Paulson, E.S.

Introduction Radiation therapy for head and neck squamous cell carcinoma is constrained by radiotoxicity to normal tissue. We demonstrate 100 nm theranostic nanoparticles for image-guided radiation therapy planning and enhancement in rat head and neck squamous cell carcinoma models. Methods PEG conjugated theranostic nanoparticles comprising of Au nanorods coated with Gadolinium oxide layers were tested for radiation therapy enhancement in 2D cultures of OSC-19-GFP-luc cells, and orthotopic tongue xenografts in male immunocompromised Salt sensitive or SS rats via both intratumoral and intravenous delivery. The radiation therapy enhancement mechanism was investigated. Results Theranostic nanoparticles demonstrated both X-ray/magnetic resonance contrast in a dose-dependent manner. Magnetic resonance images depicted optimal tumor-to-background uptake at 4 h post injection. Theranostic nanoparticle + Radiation treated rats experienced reduced tumor growth compared to controls, and reduction in lung metastasis. Conclusions Theranostic nanoparticles enable preprocedure radiotherapy planning, as well as enhance radiation treatment efficacy for head and neck tumors.

The past decade has seen the increasing integration of magnetic resonance (MR) imaging into radiation therapy (RT). This growth can be contributed to multiple factors, including hardware and software advances that have allowed the acquisition of high‐resolution volumetric data of RT patients in their treatment position (also known as MR simulation) and the development of methods to image and quantify tissue function and response to therapy. More recently, the advent of MR‐guided radiation therapy (MRgRT) ‐ achieved through the integration of MR imaging systems and linear accelerators ‐ has further accelerated this trend. As MR imaging in RT techniques and technologies, such as MRgRT, gain regulatory approval worldwide, these systems will begin to propagate beyond tertiary care academic medical centers and into more community‐based health systems and hospitals, creating new opportunities to provide advanced treatment options to a broader patient population. Accompanying these opportunities are unique challenges related to their adaptation, adoption, and use including modification of hardware and software to meet the unique and distinct demands of MR imaging in RT, the need for standardization of imaging techniques and protocols, education of the broader RT community (particularly in regards to MR safety) as well as the need to continue and support research, and development in this space. In response to this, an ad hoc committee of the American Association of Physicists in Medicine (AAPM) was formed to identify the unmet needs, roadblocks, and opportunities within this space. The purpose of this document is to report on the major findings and recommendations identified. Importantly, the provided recommendations represent the consensus opinions of the committee’s membership, which were submitted in the committee's report to the AAPM Board of Directors. In addition, AAPM ad hoc committee reports differ from AAPM task group reports in that ad hoc committee reports are neither reviewed nor ultimately approved by the committee’s parent groups, including at the council and executive committee level. Thus, the recommendations given in this summary should not be construed as being endorsed by or official recommendations from the AAPM.

PurposeA magnetic resonance (MR) biologic marker (biomarker) is a measurable quantitative characteristic that is an indicator of normal biological and pathogenetic processes or a response to therapeutic intervention derived from the MR imaging process. There is significant potential for MR biomarkers to facilitate personalized approaches to cancer care through more precise disease targeting by quantifying normal versus pathologic tissue function as well as toxicity to both radiation and chemotherapy. Both of which have the potential to increase the therapeutic ratio and provide earlier, more accurate monitoring of treatment response. The ongoing integration of MR into routine clinical radiation therapy (RT) planning and the development of MR guided radiation therapy systems is providing new opportunities for MR biomarkers to personalize and improve clinical outcomes. Their appropriate use, however, must be based on knowledge of the physical origin of the biomarker signal, the relationship to the underlying biological processes, and their strengths and limitations. The purpose of this report is to provide an educational resource describing MR biomarkers, the techniques used to quantify them, their strengths and weakness within the context of their application to radiation oncology so as to ensure their appropriate use and application within this field.

The use of dedicated magnetic resonance simulation (MR‐SIM) platforms in Radiation Oncology has expanded rapidly, introducing new equipment and functionality with the overall goal of improving the accuracy of radiation treatment planning. However, this emerging technology presents a new set of challenges that need to be addressed for safe and effective MR‐SIM implementation. The major objectives of this report are to provide recommendations for commercially available MR simulators, including initial equipment selection, siting, acceptance testing, quality assurance, optimization of dedicated radiation therapy specific MR‐SIM workflows, patient‐specific considerations, safety, and staffing. Major contributions include guidance on motion and distortion management as well as MRI coil configurations to accommodate patients immobilized in the treatment position. Examples of optimized protocols and checklists for QA programs are provided. While the recommendations provided here are minimum requirements, emerging areas and unmet needs are also highlighted for future development.

Abstract PURPOSE Previous secondary analysis of NRG/RTOG 0933 provided hypothesis-generating data supporting a relationship between larger volumes of MR-determined pre-treatment WMI and developing neurocognitive decline following HA-WBRT. The current study examines the relationship between pre-treatment WMI and neurocognitive function (NCF) following WBRT+memantine +/-HA in a substantially larger cohort. METHODS NCF testing was performed at baseline,2,4,6,and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (FLAIR/(whole brain volume – metastasis FLAIR volume). Pearson correlation coefficients were used to assess association between pre-treatment WMI and change from baseline for each standardized NCF score. RESULTS Of 518 randomized patients, 442 (217,WBRT+Memantine; 225,HA-WBRT+Memantine) had WMI data and were included. In the entire cohort, mean FLAIR volume was 9.3cc (0.1-68.2cc), mean metastases FLAIR volume was 61.5cc (0-423.5cc), mean Whole Brain volume was 1336.4cc (949.4-2397.8cc). At 2 months, there were no significant correlations between neurocognitive test change scores and pre-treatment WMI volume. However, at 4 months, both HVLT-R Total Recall and TMT Part B change score and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.22 p=0.042 and ρ=-0.27, p=0.013). At 12 months, both TMT Part A and TMT Part B change scores and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.30, p=0.046 and ρ=-0.53, p< 0.001). CONCLUSIONS Pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggests patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not following standard WBRT. Dose heterogeneity inherent to HA-WBRT delivery may contribute to these findings and are hypothesis generating.

Abstract PURPOSE: RTOG 0933 demonstrated benefits to memory following HA-WBRT, supporting the hypothesis of hippocampal radiosensitivity and associated memory specificity. However, some patients demonstrated cognitive decline, suggesting mechanisms outside hippocampal radiosensitivity playing a role. WMI has been implicated in RT-induced cognitive decline. This secondary analysis explored the relationship between pre-treatment WMI and memory following HA-WBRT. METHODS AND MATERIALS: 113 patients received HA-WBRT. Standardized cognitive assessments were performed at baseline, 2, 4, and 6 months. The primary endpoint was Hopkins Verbal Learning Test Delayed Recall (HVLT-DR) at 4 mos. Secondary endpoints included HVLT Total Recall (HVLT-TR) and Recognition (HVLT-Recog). Of 113 patients, 34 underwent pre-treatment and 4-month post-treatment HVLT testing and pre-treatment post-contrast volumetric T1 and axial T2/FLAIR MRI. Volumetric analysis of metastatic disease burden and disease-unrelated WMI was conducted on the pre-treatment MRI. Correlational analyses were performed examining the relationship between pre-treatment WMI and HVLT outcomes following HA-WBRT. RESULTS: Correlation was found between larger volumes of pre-treatment WMI and decline in HVLT-Recog (r=.54, p< .05) and a correlational trend was observed between larger volume of pre-treatment WMI and decline in HVLT-DR (r=.31, p=.08). Patients with higher pre-treatment disease burden experienced a greater magnitude of stability or positive shift in HVLT-recall and –delayed recall following HA-WBRT. (r=-.36 and r=-.36, p’s < .05), compared to the magnitude of stability/positive shift in those with lesser disease burden. CONCLUSION: In patients receiving HA-WBRT, pre-treatment-WMI predicts memory decline, suggesting white matter integrity pre-treatment contributes to the pathogenesis of post-WBRT cognitive toxicity independent of hippocampal stem cell radiosensitivity. Less decline or improvement in HVLT following HA-WBRT for patients with higher pre-treatment intracranial metastatic burden supports the importance of WBRT-induced intracranial control on cognition. These imaging biomarkers for cognitive toxicity will be further explored on NRG CC001 and CC003, phase III trials of WBRT with or without HA.