Stem Cells Simplify Transplant in Pediatric Solid Tumors

SEATTLE--Studies are underway using high-dose chemotherapy followedby autologous hematopoietic stem cell transplant for the treatment of neuroblastoma,Ewing's sarcoma, and other solid tumors in children, Julie Park, MD, ofChildren's Hospital and Medical Center, Seattle, said at the Associationof Pediatric Oncology Nurses meeting.

Survival in children with stage III or IV disseminated neuroblastomais only around 30%. In patients whose tumor cells have an amplified numberof copies of the n-myc protooncogene, the prognosis is even worse. Andfor children with disseminated or recurrent sarcoma such as Ewing's orosteosarcoma, survival using standard treatment protocols has been virtuallynil.

"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 HutchinsonCancer Research Center, 50% (7/14) of the Ewing's sarcoma patients enrolledhave survived a median of two years after second transplant using a high-dosechemotherapy regimen with autologous stem cell rescue.

The ability to use peripheral blood as a source for autologous stemcells has greatly simplified this approach, she said. It eliminates thenecessity of general anesthesia, bone marrow collection, and pain for thepatient, and collection can be done on an outpatient basis.

Engraftment and recovery of hematopoietic cells also may occur soonerwith the use of stem cells rather than bone marrow, Dr. Park said. Using5 × 10⁶ CD34+ peripheral blood cells per kilogram of bodyweight, the Hutchinson Cancer Center study has found that the median timeto engraftment of white blood cells is 13 days.

Detecting Tumor Cells

Dr. Park stressed that prior to reinfusion, it is crucial that the patient'sstem 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 usedto examine bone marrow samples from patients with stage I/II neuroblastomafor the presence of tumor cells. These patients had normal marrow morphologyand were thus considered to be "low risk" for recurrence.

The study showed, however, that if tumor cells were found in the bonemarrow, even at levels as low as 6 tumor cells per 100 bone marrow cells,there was a significant decrease in survival, indicating the presence ofdisease 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 therapyfrom the beginning. We need to find better ways to detect tumor cells inthe stem cell product, and perhaps ways of purging tumor cells from thestem 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) techniqueto test stem cell preparations for the presence of these tumor cells.

Dr. Park stressed the need for larger, randomized trials of the chemotherapy/transplantapproach in children. Although the studies currently being conducted haveshown promising results, she emphasized that most have been small and nonrandomized.

One randomized study involving 300 stage III and IV neuroblastoma patientshas just been completed by the Childrens Cancer Group; however, becauserelapse can occur as long as two years after remission, Dr. Park notedthat it will take several years of follow-up before the final results ofthis study are known.