LOS ANGELES (Feb. 25, 1999) -- In a study that was so carefully designed and controlled that it will likely serve as a "gold standard" for future research projects, doctors have found that in treating children who have certain malignant brain tumors, a "tried-and-true" chemotherapy protocol provides better results than a newer, more experimental method.
The results of the study, appearing in the March issue of the Journal of Clinical Oncology, also show that the "quality" of neurosurgery -- the ability of the surgeon to remove nearly all of a tumor -- can impact survival rates years later.
Researchers at more than 40 medical centers and children's hospitals across the country followed the progress of 203 children from the United States, Canada and Australia who were treated between 1986 and 1992. The study focused on medulloblastomas, a type of malignant tumor located in the cerebellum, and similar tumors in other areas of the brain, known as primitive neuroectodermal tumors. According to Paul M. Zeltzer, M.D., lead investigator on the project and a specialist in neurooncology at the Cedars-Sinai Medical Center Maxine Dunitz Neurosurgical Institute, about 25 percent of all malignant brain tumors of childhood fit into this group.
Surgery to remove the tumor preceded radiation therapy and one of two types of chemotherapy: the "standard" three-drug mix known as VCP (vincristine, CCNU and prednisone) that was developed in the 1970s, or the "8-drugs-in-one-day" protocol, which has been available since the early 1980s and looked promising in previous studies.
"Although the eight-drug therapy appeared to be more aggressive, more intensive, we found that the standard therapy gave significantly better chances of survival," said Dr. Zeltzer. "In fact, one of the conclusions of our study was that when there are differences of opinion among physicians about which of two therapies is better, the only way to settle the issue is to do randomized, parallel studies. In this case, even though the hype and the opinions were strong, the data spoke for itself."
According to the results, five-year progression-free survival rates were 63 percent among patients treated with VCP, compared to 45 percent when "8-in-1" was used.
Of the 203 total patients, 188 were confirmed to have medulloblastoma. Based on the circumstances and survival rates of these patients, several factors were analyzed to determine their value in predicting outcomes. For example, as anticipated, children who had more advanced tumors had lower rates of survival. But an unexpected finding indicated that children ages 1 1/2 to 3 years had lower progression-free survival rates than older children -- about 32 percent compared to 58 percent. Dr. Zeltzer said this is the result of differences in treatment, not of age itself. "We tend to 'lighten up' radiation therapy for infants because we know radiation harms their brains and we want to do as little harm as possible," he said. "But one of the hard lessons we've learned is that when you lighten the therapy, you also lighten the results."
One of the more notable secondary findings of the study emphasized the importance of the surgeon's ability to remove the majority of the tumor. In fact, while previous studies have suggested that surgical skill is an important factor, this is the first to definitively show the impact on a patient's long-term prospects of survival in a randomized controlled study of medulloblastoma.
"The ability to remove the tumor as completely as possible is critical, absolutely critical," said Dr. Zeltzer. "It has a survival effect five, seven or 10 years later. There is about a 25 percent decrease in survival rates if the neurosurgeon leaves more than 1 1/2 cubic centimeters of tumor. In other words, if the surgeon leaves more than about 1/4 teaspoon of detectable tumor, the survival rate drops from 78 percent to approximately 53 percent."
Funded primarily by the National Cancer Institute, and supported by the Children's Cancer Group, one of the nation's largest entities researching pediatric brain tumors, the results of this study set a "gold standard" that will be used by future studies to assess their results. Dr. Zeltzer said the team that designed the research between 1983 and 1985 included specialists with expertise in neurosurgery, neuroradiology and biostatistics.
"We had allowed for and controlled things that hadn't been controlled in other studies," he said. "For example, every single patient who was in the study was "staged" -- we knew both in terms of their spinal fluid and their spinal films exactly how much tumor they had coming into therapy. That had never been done in any previous study. Every single scan that was taken on every single patient was reviewed by myself and a committee of two neuroradiologists. Every patient had their tumor reviewed by at least one and sometimes two specialists in pathology."
Dr. Zeltzer is the neurooncologist in the Pediatric Brain Tumor Program of the Maxine Dunitz Neurosurgical Institute. The Institute, launched in 1997 and directed by Keith L. Black, M.D., one of the most respected neurosurgeons in the world, has quickly established a reputation for its innovative approaches to treating tumors of the brain.
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Journal
Journal of Clinical Oncology