Clinical trial demonstrates that bone marrow transplant followed by vitamin A-derivative treatment improves survival from a major childhood cancer

October 14, 1999

Combining the efforts of children's cancer treatment programs nationwide, a randomized clinical trial of 539 children has shown that two innovative treatments, taken together, offer nearly a three-fold improvement in the disease-free survival of children with high-risk neuroblastoma, the third most common - and one of the most deadly -- of childhood cancers.

The National Cancer Institute-sponsored study showed that these children have the best chance of disease-free survival if their initial chemotherapy and surgery is followed by high-dose chemoradiotherapy and an autologous bone marrow transplant, where a child is re-implanted with her own bone marrow after it has been cleared of cancer cells. The results are improved even further if this treatment is followed by a high-dose course of 13-cis retinoic acid, a derivative of Vitamin A that also is prescribed for acne.

The study was led by Katherine K. Matthay, M.D., 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. The retinoic acid portion of the trial was led by C. Patrick Reynolds, M.D., Ph.D., of Childrens Hospital Los Angeles (CHLA), associate professor of pediatrics and pathology at the University of Southern California School of Medicine. Their results were reported in the October 14, 1999 issue of the New England Journal of Medicine.

The randomized multi-center Phase III clinical trial was the only way to prove the worth of these two treatments, which had shown promise in pilot studies, according to Matthay. "Studies had been done of bone marrow transplant, and of intensive chemotherapy. There were advocates of both treatments. But no one had done a randomized study of the two in comparison," she said.

Matthay credits the Children's Cancer Group, a national cooperative research organization, for enlisting the help of more than 100 cancer centers nationwide to join the study. Though neuroblastoma is common in terms of childhood cancer, it still is relatively rare. No single cancer center cares for enough young patients to mount a randomized trial comparing the effectiveness of the two treatments.

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

"The reason this study was possible is that a whole lot of people didn't think it was right that children should die so young," Reynolds said. 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, but affects one in 6,000 children under the age of five. It usually is fatal -- the long-term survival rate is only 15 percent. While cure rates for other children's cancers have improved dramatically in recent years, neuroblastoma and brain tumors remain serious threats. The neuroblastoma patients who received treatment as part of the Children's Cancer Group Study were at high risk -- the majority had tumors that had spread to other sites.

The study was conducted from 1991 to 1996, with results on patients collected until 1999. All children participated in the trial with the signed, informed consent of their parents or guardians. All of the children first were treated with induction chemotherapy and had surgery to remove their tumors. A control group of children received the standard follow-up treatment of three cycles of intensive chemotherapy alone.

A second, randomly selected group of the children received a different continued treatment including purged autologous bone marrow transplants. For this 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 total-body 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.

In a second phase of the trial, a subsequent therapy of high doses of 13-cis retinoic acid was given to a randomized selection of children from both groups - both those who had received bone marrow transplant after surgery, and those who had received intensive chemotherapy after surgery.

The results of the first phase of the study showed that bone marrow transplants offered a significant improvement in disease-free survival -- 34 percent of these children survived three years without relapses, while only 22 percent of the children receiving standard therapy did. Previous research shows that a greater time without relapses corresponds with a better chance of long-term survival.

In the second randomized phase, those children who survived after either bone marrow transplant or chemotherapy and then received 13-cis retinoic acid, 46 percent had no relapses within three years, versus 29 percent of children who received no retinoic acid. For patients who were randomized to both bone marrow transplantation and retinoic acid therapy, the 3-year survival after the time of starting retinoic acid was raised to 55%.

By analyzing all patients, including those who had early tumor relapse before being included in the randomized study, the researchers estimated conservatively that the disease-free survival rate 3.7 years from the time of diagnosis would be 29 percent for children who received both transplantation and 13-cis retinoic acid therapy. That rate compares to 11 percent for those who received intensive chemotherapy alone - nearly a three-fold improvement.

An additional finding of the study was that 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," Matthay said.

The Children's Cancer Group is a national cooperative research organization which coordinates research at 35 academic medical centers and their affiliated institutions - a total of 115 cancer treatment centers for children and young adults.

Principal authors of the article in the New England Journal of Medicine included Matthay, of UCSF; Reynolds and Judith G. Villablanca, M.D., Robert C. Seeger, M.D.; Daniel O. Stram , Ph.D., and Hiroyuki Shimada, M.D., of CHLA and USC; Richard E. Harris, M.D., of Children's Hospital Medical Center, Cincinnati; Norma K. Ramsay, M.D., of the University of Minnesota School of Medicine, Minneapolis; Patrick Swift, M.D., of Alta Bates Medical Center, Oakland; C. Thomas Black, M.D., of M.D. Anderson Hospital, Houston; Garrett M. Brodeur, M.D., of the University of Pennsylvania School of Medicine, Philadelphia; and Robert Gerbing, MA of the Children's Cancer Group, Arcadia, California.

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

To interview C. Patrick Reynolds, M.D., Ph.D., please contact Steve Rutledge at Childrens Hospital Los Angeles at 213-669-4121.

University of California - San Francisco

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