Infants and children with intermediate-risk neuroblastoma who received a less-intensive chemotherapy regimen had three-year overall survival rates as good as those patients in an earlier trial who received treatment that was more intensive and more toxic
Background
Neuroblastoma, the fourth most common solid tumor in children under the age of 16, begins in immature nerve cells, most often in the adrenal gland, neck, chest, or spinal cord. Neuroblastoma is classified as low, intermediate, or high risk of disease recurrence after treatment, based on factors such as the patient’s age, how far the disease has spread (metastasized), and what genetic mutations are found in the tumor.
For neuroblastoma tumors that have already spread within a limited region at the time of diagnosis, doctors can use a combination of surgery and chemotherapy to kill both the original tumor and cancer cells elsewhere. For children with intermediate-risk neuroblastoma, this treatment approach is very effective at preventing the cancer from returning and also increases survival.
However, while effective, this approach requires many months to complete and causes potentially serious side effects, including damage to the kidneys, heart, and hearing as well as a temporary decrease in white blood cells that can expose the patient to dangerous infections.
The clinical trial described below examined whether a shorter, less-intense course of chemotherapy could be as effective in preventing disease recurrence and extending survival as more-intense regimens in children with intermediate-risk neuroblastoma.
The Study
Between March 1997 and May 2005, this single-arm phase III clinical trial (called A3961) enrolled 467 eligible patients with intermediate-risk neuroblastoma from participating hospitals in Australia, New Zealand, and North America. The study used historical patient controls. That is, the investigators compared the results from the A3961 trial to an earlier study (called CCG 3881) performed by the Children’s Cancer Group among a similar population of neuroblastoma patients who had received a more-intense chemotherapy regimen between 1989 and 1996.
All participants in the A3961 trial underwent initial surgery, and were divided into two groups based on the relative likelihood of tumor recurrence—a ‘favorable’ prognosis group and an ‘unfavorable’ prognosis group.
Infants and children in the favorable-prognosis group were scheduled to receive four cycles of chemotherapy, and those in the unfavorable-prognosis group were scheduled to receive eight cycles. If a patient in the favorable-prognosis group did not experience a satisfactory tumor response to the initial treatment, the patient could receive the full eight cycles of chemotherapy. The cycles consisted of different combinations of the drugs carboplatin, etoposide, cyclophosphamide, and doxorubicin.
Based on the results from the earlier CCG-3881 study, investigators determined that the less-intense regimen would be effective if more than 90 percent of A3961 participants were alive after three years of follow up.
The trial was organized by the Children’s Oncology Group. The lead author of the study is David L. Baker, M.B.B.S., director of the pediatric and adolescent hematology-oncology program at Princess Margaret Hospital for Children, Perth, Australia.
Results
Of the 467 eligible patients, 362 were infants (under 1 year of age) and 105 were children. Seventy-one percent (330) of all patients had a favorable prognosis, and 29 percent (137) had an unfavorable prognosis. A total of 192 patients received only four cycles of chemotherapy. The other 275 received eight cycles (including 42 percent of those in the favorable prognosis group).
At three years of follow up, 96 percent of patients remained alive and 88 percent had no progression of their cancer, an outcome indicating that the treatment was indeed effective. What’s more, the patients’ overall length of treatment and the actual number of treatment days were much less compared to the CCG-3881 historical controls.
In the earlier study using a higher-intensity regimen, patients received 71 days of treatment over the course of 268 days. In the A3961 lower-intensity study, patients with an unfavorable prognosis received 18 days of treatment (a 75 percent reduction) over the course of 168 days (a 40 percent reduction). Patients in the favorable group received 10 days of treatment (an 85 percent reduction) over the course of 84 days (a 70 percent reduction).
Damage to the kidneys, heart, and hearing each occurred in less than 2 percent of patients. Almost 70 percent of patients experienced a reduction in their number of white blood cells, but this side effect went away after treatment ended. Four of the 467 patients died from treatment-related infections during the trial. Two patients developed a second cancer - acute myeloid leukemia.
Limitations
While the overall side effects were acceptable after three years of follow up, “the long-term toxicity is unknown,” said pediatric oncologist Andrew Pearson from the Royal Marsden Hospital, Surrey, United Kingdom, in a discussion at the ASCO meeting. Because patients in the unfavorable prognosis group still received a substantial dose of doxorubicin (which can permanently damage the heart), and because several cases of second cancers have already been observed, he explained, “we must aim to reduce therapy even more in this group of patients.”
Comments
Even with further room for improvement in toxicity reduction, “Without question, this is a major success,” said Pearson.
“Their goal was to have an equivalent survival outcome while using much less treatment [compared to the historical control group], and they were able to do that. It’s significant that they were able to get that same outcome with about half the number of cycles of chemotherapy,” agreed Barry Anderson, M.D., Ph.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program.
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