Can New Standard of Care in Neuroblastoma Be Used in the US?

Zosia Chustecka

June 06, 2011

June 6, 2011 (Chicago, Illinois) — Improved outcomes in high-risk neuroblastoma have been reported with a high-dose myeloablative regimen that the European investigators say should be the new standard of care. The data were reported at the plenary session here at the American Society of Clinical Oncology 2011 Annual Meeting.

"The results are important for patients with this extremely difficult-to-treat disease," said principal investigator Ruth Ladenstein, MD, MBA, associate professor of pediatrics at the University of Vienna, Austria.

Until now, the best outcome in neuroblastoma has hovered around the 50% survival threshold, but the new regimen tested has pushed this up to 60%.

"This is an incredible success and a great achievement for pediatric oncology," said Julie Park, MD, from Seattle Children's Hospital in Washington, who acted as discussant for the study. But she and other American experts say that these results will need to be considered further before they are incorporated into clinical practice in the United States. Discussions about the results are now underway.

One of the issues is that the trial used an induction regimen that is popular in Europe; it was that regimen combined with the high-dose myeloablative regimen that together produced the improvement in survival.

In the United States, a different induction regimen is used, and it is unclear whether changing the myeloablative regimen without also changing the induction regimen would produce similarly good results.

"This is something that we will have to discuss, and there are some questions over this," said George Armstrong, MD, from St. Jude Children's Hospital in Memphis, Tennessee, who discussed the study in a "highlights of the day" session. He suggested that there is some synergy between the European induction regimen and the high-dose myeloablative regimen that led to the good results, but he did agree with the European investigators that their trial "established a standard of care for a common pediatric tumor."

Intense Treatment

Treatment for neuroblastoma comprises several steps. It begins with intense upfront chemotherapy to induce remission (induction), and is followed by surgery and radiation, myeloablative therapy with stem cell transplantation, and then consolidation therapy with 13-cis-retinoic acid and immunotherapy, if available.

The European trial used an induction regimen known as rapid COJEC, which consists of both cisplatin and carboplatin, and then compared a high-dose myeloablative regimen known as BuMel (busulphan plus melphalan) with carboplatin, etoposide, and melphalan (CEM; control group).

The BuMel group led to significantly improved survival at 3 years, compared with the control group (60% vs 48%). "The superiority was based on a lower relapse rate," noted Dr. Ladenstein.

In addition, BuMel had a significantly lower toxicity profile, she said. The severe toxicity rate up to day 100 (including admission into intensive care units and toxic deaths) was less than 10% in the BuMel group, but was significantly higher in the control group, she explained.

"Current practice should now veer toward the BuMel regimen," Dr. Ladenstein concluded.

However, applying these results to the United States will take some discussion, Lisa Diller, MD, clinical director of pediatric oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, told Medscape Medical News.

Current practice in the United States involves a different induction regimen, she explained, which was developed by the Children's Oncology Group (COG) on the basis of clinical trials conducted at Memorial Sloan-Kettering Cancer Center in New York City. It uses less platinum than the European rapid COJEC regimen, and notably it does not use carboplatin. In the United States, this is typically followed by the CEM myeloablative regimen. Together, these 2 interventions give better results than were seen in the control group of the trial that Dr. Ladenstein reported, which also used CEM but used a different induction.

Another issue is that the European induction regimen stacked the cards in favor of BuMel, and it is not clear whether using the American COG induction regimen with BuMel would give equally good results, she said.

"We have already been discussing these results," Dr. Diller said; they raise the question of whether an ongoing COG trial that uses CEM should be stopped for ethical reasons, given the good results from the European trial. However, because of questions about the different induction regimens, and because the trial is also comparing single with tandem transplantation, the data monitoring committee concluded that the trial should continue accruing patients.

"So the study is continuing, but we are worried about enrolment," she said; "the data monitoring committee will be keeping a close eye on it."

These results from the European trial offer hope for patients with neuroblastoma and the parents of these infants, Dr. Diller noted. This is the most common cancer identified in the first year of life, and it accounts for 15% of childhood cancer deaths. About 650 cases are diagnosed annually in the United States.

"When I first started in oncology about 20 years ago, the diagnosis of high-risk neuroblastoma was the one that I hated the most," Dr. Diller explained. "There was really very little hope to offer — all we had was aggressive chemotherapy; the long-term survival rates were only 10%."

"Discussing this with young parents was just heartbreaking," she said.

"The diagnosis of neuroblastoma is still devastating," she said. "There is a very long road of treatment ahead, but now we can offer hope. We have treatment regimens that have been proven in randomized clinical trials, and we have raised the long-term survival to around 50%," she said.

That bar has just been raised a little higher. Dr. Ladenstein said that "we have overcome the 50% threshold in survival rates by choosing the right high-dose myeloablative regimen for these patients."

The busulphan used in the study was donated by Pierre Fabre. Dr. Ladenstein and colleagues have disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting: Abstract 2. Presented June 5, 2011.


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