Residual Tumor Volume, Cell Volume Fraction, and Tumor Cell Kill During Fractionated Chemoradiation Therapy of Human Glioblastoma using Quantitative Sodium MR Imaging

Abstract

Purpose: Spatial and temporal patterns of response of human glioblastoma to fractionated chemoradiation are described by changes in the bioscales of residual tumor volume (RTV), tumor cell volume fraction (CVF), and tumor cell kill (TCK), as derived from tissue sodium concentration (TSC) measured by quantitative sodium MRI at 3 Tesla. These near real-time patterns during treatment are compared with overall survival.Experimental Design: Bioscales were mapped during fractionated chemoradiation therapy in patients with glioblastomas (n ¼ 20) using TSC obtained from serial quantitative sodium MRI at 3 Tesla and a two-compartment model of tissue sodium distribution. The responses of these parameters in newly diagnosed human glioblastomas undergoing treatment were compared with time-to-disease progression and survival.Results: RTV following tumor resection showed decreased CVF due to disruption of normal cell packing by edema and infiltrating tumor cells. CVF showed either increases back toward normal as infiltrating tumor cells were killed, or decreases as cancer cells continued to infiltrate and extend tumor margins. These highly variable tumor responses showed no correlation with time-to-progression or overall survival.Conclusions: These bioscales indicate that fractionated chemoradiotherapy of glioblastomas produces variable responses with low cell killing efficiency. These parameters are sensitive to real-time changes within the treatment volume while remaining stable elsewhere, highlighting the potential to individualize therapy earlier in management, should alternative strategies be available.

Sodium homeostasis in the tumour microenvironment

“…Further detailed 23 Na MRI studies followed in human brain and breast tumours (4,9,285). More recent advances in sodium imaging have shown that 23 Na MRI can both predict IDH status (197) and show early response to pre-clinical therapeutic interventions (198). Furthermore, relaxation-weighted 23 Na MRI has now been shown to differentiate between brain tumours of grades I-III and grade IV when spin-weighted 23 Na…”

“…In addition, 23 Na MRI measurement of total tumour [Na + ] has been shown to be superior to isocitrate dehydrogenase (IDH) mutation status in predicting progression-free survival, suggesting that tumour [Na + ] may be a promising tool for non-invasive outcome prediction (197). Furthermore, 23 Na MRI may also have value for detecting changes in real-time during treatment as a potential early biomarker for therapy assessment (198). However, it must be noted that [Na + ] is likely to change following initiation of treatment as a result of physiological changes in the tumour and so the relationship between [Na + ] and therapy response may be complex.…”

Beyond T2 and 3T: New MRI techniques for clinicians

“…In oncology, a change in the intracellular 23 Na concentration is a biomarker for tumor malignancy [52][53][54][55][56], and cellular viability [57], and has shown promise as an indicator of treatment response. This has been demonstrated in animal models [58,59], and more recently in glioblastoma patients measured at 3T [60] and 7T [61].…”

23Na‐MRI as a Noninvasive Biomarker for Cancer Diagnosis and Prognosis

“…Also, 23 Na‐MRI quantified parameters have clinically demonstrated sensitivity to variations in treatment response between patients, and are therefore poised for treatment customization 62 . In addition, 1,3‐bis(2‐chloroethyl)‐1‐nitrosourea (BCNU)‐treated subcutaneous glioma 63 revealed lower TS and IS signal intensity in the treated group 5 days after therapy, when compared to untreated control tumors.…”