Three drug regime shows tolerability in pediatric high-grade glioma patients

From the Vitanza Group, Clinical Research Division and Seattle Children’s Hospital

Pediatric high-grade glioma (pHGG) is a devastating group of cancers with few long-term survivors. This group of diverse cancers includes anaplastic astrocytoma, glioblastoma multiforme (GBM), and diffuse intrinsic pontine glioma (DIPG). Of these, DIPG is universally fatal with historical progression free survival (PFS) and overall survival (OS) times of seven and eleven months, respectively. Radiation is the most impactful treatment for primary and recurrent pHGG. However, children under three years of age do not receive radiation, but a cocktail of intensive chemotherapy. Many chemotherapeutic regimes have been tested, with few showing significant changes in PFS or OS. In 2009, researchers at Seattle Children’s Hospital proposed a three-drug regime using adjuvant temozolomide (TMZ), irinotecan, and bevacizumab (BEV) for the treatment of pHGG based on previous studies of TMZ and irinotecan, and studies of BEV efficacy in adults with GBM. Drs. Erin Crotty and Nick Vitanza (Clinical Research Division and Seattle Children’s Hospital) wanted to better understand whether the three-drug regime (called TIB) was effective at prolonging survival. The results of their retrospective study were recently published in the Journal of Neuro-Oncology.

In all, 61 patients with pHGG were treated from January 2009 to December 2018. Of those, 36 received TIB treatment, 10 with DIPG and 26 with other pHGGs. 42% of patients received a full 12 cycle regime. Therapy was stopped for multiple reasons, including progressive disease and patient or family preference. The regime was well tolerated with minimal adverse events. The most common adverse events were low platelet counts (thrombocytopenia), nausea and vomiting. Out of the 36 patients, 32 had specimens available for molecular testing, a practice that is becoming increasingly important as researchers try to understand the complexity of pHGG. The authors found alterations in a total of 26 different genes among the 32 patients, highlighting the diversity of pHGG. The most common mutation among those patients occurred in the TP53 gene, the master-regulator gene of cell growth that acts like the brake pedal of a car to allow normal cells to repair damage to the DNA code and prevent tumor growth. Of the ten DIPG patients, their mean event free survival (EFS) was 9.3 months, and mean OS was 13.3 months. At 1, 2, and 5 years, their survival rates were 80%, 10%, and 0%, respectively, highlighting the devastating nature of this disease. For the 26 other pHGG patients, mean EFS was 16.2 months, and mean OS was 20.1 months. Their survival rates were 85%, 38%, and 16% for 1, 2, and 5 years, respectively. Greater tumor resection (when possible) was associated with longer survival, while mutation of histone protein H3 at position 27 (frequently found in DIPG) was associated with lower survival. Patient death was due to tumor progression in all but one patient. In all, the TIB regime at Seattle Children’s showed similar results to studies at other institutions with similar chemotherapeutic regimes, and increased survival compared to historical single therapies, offering hope to this vulnerable patient population.

This study was supported by the Seattle Run of Hope, the Pediatric Brain Tumor Research Fund Guild of Seattle Children’s Hospital, the McKenna Claire Foundation, Unravel Pediatric Cancer, Team Cozzi Foundation, the Julianna Sayler Foundation, the Grousemont Foundation, the Michael Mosier Defeat DIPG Foundation, and the ChadTough Foundation.

UW/Fred Hutch Cancer Consortium members Sarah Leary, J Russell Geyer, James Olson, Ralph Ermoian, Christina Lockwood, and Nicholas Vitanza contributed to this work. 

Crotty E, Leary S, Geyer JR, Olson J, Millard N, Sato A, Ermoian R, Cole B, Lockwood C, Paulson V, Browd S, Ellenbogen R, Hauptman J, Lee A, Ojemann J, Vitanza N. 2020. Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children's Hospital experience. Journal of Neurooncology. doi: 10.1007/s11060-020-03558-w.


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