SEATTLE--Studies are underway using high-dose chemotherapy followed by autologous hematopoietic stem cell transplant for the treatment of neuroblastoma, Ewing's sarcoma, and other solid tumors in children, Julie Park, MD, of Children's Hospital and Medical Center, Seattle, said at the Association of Pediatric Oncology Nurses meeting.
Survival in children with stage III or IV disseminated neuroblastoma is only around 30%. In patients whose tumor cells have an amplified number of copies of the n-myc protooncogene, the prognosis is even worse. And for children with disseminated or recurrent sarcoma such as Ewing's or osteosarcoma, survival using standard treatment protocols has been virtually nil.
"We hope that by intensifying the therapy these children receive, we may be able to increase their survival," she said.
Thus far, in a study by Dr. Park and her colleagues at the Fred Hutchinson Cancer Research Center, 50% (7/14) of the Ewing's sarcoma patients enrolled have survived a median of two years after second transplant using a high-dose chemotherapy regimen with autologous stem cell rescue.
The ability to use peripheral blood as a source for autologous stem cells has greatly simplified this approach, she said. It eliminates the necessity of general anesthesia, bone marrow collection, and pain for the patient, and collection can be done on an outpatient basis.
Engraftment and recovery of hematopoietic cells also may occur sooner with the use of stem cells rather than bone marrow, Dr. Park said. Using 5 × 106 CD34+ peripheral blood cells per kilogram of body weight, the Hutchinson Cancer Center study has found that the median time to engraftment of white blood cells is 13 days.
Detecting Tumor Cells
Dr. Park stressed that prior to reinfusion, it is crucial that the patient's stem cells be uncontaminated by tumor cells (particularly in neuroblastoma, which readily metastasizes to the bone marrow).
She described a study in which immunocytochemical techniques were used to examine bone marrow samples from patients with stage I/II neuroblastoma for the presence of tumor cells. These patients had normal marrow morphology and were thus considered to be "low risk" for recurrence.
The study showed, however, that if tumor cells were found in the bone marrow, even at levels as low as 6 tumor cells per 100 bone marrow cells, there was a significant decrease in survival, indicating the presence of disease not detected morphologically.
If physicians had better techniques for detecting minimal residual disease, "we might treat these patients differently up front," she noted. "We might enroll these patients in high-dose consolidative therapy from the beginning. We need to find better ways to detect tumor cells in the stem cell product, and perhaps ways of purging tumor cells from the stem cells before giving them back to the patient."
Currently, the team is using immunocytochemistry for tumor cell detection, and contaminated stem cell preparations are not used in autologous therapy. For Ewing's sarcoma, a specific cytogenetic rearrangement has been identified, so the team hopes to use the polymerase chain reaction (PCR) technique to test stem cell preparations for the presence of these tumor cells.
Dr. Park stressed the need for larger, randomized trials of the chemotherapy/transplant approach in children. Although the studies currently being conducted have shown promising results, she emphasized that most have been small and nonrandomized.
One randomized study involving 300 stage III and IV neuroblastoma patients has just been completed by the Childrens Cancer Group; however, because relapse can occur as long as two years after remission, Dr. Park noted that it will take several years of follow-up before the final results of this study are known.