Hypoxia Imaging and Adaptive Radiotherapy: A State-of-the-Art Approach in the Management of Glioma

Abstract

Severe hypoxia [oxygen partial pressure (pO 2 ) 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.

Radioresistance in Glioblastoma and the Development of Radiosensitizers

“…For example, improving intratumoral oxygenation has been reported to increase glioma radiosensitivity in vitro and in vivo. Tracing and applying increasing doses of radiation in hypoxic regions is also being investigated [ 108 , 109 ]. However, more studies are needed to target GBM hypoxia to improve the response to radiotherapy in patients.…”

The Role of Hypoxia and SRC Tyrosine Kinase in Glioblastoma Invasiveness and Radioresistance

“…The aerobic value of the brain tissue is of about 40 mmHg in physiological conditions, whereas it has been shown to be significantly lower in GBM [ 25 ]. To be defined hypoxic, a tissue must reach a pO 2 value below 10 mmHg, which is the result of the unbalanced oxygen supply and consumption rate [ 26 ]. In GBM, hypoxia ranges from mild (pO 2 = 20 to 4 mmHg) to severe condition (pO 2 = 4 to 0.75 mmHg), especially in necrotic and micronecrotic areas [ 26 ].…”

“…To be defined hypoxic, a tissue must reach a pO 2 value below 10 mmHg, which is the result of the unbalanced oxygen supply and consumption rate [ 26 ]. In GBM, hypoxia ranges from mild (pO 2 = 20 to 4 mmHg) to severe condition (pO 2 = 4 to 0.75 mmHg), especially in necrotic and micronecrotic areas [ 26 ]. Hypoxia occurs when the distance to the nearest blood vessel is impeding appropriate exchanges but also when blood perfusion is altered.…”

The Added Value of Diagnostic and Theranostic PET Imaging for the Treatment of CNS Tumors

“…Another category of metabolic tracers is based on hypoxia, which is often present in cancer owing to the fact that rapidly growing tumor cells outgrow their blood supply. The presence of hypoxia has shown to be a poor prognostic factor for survival as it induces resistance to radiotherapy (i.e., hypoxia-induced radioresistance) [58]. PET offers a non-invasive tool to identify hypoxic areas or map oxygenation within CNS tumors, which potentially has great clinical impact by providing avenues for treatment adaptation before and during radiotherapy.…”