For Immediate ReleaseMay 7, 2001
Contact: John Ascenzi 215-590-7332[email protected]
Pooling International Data About Childhood Tumors Helps Researchers Gauge How Aggressive Treatment Must Be
Runaway Neuroblastoma Tumors Respond to New Molecular Methods
Philadelphia, Pa.--Sorting types of cancer into higher- and lower-risk groups is not merely a matter of scientific interest, but a matter of life and death. Undertreating a highly aggressive cancer could lead to the preventable death of a child, whereas overtreating a less aggressive form may subject a child to unnecessary side effects and complications. With some children, what is left undone may be just as important as what is done to treat their tumors.
Yet some cancers behave in ways that defy easy categorization. A case in point is neuroblastoma, a solid tumor of the peripheral nervous system that accounts for 10 percent of all childhood cancers and 15 percent of cancer deaths in children. These tumors occur almost exclusively in children, usually arising in the abdomen or chest.
Unfortunately, Hunter Tuccio had a very aggressive form of neuroblastoma. In September 1997, two months short of his second birthday, the active toddler abruptly lost his characteristic energy and appetite. "In less than a week, he deteriorated to the point that he couldn't move his eyeballs," said his mother, Susan Tuccio. His pediatrician, in Ridgefield, Conn., had him admitted to the local hospital where ultrasound detected a tumor in Hunter's abdomen, on his adrenal gland.
The diagnosis was neuroblastoma. "After you find out your child has cancer, your world is never the same," said Mrs. Tuccio. A search for answers led her to The Children's Hospital of Philadelphia, where pediatric oncologists have been world leaders in caring for children with neuroblastoma and studying this disease in the laboratory.
Hunter's neuroblastoma was classified as stage 4: the cancer had spread beyond the primary tumor. Even worse, the tumor cells contained multiple copies of a particular gene, labeled MYCN, which is a cancer-causing "oncogene." Often compared to an accelerator pedal, MYCN can cause cancer cells to multiply in a runaway fashion. When MYCN is amplified -- which means that cells have 200 copies rather than the normal two copies of the defective gene -- the prognosis is grave. In fact, at the time of Hunter's diagnosis, only about 20 percent of children with this high-risk type of neuroblastoma were surviving with the conventional treatment of chemotherapy, radiation and surgery.
"MYCN amplification is the most important factor predicting a patient's likelihood of survival from neuroblastoma," says Garrett Brodeur, M.D., chief of Oncology at The Children's Hospital of Philadelphia, whose research has helped oncologists worldwide establish better standards for diagnosing and treating children with neuroblastoma. "If we use only the child's age and disease stage as criteria for assigning risk, some patients will be undertreated and some will be overtreated."
Raising the Bar in Neuroblastoma TreatmentHunter underwent intensive treatments at Children's Hospital, under pediatric oncologist Stephan Grupp, M.D., Ph.D., director of Stem Cell Biology. The regimen required a succession of high-dose chemotherapy drugs, surgery to remove the primary tumor, local and full-body radiation, and two stem cell transplants, six weeks apart.
The stem cells used are those that develop into blood cells, including crucial immune system cells. They were removed from Hunter's blood, then frozen and stored while the boy received intensive doses of chemotherapy and radiation to kill tumor cells. Because those high-dose treatments also killed healthy blood cells, his stem cells were thawed and transplanted back into Hunter to help make blood cells again, after being purged to eradicate any lurking cancer cells.
Such transplants formerly were done with stem cells taken from the bone marrow of neuroblastoma patients. However, stem cells found in peripheral blood provide better results. "Peripheral blood stem cells regenerate faster than bone marrow stem cells," says Dr. Grupp. "By doing tandem transplants, six weeks apart, we can use higher doses and a greater variety of treatments to kill the tumor cells. This isn't possible with bone marrow."
Hunter's tumor shrank after a second round of chemotherapy and his nurses nicknamed him "the Bull," in recognition of his big size and hearty personality. Because he had not tolerated sedation drugs well, his mother coached Tuccio as he remained still for 30 minutes during his full-body radiation treatment. Three years after finishing his treatments, Hunter is an active, growing 5-year-old, preparing for kindergarten in the fall.
"We don't say a child is cured three years after neuroblastoma treatment, but after three years, the likelihood of a relapse is low," said Dr. Grupp, who added that Hunter participated in a clinical trial that helped raise the bar for treating high-risk neuroblastoma. The tandem treatment protocol achieved survival rates (after three years) of 60 percent, three times the survival rate before stem cell transplants. (Journal of Clinical Oncology, July 2000, vol. 18, pp. 2567-2575)
Based on these results, the Children's Cancer Group, a multicenter national cooperative group of pediatric oncology centers, will conduct a larger study of the tandem transplant protocol for high-risk neuroblastoma, with Dr. Grupp as the principal investigator.
Pooling the Expertise of International Experts While Dr. Grupp works to refine treatments, Dr. Brodeur's team continues to define more accurate risk groupings. He chaired the medical committees that devised the International Neuroblastoma Staging System published in 1988 and 1993, as well as the International Neuroblastoma Risk Groups published in 1997. Working with pediatric oncologists from the U.S., Europe and Japan, Dr. Brodeur helped establish diagnostic standards that have been adopted by numerous other medical groups worldwide.
"Having international criteria with common definitions allows us to compare data from studies performed around the world," said Dr. Brodeur, who noted that the numbers of children in any one center's study are too small from which to draw sound scientific conclusions. "Having uniform standards makes it possible to pool data from more than one center and to evaluate the effectiveness of different treatments. What is unique about the consensus we have reached for neuroblastoma is that it goes beyond conventional clinical staging to incorporate molecular characteristics of the cancers, yielding more accurate risk groupings and guiding better treatments."
Pushing Tumors Toward SuicideDr. Brodeur's team also continues to explore the molecular mechanisms of neuroblastoma. While important, the MYCN oncogene is not the whole story. For instance, specific genes, called Trk genes, govern production of cell receptors for nerve growth factors. Those nerve growth factors, in turn, affect whether neuroblastoma cells continue to grow, mature into nondividing cells, or die.
By using drugs called Trk inhibitors to block the Trk receptor pathways, it may be possible to trigger tumor cells to undergo apoptosis--the process of cellular suicide. Trk inhibitors may also weaken the resistance of neuroblastoma cells to chemotherapy, and could be used in combination with conventional anticancer drugs.
Dr. Brodeur and his colleagues found that a Trk inhibitor, designated CEP-751, significantly slowed neuroblastoma tumor growth in mice, with minimal side effects. (Medical Pediatric Oncology. 2001, vol. 36, pp. 181-184). It is not yet ready for human trials. However, by targeting specific signaling pathways known to be important in this cancer, this approach may produce effective treatment with fewer of the toxic side effects seen with many chemotherapy drugs.
"We may have reached almost as far as we can in killing cells with conventional chemotherapy and radiation," says Dr. Brodeur. "The next steps will involve manipulating molecular pathways to prevent tumor growth or to make tumors more susceptible to cancer drugs. We may also induce them to differentiate into benign tumors, or to trigger the cell death pathway. Such approaches are likely to be more effective and less toxic than current approaches. In my opinion, these newer approaches represent the future of cancer treatment."
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Note to reporters: The Children's Hospital of Philadelphia has prepared a media kit on research and treatment of childhood cancers, with 4 press releases, fact sheets and background information about our specialists in pediatric oncology. For a full kit, call John Ascenzi at 215-590-7332.
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