The role and limitations of apparent diffusion coefficient in assessing tumour oxygenation for vertex placement in biologically guided lattice radiotherapy

Lattice radiotherapy (LRT), an advanced form of spatially fractionated radiotherapy, delivers alternating high-dose peaks and low-dose valleys within the tumour volume, enabling focal dose escalation while reducing the integral dose to surrounding organs at risk. Beyond dosimetric advantages, LRT may trigger immune-mediated effects contributing to tumour control. However, vertex placement in current practice remains largely geometric rather than biologically driven, disregarding the spatial heterogeneity typical of bulky tumours. Recent efforts have explored biologically guided LRT, in which vertex positioning is informed by functional imaging biomarkers, particularly the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (MRI). Yet, the biological interpretation of ADC in relation to tumour hypoxia remains controversial. Evidence from preclinical and clinical studies is inconsistent: while several reports suggest an inverse correlation between ADC and hypoxia, others show a direct relationship or no relationship. These discrepancies reflect the multifactorial determinants of ADC, which is influenced not only by cellularity but also by stromal composition, necrosis, and perfusion. Consequently, relying on ADC alone to delineate hypoxic subvolumes risks misclassifying necrotic or normoxic regions as radioresistant targets. Emerging multiparametric approaches, such as the consumption-supply hypoxia (CSH) model and functional MRI techniques like blood oxygenation level-dependent (BOLD) and dynamic contrast-enhanced (DCE) MRI, integrate diffusion, perfusion, and oxygenation metrics to improve physiological specificity. This perspective emphasizes that ADC should be interpreted contextually within such frameworks to guide biologically informed LRT planning and to align spatial dose modulation with the true metabolic and oxygenation landscape of solid tumours.