HIGH DOSE CHEMOTHERAPY HELPFUL FOR SOME PEDIATRIC NEUROBLASTOMAS

May 21, 2010 — Marrow-scorching high-dose chemotherapy plus autologous stem cell transplantation is firmly established as the standard of care for higher-risk pediatric neuroblastoma in the wake of a review published online May 12 in the Cochrane Database of Systematic Reviews, but experts tell Medscape Oncology that new treatments now in clinical trials are likely to change that.

Nita L. Seibel, MD, head of pediatric solid tumor therapeutics at the National Cancer Institute (NCI) Cancer Therapy Evaluation Program's Clinical Investigations Branch, said that "we're making improvements. Our goal is to cure every child with neuroblastoma, and it would be fair to say that in the past few years, we have made definite progress toward that goal."

The starting line was set by the Cochrane reviewers, led by Bilgehan Yalçin, MD, and was based on pooled data from 3 randomized controlled trials of high-dose chemotherapy for neuroblastoma.

"We found many studies that reported on the results of high-dose chemotherapy for neuroblastoma, but only 3 were real randomized controlled trials," said Dr. Yalçin, professor of pediatrics and a pediatric oncologist at Hacettepe University Faculty of Medicine in Ankara, Turkey.

The meta-analysis involved 739 children whose neuroblastoma was judged high risk (older than 1 year of age, disseminated disease, MYCN oncogene amplification, and unfavorable histopathologic findings).

The reviewers found that children who had received high-dose chemotherapy with hematopoietic stem cell rescue remained well and without recurrent disease for longer than those who received conventional chemotherapy. They also lived significantly longer. In the 1 of the 3 studies, for example, 47% of the patients who received myeloablative therapy were alive and free of disease 3 years later, compared with 31% of those who had received standard therapy.

Senior author of the meta-analysis, Elvira C. van Dalen, MD, PhD, from Emma Children's Hospital/Academic Medical Center in Amsterdam, the Netherlands, told Medscape Oncology that "our most important conclusion is that, based on the currently available evidence, myeloablative therapy seems to be a good treatment option for children with high-risk neuroblastoma. It results in higher survival rates (both overall and event-free) than conventional therapy, although possible higher levels of adverse effects should be kept in mind."

Dr. Seibel, who was approached for comment, agreed that, on balance, the benefits appear to outweigh the risks. "On the whole, our neuroblastoma patients are able to tolerate high-dose chemotherapy quite well. That is partly because we have been able to refine the regimens and partly because clinicians are more experienced with them now and better able to prevent and/or manage side effects."

Data on adverse effects were "very limited" in the studies included in the meta-analysis. Two studies contained information on treatment-related death and secondary malignant disease. These events were rare, and no more likely in children who received myeloablative therapy than in those who received conventional chemotherapy.

The only study with detailed information on other severe adverse effects found that treatment made no difference in the risk for sepsis or serious infection. However, children who received high-dose chemotherapy were significantly more likely to experience certain adverse effects affecting their kidneys, lungs, and liver. None of the studies described the effect of treatment on quality of life.

"Each of these [adverse] effects can be life-threatening, but medical teams have gotten much better at treating them and identifying them as early as possible," Dr. Seibel said. "In high-risk neuroblastoma, the risk of dying from the cancer is much greater than and worth the risk of the side effects," she added.

Optimism Over New Treatments

Dr. Seibel said that there is considerable optimism among neuroblastoma researchers that the improvements in the overall and event-free survival seen with high-dose chemotherapy and stem cell rescue will be expanded with some of the neuroblastoma treatments now in development.

These include the chimeric anti-GD2 antibody ch14.18; 13-cis-retinoic acid use during and after conventional treatment; fenretinide oral powder, a new form of retinoic acid; 131I-metaiodobenzylguanidine (13II-MIBG); Ultrase, a new form of iobenguane 131I; TPI 287 with or without teozolomide; and gene therapy using interleukin (IL)-2-gene modified neuroblastoma cells.

Encouraging data with the chimeric 14.18 antibody were reported last year from a phase 3 trial presented at the 2009 meeting of the American Society of Clinical Oncology, as reported by Medscape Oncology. The results showed that, compared with the standard therapy of 13-cis-retinioic acid given in complete remission or in very good partial remission after intensive induction and consolidation, patients who received 13-cis-retinioic acid plus ch14.18 combined with GM-CSF or IL-2 had significantly higher event-free survival, with 2-year estimates of 66%, compared with 46%. Preliminary overall survival was also significantly higher, to the degree that the trial was stopped early.

Dr. Seibel told Medscape Oncology that the NCI-funded researchers are now seeking a commercial partner for the clinical development of the ch 14.18 antibody for the treatment of high-risk neuroblastoma. "The main limitation right now is the the supply of the antibody," she said.

Dr. Seibel also said that 13II-MIBG is in pilot studies to see whether it can be tested in a multicenter study throughout the country, and that work with fenretinide is exciting as a possible alternative to IL-2 for maintenance therapy.

The big unknown is the form in which myeloablative therapy and stem cell rescue will be most effective. Dr. van Dalen warned that the improved outcome with myeloablative therapy must be viewed in the context of the complete therapy. That would include the effect of the preceding therapy (such as induction chemotherapy, surgery, and/or radiotherapy), the myeloablative regimen with or without total body irradiation, the stem cells (purged or not), the origin of the stem cells (bone marrow or peripheral blood), and the presence and type of consolidation chemotherapy.

Because those factors differed among the studies examined, the meta-analysis supports conclusions only on the concept of myeloablative treatment vs control treatment. "We cannot make conclusions with regard to specific versions of these treatments," Dr. van Dalen emphasized.

The researchers have disclosed no relevant financial relationships.

Cochrane Database Syst Rev. 2010;5:CD006301. Abstract