Abstract
Severe hypoxia [oxygen partial pressure (pO2) below 5–10 mmHg] is more frequent in glioblastoma multiforme (GBM) compared to lower-grade gliomas. Seminal studies in the 1950s demonstrated that hypoxia was associated with increased resistance to low–linear energy transfer (LET) ionizing radiation. In experimental conditions, the total radiation dose has to be multiplied by a factor of 3 to achieve the same cell lethality in anoxic situations. The presence of hypoxia in human tumors is assumed to contribute to treatment failures after radiotherapy (RT) in cancer patients. Therefore, a logical way to overcome hypoxia-induced radioresistance would be to deliver substantially higher doses of RT in hypoxic volumes delineated on pre-treatment imaging as biological target volumes (BTVs). Such an approach faces various fundamental, technical, and clinical challenges. The present review addresses several technical points related to the delineation of hypoxic zones, which include: spatial accuracy, quantitative vs. relative threshold, variations of hypoxia levels during RT, and availability of hypoxia tracers. The feasibility of hypoxia imaging as an assessment tool for early tumor response to RT and for predicting long-term outcomes is discussed. Hypoxia imaging for RT dose painting is likewise examined. As for the radiation oncologist's point of view, hypoxia maps should be converted into dose-distribution objectives for RT planning. Taking into account the physics and the radiobiology of various irradiation beams, preliminary in silico studies are required to investigate the feasibility of dose escalation in terms of normal tissue tolerance before clinical trials are undertaken.
Highlights
Brain Tumors and HypoxiaBrain tissue physiologically has a tissue pO2 of ∼40 mmHg, referred to as a normoxic or aerobic state
A specific focus was placed on hypoxia, known to play a crucial role in tumor angiogenesis, genetic instability, and tumor invasion [3]
Hypoxia imaging could be used to provide the level of ptO2 and, subsequently, the spatial distribution of potentially radioresistant regions [54]
Summary
Brain tissue physiologically has a tissue pO2 (ptO2) of ∼40 mmHg, referred to as a normoxic or aerobic state. High-LET radiation therapy is supposed to be more efficient than low-LET conventional RT (photons or protons) when treating hypoxic tumors [33, 34]. This could be explained by the in situ “oxygen production in the heavy ion track” phenomenon [35,36,37,38]. Compared to low-LET conventional RT (photons or protons), high-LET RT, over a few hundreds of keV/μm (carbons), is expected to be less sensitive to hypoxia and could be more efficient for treating hypoxic tumors
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