4. Discussion
tumor, toxicity, toxicities, edema, necrosis, BrICS-LIT, IDH
DISEASE PROGRESSION, TUMOR, RECURRENCE, EDEMA, TUMOR PROGRESSION, NECROSIS, PATHOLOGY, TUMOR RECURRENCE
In this study we describe the use of novel imaging visualization tools and structured reporting to analyze the results to date of our 30-patient clinical trial utilizing dose-escalated radiation guided by Cho/NAA sMRI maps. With standard-of-care therapy including standard RT with concurrent and adjuvant TMZ, GBM prognosis remains poor with a median OS that is consistently limited to about 16 months and an incidence of recurrence at one year from start of treatment of 60–70% [While escalated radiation shows promising results, most patients on the trial exhibited pseudo-progression and radiation necrosis that lasted far longer than patients on standard radiation therapies. In standard clinical practice, T1w-CE imaging is the mainstay for defining tumor recurrence. However, under high-dose irradiation, post-treatment radiation effects often mimic those of tumor recurrence on clinical images, prompting labeling of disease progression before true tumor recurrence. Multiple patients on the trial were recommended for additional surgeries due to the apparent increase in contrast enhancing volume on T1w-CE imaging; however, these lesions were often in-field of the high-dose target and were later confirmed to be either pseudo-progression or radiation necrosis via pathology reports. The pathology reports for the first patient from our results section showed zero and minimal tumor both one year and two years after completion of RT. It was common to see pathology reports five to even nine months after completion of RT finding minimal tumor in samples biopsied. Our dependence on pathology reports from biopsy for in-field recurrence determination is a limitation for our criteria, especially in cases where there were not additional surgical interventions at critical timepoints.While we acknowledge that quantitative tools such as BrICS-LIT do not necessarily solve the problem of differentiating tumor from necrosis, they were helpful in tracking the patient’s disease-state during follow-up. Using our LIT database, radiation dose maps, and post-surgery pathology reports, we performed a retrospective analysis showing a ten month improvement of PFS compared to standard therapy using sMRI-guided dose escalation. With BrICS-LIT, we can graph lesion volumes and structured reporting scores throughout the patient’s follow-up period. Rather than manually inspecting independent images and qualitatively assessing the patient across their latest few follow-up dates, with BrICS-LIT we can use segmentation algorithms to calculate lesion volumes and make comparisons quantitatively. If, for example, enhancing lesion volume is increasing at an exponential rate, there is good reason to be suspicious for tumor progression. However, if the lesion volume stays within-field and remains stable over several months, the enhancing lesion could be mostly radiation necrosis unless proven otherwise through biopsy. A limitation of this study is that we did not use MRI perfusion-weighted imaging or other advanced imaging to further differentiate imaging findings. While some studies have shown benefits in using MRI perfusion to characterize indeterminate cases, there is wide variation in how it is applied, including at the three trial sites on this study, which would lead to variations in interpretation [Future plans involve fully automating lesion segmentation in both FLAIR and T1w-CE MRIs as well as generating suggestive, structured reporting scores for each follow-up visit. While escalating the radiation dosage to 75 Gy led to minimal clinical toxicity for patients on this trial, there was one patient who had grade 3 toxicities as a result of their radiation, with edema on FLAIR imaging pushing across the midline of their brain. Additionally, there were a handful of cases where 75 Gy was not sufficient to control tumor as at least seven cases had in-field recurrence. External factors such as MGMT hypermethylation and IDH mutation likely contribute to how patients respond to different amounts of radiation [