Three-Times Daily Ultrafractionated Radiation Therapy, A Novel and Promising Regimen for Glioblastoma Patients

Abstract

Glioblastomas are considered to be one of the most radio resistant tumors. Despite new therapies, the prognosis of this disease remains dismal. Also, the mechanisms of radiation resistance in mammalian cells are more complex than once believed. Experimental studies have indicated that some human cell lines are sensitive to low radiation doses of <1 Gy. This phenomenon has been termed low-dose hyper-radio-sensitivity (HRS), and is more apparent in radio resistant cell lines, such as glioblastoma cells. Sensitivity may result from the inability of low dose radiation to efficiently induce repair mechanisms, whereas higher doses cause enough damage to trigger repair responses for radio resistance. In vitro studies have demonstrated this phenomenon using various human malignant glioma cell lines: (1) daily repeated irradiation of cells with low doses compared to irradiation using a single biologically equivalent dose resulted in significantly higher cell killing; (2) experiments conducted on glioma xenografts demonstrated that repeated irradiation with low doses was more effective for inhibiting tumor growth than a single dose. In order to confirm and validate these promising studies on HRS, a few phase II trials were developed. For translating the experimental observations into the clinic, ultra fractionation protocols (with three daily doses) were tested in glioblastoma patients. Tolerance and toxicity were the primary endpoints, with overall survival as a secondary endpoint. These protocols were initiated before concomitant radio chemotherapy became the standard of care. For these trials, patients with an unfavorable clinical prognostic factor of newly unresectable GBM were included. When comparing the results of these trials with international literature using multivariate analysis for both progression free survival and overall survival, ultra fractionated irradiation showed superiority over radiotherapy alone. In addition, it was found to be equivalent to treatment using radiotherapy and temozolomide. Therefore, ultra fractionated protocols may prolong survival of glioblastoma patients. In this review, we describe the main experimental data regarding low-dose hypersensitivity as well as the findings of clinical trials that have investigated this new radiotherapy regimen.

A concurrent ultra‐fractionated radiation therapy and temozolomide treatment: A promising therapy for newly diagnosed, inoperable glioblastoma

“…[25][26][27][28][29][30] Our previous studies, especially the in vitro ones, showed that daily repeated low-dose irradiation of cells, compared to a single biologically equivalent dose, resulted in significantly higher cell death. 7,17 Experiments conducted on glioma xenografts demonstrated that repeated low-dose irradiation was more effective for inhibiting tumor growth than a single large dose. 7,17 The exact mechanisms underlying HRS are not clear.…”

“…7,17 Experiments conducted on glioma xenografts revealed that repeated irradiation with low doses (0.8 Gy, three times a day) is more effective than a single dose (2 or 2.4 Gy, once a day) in inhibiting tumor growth. 7,17 Consequently, in 2003, we began a phase II study testing an ultra-fractionated RT for inoperable de novo GBM. 18 The results were promising, and are comparable with the results using the TMZ/RT treatment from the EORTC/NCIC trial.…”

“…The mechanisms involved in radiation resistance in mammalian cells are more complex than once believed. 7 In vitro studies have…”

“…[8][9][10][11][12][13][14][15][16][17] We demonstrated this phenomenon in a number of various human malignant glioma cell lines using a common clinical device for irradiation. 7,17 Daily irradiation with a single biologically equivalent dose resulted in significantly higher cell death (using a clonogenic assay). 7,17 Experiments conducted on glioma xenografts revealed that repeated irradiation with low doses (0.8 Gy, three times a day) is more effective than a single dose (2 or 2.4 Gy, once a day) in inhibiting tumor growth.…”

“…7,17 Daily irradiation with a single biologically equivalent dose resulted in significantly higher cell death (using a clonogenic assay). 7,17 Experiments conducted on glioma xenografts revealed that repeated irradiation with low doses (0.8 Gy, three times a day) is more effective than a single dose (2 or 2.4 Gy, once a day) in inhibiting tumor growth. 7,17 Consequently, in 2003, we began a phase II study testing an ultra-fractionated RT for inoperable de novo GBM.…”