Current clinical application of stem cells is considered as part of combination treatment of brain tumors of using surgical, chemotherapy and radiation therapy to rejuvenate blood and immune systems. Only limited complete data sets are available currently even though autologous hematopoietic stem cell transplantation (AHSCT) has been advocated as a form of salvage therapy for children with high-risk or relapsed brain tumors for decades .
Worldwide there are 38 registered stem cell-based clinical trials for variety of pediatric brain and central nerve system (CNS) tumors; most of which are in Phases I/II (see the Additional file 1). Majority of these trials are for intravenous administration of autologous transplants using bone marrow and peripheral blood derived stem cells and only one study (NCT00005796) is conducted with in vitro treated peripheral blood stem cells, which are Fibronectin-assisted, retroviral-mediated modification of CD34+ PBSC carrying O6-methylguanine DNA methyltransferase. The rationale for using the stem cell is not to directly target the tumor but to replace immune cells that were destroyed by chemotherapy.
In the Schneider Children's Medical Center of Israel Rabin Medical Center (NCT00607984), patients with metastatic and relapsed brain tumors were treated with a high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) as the consolidation therapy. A large randomized study in children with high risk neuroblastoma showed that application of autologous stem cell transplant can lead to improved disease free and overall survival, effects that were further augmented by the administration of biological agents with specific activity against this tumor. Smaller non-controlled studies and case series have shown that ASCT is feasible in children with solid tumors or with tumors of the central nervous system.
A major limitation of many high-dose chemotherapy (HDC) protocols, experimental gene therapies, and biologic therapies is that the administered agents are unable to traverse the blood brain barrier (BBB) in order to reach the site of the tumor. Thiotepa, a highly myeloablative bifunctional alkylating agent, was considered a major breakthrough in the application of high dose chemotherapies in children with CNS tumors because it partitions equally across the BBB. Thiotepa remains a mainstay of HDC protocols for children with CNS tumors. As such, combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Similarly, TEMOZOLOMIDE (Temodor) is the American Food and Drug Administration (FDA) approved for grade III anaplastic astrocytoma based largely on low side effects profile and excellent CNS penetration. Preliminary studies suggest that stem cells can cross BBB to reach brain tumors targets. Alternatively, therapeutic stem cells population can be directly introduced via stereotactic injection into the CNS tumor tissue.
Cheuk and colleagues report the long-term effects of AHSCT treatment for 13 pediatric brain tumor patients for a period of 10 years (1996–2006) in Hong Kong, including medulloblastoma (n = 9), cerebral primitive neuroectodermal tumor (n = 1), ependymoma (n = 1), germ cell tumor (n = 1) and cerebellar rhabdoid (n = 1) with tumor residual (n = 1) or recurrence (n = 12). Prior to AHSCT, 8 patients (61.5%) achieved complete remission and 5 (38.5%) were in partial remission with conditioning employed thiotepa, etoposide and carboplatin. Adverse effects of mucositis and neutropenic fever in all patients, grade 4 hepatic toxicity in 4 patients and grade 4 renal toxicity in 1 patient were observed associated with the chemotherapy. The results with AHSCT in the study include: 1) The 5-year event-free survival was 53.9%; 2) Five patients died of disease recurrence or progression 8–21 months after transplant with a median disease-free period of 8 months post-transplant; 3) One died of transplant-related complications in the early post-transplant period; 4) Seven survived for a median of 5.4 years (maximum follow-up of 9.8 years), with 6 having Lansky-Karnofsky performance score above 80; 5) All survivors had complete remission before transplant though 2 had leptomeningeal spread . It appears that AHSCT can empower long-term survival in children with recurrent brain tumor, however; those patients with macroscopic residual tumors before the transplant could not be salvaged.
Nonetheless, controversial efficacies raised doubt about the clinical benefits of conventional stem cell therapy. The efficacy can be fluctuated by many factors including the quality of the stem cell (number of effective stem cell sub-population, the differentiation status, and the age of the stem cell), the occurrence of graft versus host reaction, overall survival, disease free survival and immune recovery . Some of these efficacious variations may stem from the biological differences related to a cancer or treatment of interest. Others, however, may reflect the heterogeneity of patients across multiple sites, the inherent biological complexity and diversity of different cancer types, and even small differences in stem cell preparation, processing, handling, and analysis techniques used by multiple operators across multiple locations. As a consequence, data may be differed by site-, study-, population-, or sample-specific anomalies and, therefore, not be sufficiently robust for making a concrete conclusion. There is an urgent need for development of a uniform technical platform to clarify the ultimate clinical viability of stem cell therapy for brain tumors.