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.

Inclusion criteria

• Histologic confirmation of glioblastoma or grade 4 astrocytoma
• Age >18
• KPS at least 60
• Patients must have normal organ and marrow function as defined below:

• leukocytes >3,000/mcL
• absolute neutrophil count >1,500/mcL
• platelets >100,000/mcL
• total bilirubin within normal institutional limits
• AST(SGOT)/ALT(SGPT) <2.5
• institutional upper limit of normal
• creatinine within normal institutional limits OR creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
• Patients of child-bearing potential (male or female) must practice adequate contraception due to possible harmful effects of radiation therapy on an unborn child.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• Patients who are unable to receive MRIs will be excluded from the study.
• Patients may not be receiving any other investigational cancer treatment agents at the time of enrollment.
• Patients may not have previously been treated with an overlapping course of radiotherapy to the brain.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant and/or breastfeeding women are excluded. Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and up to 12 weeks after the study are excluded. Male subjects must also agree to use effective contraception for the same period as above.