaining 302 patients received a CEM regimen of carboplatin infusion, etoposide infusion, and melphalan. Local therapy included surgery and radiotherapy.

Attendees watch the Plenary Session during the 2011 ASCO Annual Meeting.
During her 2011 Plenary presentation, Dr. Ladenstein reported a 3-year survival rate of 60% in the BuMel group compared with 48% in the CEM group. She told the ASCO Daily News that severe toxicities were lower with BuMel (4%) than with CEM (10%) and that BuMel had fewer grades 3 and 4 non-hematologic toxicities. BuMel was associated more often with veno-occlusive disease (18% occurrence of Bearman toxicity grades 2 to 3; 5% were grade 3) than CEM (9% occurrences of grades 2 to 3; 1% were grade 3). EFS at 5 years was 45% in patients randomly assigned to BuMel compared with 33% in patients randomly assigned to CEM (p = 0.0005), she said.

Comparison of SIOPEN and COG Trial Results

Julie R. Park, MD, of the University of Washington, was the discussant during the presentation in 2011. She compared the results of the SIOPEN trial with previous Children’s Oncology Group (COG) research in which the 3-year EFS for the CEM group was 46%—substantially better than the 33% reported for the SIOPEN trial. She suggested during her remarks that the rapid COJEC induction regimen used in the SIOPEN trial could have a negative interaction with CEM. The COG research had included an induction regimen that did not involve carboplatin and that used lower doses of cisplatin and etoposide than the COJEC regimen used in the SIOPEN trial.

Dr. Julie Park, credit Nancy LeVine

In a recent interview, Dr. Park said that one of the reasons that SIOPEN did not change the standard of care in North America was the concern that the induction regimen was heavily weighted toward intense platinum. North American researchers had other concerns about BuMel, including the difference in the toxicity profile.

“In some ways, BuMel has less risk for severe mucositis and therefore some of the infectious complications,” Dr. Park said. “But it has a much higher risk for sinusoidal obstruction syndrome. We felt it was important to further study whether incorporation of BuMel into the backbone of North American therapy was tolerable, especially to ensure that toxicities such as sinusoidal obstructive syndrome did not preclude patients from going on to receive post-consolidation immunotherapy.”

[2011 Plenary marked the ‘beginning of the renaissance’ for melanoma]

Other North American Studies

Dr. Susan Cohn
After the SIOPEN results were presented in 2011, pilot studies were initiated in North America to look at the BuMel regimen.

“When the results were reported at the ASCO [Annual Meeting] in 2011, we thought this could be the new standard of care. We carefully evaluated the data, although we didn’t completely understand why the survival results with CEM in the SIOPEN study were inferior to the results we were observing in our COG study,” Susan L. Cohn, MD, of the University of Chicago, said. “Nevertheless, the demonstration that BuMel was more effective than CEM and less toxic was a significant finding. COG developed a pilot study to test BuMel following our induction regimen, and we had every intention of adopting BuMel if the pilot study demonstrated feasibility.”

Results of another study that was underway in 2011, however, changed clinical practice in North America. Both Dr. Park and Dr. Cohn were investigators on a trial performed through COG in which patients were randomly assigned to either a single autologous stem cell transplantation (ASCT) after CEM or tandem ASCT after cyclophosphamide/thiotepa and a modified regimen of CEM.2 Approximately 70% of patients who completed induction and consolidation entered a second trial that evaluated post-consolidation immunotherapy with isotretinoin alone compared with isotretinoin plus dinutuximab and cytokines (i.e., GD2-directed immunotherapy).

Dr. Park presented the results of that trial during the 2016 ASCO Annual Meeting. Results showed that tandem ASCT improved EFS at 3 years without additional toxicity. The 3-year EFS was 61.4% with tandem ASCT and 48.4% with single ASCT (p = 0.0081); overall survival was 74.0% and 69.1%, respectively (p = 0.1850). The benefit of tandem ASCT was preserved in patients who also received GD2-directed immunotherapy. For those patients, the 3-year EFS was 73.7% with tandem ASCT and 56.0% with single ASCT (p = 0.0033).

“The results for patients with high-risk neuroblastoma receiving tandem transplant and subsequent immunotherapy are the best that have been reported to date,” Dr. Park said. “This has led to the incorporation of tandem transplant into therapy for patients with high-risk neuroblastoma diagnosed in North America.”

Further investigation will be needed to understand how to incorporate the BuMel results into this new North American standard, she said.

Continued randomized clinical trials that evaluate new therapies for high-risk neuroblastoma are vital to improve the outcome for this disease, Dr. Park said. “Such trials help to define the standard and allow subsequent comparison to novel therapies. The SIOPEN trial was a remarkable accomplishment made possible by collaboration across more than 20 countries. It cannot be overstated how important it is to continue multisite and international collaborations that enable the conduct of rigorous randomized clinical trials for rare diseases such as neuroblastoma.”  

–Kathy Holliman, MEd