History of Chemotherapy for Tumors in the Nervous System of Children

Understanding of Disease Management

Early experience with chemotherapy

• 1950s – chemotherapy useful: The realization that chemotherapy could cure systemic cancer in humans dates back to the 1950s. In 1955 the National Cancer Institute (NCI) organized and set in motion drug development and clinical trials for the treatment of cancers with chemotherapy.
• 1966 – formation of the Brain Tumor Chemotherapy Study Group: This group was formed to develop cooperative group protocols.
• 1970s – development of CNS protocols: Early in the 1970s it was found that the chemotherapy drug BCNU crosses the blood-brain barrier and shrinks some brain tumors (53).
• 1975-1981 – CSG-942: This study enrolled 232 patients with medulloblastomas for treatment with CCNU, vincristine, and prednisone (14).

Establishment of efficacy for CNS tumors

• 1980s – first efficacy protocols: The first phase III trial (CSG 943) for pediatric HGGs randomized treatment after resection between radiation alone and radiation plus adjuvant chemotherapy (CCNU, vincristine, prednisone) (13). Those receiving chemotherapy were found to have a survival advantage.
• 1990s – increasing evidence for chemotherapy: The results of protocols completed in the 1990s showed that chemotherapy could be used with a reduced amount of radiation to the craniospinal axis to treat medulloblastomas with an increased cure rate (36). It was also shown that chemotherapy could provide a cure in the absence of radiation in some infant tumors (9) and that it was effective in treating malignant gliomas (18). In addition, there appeared to be a role for chemotherapy in treating unresectable progressive LGGs (35). Neoadjuvant carboplatin was also identified as being highly active in newly diagnosed CNS germinomas (1).

Recent developments

• Linkage to radiation: Chemotherapy appears to be most beneficial when administered during and after radiation and is most successful as an adjunct to radiation.
• Uses for intensive chemotherapy: In the new millennium, the approach of intensive chemotherapy and submyeloablative therapy has been explored in particular for young children to avoid the devastating long-term effects of radiation to the developing brain (2, 12, 25). This approach has been particularly successful in the treatment of certain subgroups of medulloblastoma, particularly those tumors with desmoplastic histology (11).
• Tailoring chemotherapy to molecular biology: MGMT gene alteration was found to predict responsiveness of malignant gliomas to chemotherapy (38). Also in the new millennium there has been a rapid development in the understanding of oncogenes and signaling pathways leading to the development of specific targeted therapies for brain tumors (28). However, for the most part, they remain part of phase I and II clinical trials at this time.
• Additional indications for chemotherapy: Intracystic bleomycin was found to be effective in treating craniopharyngiomas (23), and promising reports suggested that carboplatin might be a radiosensitizer in treatment of high-risk medulloblastomas (29).

Technological Development

• Increasingly effective treatments for risk of infection: Increased bacterial and viral immunization programs decrease the incidence of infections. Better supportive care for fever and neutropenia and the prevention of septic shock have allowed more aggressive chemotherapy and less toxicity. The use of G-csf [1]to aid in recovery of neutrophil count has allowed more intense chemotherapy and decreased rates of bacterial infection-related morbidity.
• Stem cell rescue: The development of autologous stem cell harvesting and reinfusion has allowed for the development of submyeloablative protocols and decreased morbidity.
• Molecular profiling of tumors: The revolution in molecular diagnostics is allowing us to identify subgroups of specific brain tumor histologies (e.g., medulloblastoma), which will lead to stratification of therapy in the future according to molecular subtype (34).
• Improved surgical resections: Improved neurosurgical techniques have increased the rate of gross total resection and the likelihood of chemotherapy to be a valuable adjunctive therapy (with minimal residual disease).
• Improved imaging of tumors: Improved neuroimaging techniques have allowed more accurate evaluation of the extent of disease at diagnosis, the extent of the surgical resection, and the response of the residual tumor to adjuvant treatments.