Clinical Trials Show That Bone Marrow Transplant And Vitamin A Derivative Both Improve Survival From Neuroblastoma

May 18, 1998

LOS ANGELES -- Two innovative treatments -- bone marrow transplant and follow-up therapy with high doses of retinoic acid, a derivative of Vitamin A -- significantly improve the disease-free survival of children with high-risk neuroblastoma, the third most common childhood cancer.

Researchers at the University of California San Francisco and Childrens Hospital Los Angeles, working with the nationwide Children's Cancer Group, reported those findings from a randomized study of 539 children in two separate sessions at the annual meeting of the American Society for Clinical Oncology (ASCO) at the Los Angeles Convention Center on Monday, May 18.

"The improved survival rates came without a significant increase in toxic side effects or extra days in the hospital. We recommend that these therapies should be incorporated into future treatment regimens," said Katherine K. Matthay, M.D., director of the Children's Cancer Group neuroblastoma study. She is a professor of pediatrics at the University of California San Francisco and director of pediatric clinical oncology for Lucile Packard Children's Health Services at UCSF.

Matthay reported at ASCO on the bone marrow transplant results. C. Patrick Reynolds, MD, PhD, of Childrens Hospital Los Angeles (CHLA), reported on the retinoic acid stage of the trial. Reynolds is associate professor of pediatrics and pathology at the University of Southern California School of Medicine. He also described the research in an ASCO-sponsored press briefing on Sunday (May 17).

The study, a Phase III randomized trial designed to test the efficacy of the treatment, began in 1991 and was conducted at more than 100 medical centers. It showed a significant increase in event-free survival for children who received autologous purged bone marrow transplants. Results were even more dramatic for those whose initial therapy was followed up with high doses of 13-cis retinoic acid, a Vitamin A derivative commonly prescribed for acne under the trade name Accutane.

Most dramatic of all were results for a combination of the two treatments: 55% of the children who received bone marrow transplants survived free of relapse for three years after beginning follow-up treatment with retinoic acid. That rate compares to 16% for children treated with consolidation chemotherapy alone.

Neuroblastoma is a cancer of the sympathetic nervous system. The most common solid tumor, other than brain tumors, to occur in children, it rarely strikes adults. The average age of diagnosis is two-and-a-half years, and one in 6,000 children are diagnosed with neuroblastoma by the age of five. The patients who received treatment as part of the Children's Cancer Group Study were at high risk -- the majority had tumors that had metastasized to other sites.

The 539 children were treated with induction chemotherapy for five months, then surgery to remove their tumors. The surgery was followed either by a state-of-the-art therapy consisting of three cycles of intensive consolidation chemotherapy, or by chemoradiotherapy followed by purged autologous bone marrow transplants. In the latter treatment, part of the child's own bone marrow is harvested and purged of all cancer cells; the remaining bone marrow is destroyed by chemotherapy and radiation, then the frozen marrow is thawed and re-infused back into the patient to produce a cancer-free immune system. Reynolds' group at CHLA cleansed the bone marrow for all the transplant recipients in this study. Matthay reported that from a point eight weeks after diagnosis, 34 percent of the bone marrow transplant patients survived three years without a return of cancer, compared with 21 percent for those who received three cycles of intensive consolidation chemotherapy.

"This study shows that purged autologous bone marrow transplant after high dose chemoradiotherapy provides the best chance of survival in advanced neuroblastoma," said Matthay.

In the next stage of the trial, 129 patients who had received either consolidation chemotherapy or bone marrow transplants were given an additional course of high-dose 13-cis retinoic acid. The three-year event-free survival rate for children who received retinoic acid after either of the two intensive therapies was 47 percent. In comparison, 25 percent of the patients who received no further therapy survived three years with no recurrence of cancer.

This is the first randomized study to show that 13-cis retinoic acid is effective in treating neuroblastoma in patients with a poor survival prognosis. Matthay and Reynolds credit the Children's Cancer Group for the large-scale cooperative effort that made this study possible. Neuroblastoma is rare enough that it required coordination among many medical centers to conduct a randomized trial, they said.

"The reward for this cooperation is that we have shown that this is an improvement over standard chemotherapy, a way to improve the survival a little for children with this very bad disease," Matthay said.

"This was an incredible team effort," Reynolds said. "The reason it happened is that a whole lot of people didn't think it was right that kids should die so young."

The Children's Cancer Group is a national cooperative research organization which coordinates research at 115 medical centers, searching for treatments for the cancers of children and young adults. This study was funded primarily by the National Cancer Institute.

To interview Katherine Matthay, MD, please contact Janet Basu at UCSF News Services: (415) 502-4608 or (415) 476-2557.

To interview C. Patrick Reynolds, MD, please contact Steve Rutledge at Childrens Hospital Los Angeles at (213) 669-4121.

University of California - San Francisco

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