Kate Johnson

June 06, 2016

CHICAGO — For children with high-risk neuroblastoma, an intensified "tandem" myeloablative autologous stem cell transplant (ASCT) treatment has improved survival so much that research is looking ahead at survivorship issues.

"We now have an increasing number of survivors from high-risk neuroblastoma," said Julie R. Park, MD, from Seattle Children's Hospital and the University of Washington School of Medicine.

"In 1990, only 30% of children were alive at 5 years; now, with our current data, 60% will be. We're now embarking on very specific survivorship studies for these children to really start to understand the long-term risks," she explained.

Results from the Children's Oncology Group (COG) phase 3 randomized ANBL0532 trial were presented by Dr Park during the plenary session here at the American Society of Clinical Oncology 2016 Annual Meeting. On the basis of these results,  tandem ASCT treatment, along with immunotherapy, is the recommended treatment for high-risk neuroblastoma.

Although the trial did not show a statistically significant overall survival advantage with  tandem over single ASCT treatment, there was "an early signal that we think will translate ultimately into overall survival," she told Medscape Medical News.

"Our clinical trials for neuroblastoma have always been powered for event-free survival, not overall survival.... We would have had to wait 10 years to see a difference in overall survival, and we really feel that event-free survival is a surrogate," she noted.


Dr Julie Park


"The results will change the way we treat high-risk neuroblastoma in North America," she added.

The study involved children (median age, 3.1 years) who received six cycles of multiagent induction chemotherapy.

"Peripheral blood stem cells were harvested after the initial two cycles of chemotherapy, and patients underwent resection of their primary tumor after five cycles," Dr Park explained.

All study participants had adequate stem cell collection, adequate organ function, and no evidence of disease progression.

Of the study participants, 179 received single ASCT with the combination of carboplatin, etoposide, and melphalan (CEM), and 176 recevied tandem ASCT, which involved single ASCT with cyclophosphamide and thiotepa followed 6 weeks later by a modified CEM regimen and a second ASCT.

All patients went on to receive radiation of the primary site and were then eligible for another trial, in which they received immunotherapy.

"Approximately 70% of those randomized actually went on to receive immunotherapy. This is important, as previous clinical trials have established that anti-GD2 antibody in combination with isotretinoin improves outcome in children with high-risk neuroblastoma," Dr Park explained.

Three-year event-free survival was significantly better in the tandem group than in the single group (61.4% vs 48.4%; P = .0081). This advantage persisted in the children who went on to receive immunotherapy (73.7% vs 56.0%; P = .0033).

There was a nonsignificant trend toward better 3-year overall survival in the tandem group than in the single group before immunotherapy (74.0% vs 69.1%; P = .1850) and after immunotherapy (83.7% vs 74.4%; P = .0322).

There was no increase in toxicity with tandem treatment, even though "this is the most aggressive treatment we give for any childhood cancer," said Dr Park.

The adverse events most commonly seen in the tandem and single groups were infectious toxicity (18.3% vs 17.9%), mucosal toxicity (17.2% vs 13.65), and hepatic toxicity/sinusoidal obstructive disorder (6.5% vs 6.2%). Death related to toxicity affected 1.2% of the tandem cohort and 4.1% of the single cohort.

With increasing numbers of high-risk neuroblastoma patients remaining cancer-free for up to 3 years, the focus is shifting away from disease recurrence and toward the rest of the patients' lives, she said.

"If you are more than 3 years out without having a recurrence of your disease, then that is a minor issue. The survivorship issues will really be bone health, endocrine issues, ovarian function, and fertility," Dr Park reported.

Questions Remain

These results "strongly support the use of intensified treatment as a future strategy in high-risk neuroblastoma," said study discussant Dominique Valteau-Couanet, MD, PhD, from Institut Gustave Roussy in Villejuif, France.

But many questions remain, such as how the intensified treatment might affect late recurrence, she pointed out.

"We know that high-risk patients have dismal survival after relapse," she said. In fact, "postrelapse 5-year overall survival is 7%."

"We need a longer follow-up to determine the effect of intensified treatment on postrelapse survival," she explained.

Dr Valteau-Couanet noted that the benefits of immunotherapy in addition to tandem ASCT have yet to be elucidated because the two approaches were used together.

In a recent trial by her team of single ASCT that involved the treatment of 26 very-high-risk neuroblastoma patients with high-dose thiotepa plus busulfan and melphalan chemotherapy, 3-year event-free survival was 37.3% (Bone Marrow Transplant. 2016;51:227-231).

In light of different approaches to treatment in North America and Europe, closer collaboration between COG and the International Society of Paediatric Oncology European Neuroblastoma Research Network (SIOPEN) will allow the design of complementary studies to identify the most effective risk-tailored intensified strategies for these patients, Dr Valteau-Couanet explained.

Dr Park reports receiving travel, accommodations, and expenses from Roche. Dr Valteau-Couanet  has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract LBA3. Presented June 5, 2016.


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