Precision Radiotherapy Enabled by Molecular MRI

Despite advances in therapy, glioblastoma remains almost universally fatal, with a high rate of local failure and a median survival of < 2 years. The standard of care for GBM is maximum safe surgical resection, followed by radiotherapy (RT) with temozolomide (TMZ) chemotherapy, which was established two decades ago. There is an urgent need to optimize each step of this standard therapy and develop new methods to fight this devastating disease. It is the infiltrative nature of GBM that limits resection and leads to suboptimal RT planning. To address this, neurosurgeons are employing supratotal resection, in which gadolinium-enhancing macroscopic tumor plus 1-2 cm extension into gadolinium-non-enhancing peritumoral regions is resected after preserving the highly eloquent region.

RT planning is complex and varies among medical centers, particularly in terms of inclusion of non-enhancing peritumoral regions in the clinical target volume. Moreover, lack of local therapy intensification of RT is considered one of the factors that prevent this standard therapy from achieving maximal tumor control. New RT approaches, such as focused dose escalation and proton therapy, require the best possible imaging methods to accurately visualize the extent of the tumor. Furthermore, standard structural MRI cannot distinguish between treatment effect from RT and tumor progression. Notably, the treated tumor may have progressed during fractionated RT, and the newly emerging active lesion could be missed from the original RT planning, particularly at the boost phase. New tissue-specific imaging approaches, like amide proton transfer (APT) imaging, that can accurately identify the tumor burden before, during, and after RT treatment are urgently needed.

The investigators central hypothesis in this highly innovative and clinically significant study is that protein-based APT-MRI is capable of identifying a precise high-protein tumor hotspot inside and outside Gd-enhancing regions with which to guide radiation dose escalation to high-risk active tumor and to facilitate an adaptive strategy to regions of therapeutic resistance during RT.

The innovative APT-RT technique developed by the investigators at Johns Hopkins enables a personalized RT regimen with precise dose escalation in high-risk tumor regions and response-adapted dose escalation in therapeutically resistant lesions in the boost phase, which could decrease the local recurrence rate. Personalized local therapy intensification would achieve maximal tumor control and improve the survival for GBM patients. The investigator's preliminary study will lay the foundation for a more definitive phase-II prospective clinical trial to assess the impact of APT imaging on RT guidance with regard to outcomes, including overall and progression-free survival, complications, toxicity, and quality of life. The investigators expect that APT-RT should be more effective for tumor control than the current conventional therapy.