Evolution in the Presence and Evidence Category of Radiation Therapy Treatment Recommendations in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology.

Purpose: The changes in the recommended use of radiation therapy (RT) in the presence of expanding systemic cancer therapies and technological advances are poorly characterized. We sought to understand the recommended utilization of RT across a broad range of malignancies by examining National Comprehensive Cancer Network (NCCN) Guidelines. Methods and Materials: We conducted a comprehensive review and categorization of RT recommendations, with their subsequent supporting evidence categories, in 3 versions of NCCN Guidelines, specifically years 2000, 2009, and 2019. These NCCN Guidelines were individually examined for RT-specific recommendations among the 10 most common tumors. The presence of RT as a recommended modality was recorded for each tumor type in each guideline. Recommendation categories including Category 1, 2A, 2B, and 3 were tallied and compared with examine totals and percentage distributions in each tumor type. Results: A total of 3858 NCCN recommendations were individually reviewed. The presence of a recommendation inclusive of RT increased from incidence of 205 in the year 2000 to 992 in the year 2019 (383%). In the 2019 NCCN Guidelines, the most Category 1 RT recommendations were found within small cell lung (13%), non-small cell lung (5%), breast (5%), bladder (2%), rectal (2%), and non-Hodgkin lymphoma (1%). Pancreatic, uterine, prostate, melanoma, kidney, and colon cancer guidelines had no Category 1 RT recommendations. Rectal cancer had 31 (27%) preferred recommendations. The majority (89%) of 2019 RT recommendations were for initial therapy, and 9% were specific to salvage therapy. Tumor sites with the highest proportion of RT Category 1 evidence were small cell lung (29%), non-small cell lung (24%), and breast cancer (24%). Conclusions: The frequency of recommendations for using RT in NCCN Guidelines has increased by >300% in the past 20 years among the 10 most common malignancies. Consideration of the quality of evidence supporting these recommendations by tumor type is useful to identify specific malignancies in need of higher-level evidence supporting the role of RT.

Characterization of Underrepresented Populations in Modern Era Clinical Trials Involving Radiation Therapy.

PURPOSE: The demographic composition of modern radiation therapy (RT) clinical trials is incompletely studied. Understanding and minimizing disparities in clinical trials is critical to ensure health equity and the generalizability of research findings. METHODS AND MATERIALS: Clinicaltrials.gov was searched to identify RT clinical trials that occurred from 1996 to 2019. A total of 1242 trials were reviewed for patient characteristics. The demographic composition of the studies was summarized by the frequency and percentage of patients by race, gender, and ethnicity. The racial composition of the study population was compared with the 2018 US Census using a 1-sample χ2 test. Subgroup racial composition was compared using χ2 tests of independence. Analyses used a complete case approach. RESULTS: A total of 122 trials met the inclusion criteria, and 121 of these (99.1%) reported race. Trial subgroups included 63 trials in the United States (51.6%), 9 proton therapy trials (7.4%), 34 RT toxicity mitigation or prevention trials (27.9%), 24 trials for female cancer (19.7%), and 17 trials for male cancer (13.9%). US clinical trials overall, US RT toxicity mitigation or prevention trials, US trials for female cancer, and US trials for male cancer had significantly different racial compositions compared with the 2018 US Census data (P < .001 for all). Compared with all clinical trials, those for proton therapy had the largest magnitude of significantly lower enrollment of participants who identified their race as Black, Asian, or other (P < .001). CONCLUSIONS: This study characterized the racial composition of prospective RT clinical trials in a modern cohort. The racial population represented across multiple categories in the United States differed significantly from US census data and was most pronounced in trials evaluating proton therapy. This is a benchmark study for future efforts to characterize and balance the participation of underrepresented populations in RT clinical trials.

Initial Clinical Experience of MR-Guided Radiotherapy for Non-Small Cell Lung Cancer.

Curative-intent radiotherapy plays an integral role in the treatment of lung cancer and therefore improving its therapeutic index is vital. MR guided radiotherapy (MRgRT) systems are the latest technological advance which may help with achieving this aim. The majority of MRgRT treatments delivered to date have been stereotactic body radiation therapy (SBRT) based and include the treatment of (ultra-) central tumors. However, there is a move to also implement MRgRT as curative-intent treatment for patients with inoperable locally advanced NSCLC. This paper presents the initial clinical experience of using the two commercially available systems to date: the ViewRay MRIdian and Elekta Unity. The challenges and potential solutions associated with MRgRT in lung cancer will also be highlighted.

MR-Guided Radiotherapy for Brain and Spine Tumors.

MRI is the standard modality to assess anatomy and response to treatment in brain and spine tumors given its superb anatomic soft tissue contrast (e.g., T1 and T2) and numerous additional intrinsic contrast mechanisms that can be used to investigate physiology (e.g., diffusion, perfusion, spectroscopy). As such, hybrid MRI and radiotherapy (RT) devices hold unique promise for Magnetic Resonance guided Radiation Therapy (MRgRT). In the brain, MRgRT provides daily visualizations of evolving tumors that are not seen with cone beam CT guidance and cannot be fully characterized with occasional standalone MRI scans. Significant evolving anatomic changes during radiotherapy can be observed in patients with glioblastoma during the 6-week fractionated MRIgRT course. In this review, a case of rapidly changing symptomatic tumor is demonstrated for possible therapy adaptation. For stereotactic body RT of the spine, MRgRT acquires clear isotropic images of tumor in relation to spinal cord, cerebral spinal fluid, and nearby moving organs at risk such as bowel. This visualization allows for setup reassurance and the possibility of adaptive radiotherapy based on anatomy in difficult cases. A review of the literature for MR relaxometry, diffusion, perfusion, and spectroscopy during RT is also presented. These techniques are known to correlate with physiologic changes in the tumor such as cellularity, necrosis, and metabolism, and serve as early biomarkers of chemotherapy and RT response correlating with patient survival. While physiologic tumor investigations during RT have been limited by the feasibility and cost of obtaining frequent standalone MRIs, MRIgRT systems have enabled daily and widespread physiologic measurements. We demonstrate an example case of a poorly responding tumor on the 0.35 T MRIgRT system with relaxometry and diffusion measured several times per week. Future studies must elucidate which changes in MR-based physiologic metrics and at which timepoints best predict patient outcomes. This will lead to early treatment intensification for tumors identified to have the worst physiologic responses during RT in efforts to improve glioblastoma survival.

A Patient-Specific Autosegmentation Strategy Using Multi-Input Deformable Image Registration for Magnetic Resonance Imaging-Guided Online Adaptive Radiation Therapy: A Feasibility Study.

PURPOSE: Magnetic resonance-guided online adaptive radiation therapy (MRgOART) requires accurate and efficient segmentation. However, the performance of current autosegmentation tools is generally poor for magnetic resonance imaging (MRI) owing to day-to-day variations in image intensity and patient anatomy. In this study, we propose a patient-specific autosegmentation strategy using multiple-input deformable image registration (DIR; PASSMID) to improve segmentation accuracy and efficiency for MRgOART. METHODS AND MATERIALS: Longitudinal MRI scans acquired on a 1.5T MRI-Linac for 10 patients with abdominal cancer were used. The proposed PASSMID includes 2 steps: applying a patient-specific image processing pipeline to longitudinal MRI scans, and populating all contours from previous sessions/fractions to a new fractional MRI using multiple DIRs and combining the resulted contours using simultaneous truth and performance level estimation (STAPLE) to obtain the final consensus segmentation. Five contour propagation strategies were compared: planning computed tomography to fractional MRI scans through rigid body registration (RDR), pretreatment MRI to fractional MRI scans through RDR and DIR, and the proposed multi-input DIR/STAPLE without preprocessing, and the PASSMID. Dice similarity coefficient (DSC) and mean distance to agreement (MDA) with ground truth contours were calculated slice by slice to quantify the contour accuracy. A quantitative index, defined as the ratio of acceptable slices, was introduced using a criterion of DSC > 0.8 and MDA < 2 mm. RESULTS: The proposed PASSMID performed well with an average 2-dimensional DSC/MDA of 0.94/1.78 mm, 0.93/1.04 mm, 0.93/1.06 mm, 0.93/1.14 mm, 0.92/0.83 mm, 0.84/1.53 mm, 0.86/2.39 mm, 0.81/2.49 mm, 0.72/5.48 mm, and 0.70/5.03 mm for the liver, left kidney, right kidney, spleen, aorta, pancreas, stomach, duodenum, small bowel, and colon, respectively. Starting from the third fractions, the contour accuracy was significantly improved with PASSMID compared with the single-DIR strategy (P < .05). The mean ratio of acceptable slices were 13.9%, 17.5%, 60.8%, 70.6%, and 71.8% for the 5 strategies, respectively. CONCLUSIONS: The proposed PASSMID solution, by combining image processing, multi-input DIRs, and STAPLE, can significantly improve the accuracy of autosegmentation for intrapatient MRI scans, reducing the time required for further contour editing, thereby facilitating the routine practice of MRgOART.

Initial clinical experience of Stereotactic Body Radiation Therapy (SBRT) for liver metastases, primary liver malignancy, and pancreatic cancer with 4D-MRI based online adaptation and real-time MRI monitoring using a 1.5 Tesla MR-Linac.

PURPOSE/OBJECTIVES: Recently a 1.5 Tesla MR Linac has been FDA approved and is commercially available. Clinical series describing treatment methods and outcomes for upper abdominal tumors using a 1.5 Tesla MR Linac are lacking. We present the first clinical series of upper abdominal tumors treated using a 1.5 Tesla MR Linac along with the acquisition of intra-treatment quantitative imaging. MATERIALS/METHODS: 10 patients with abdominal tumors were treated at our institution. Each patient enrolled in an IRB approved advanced imaging protocol. Both daily real-time adaptive and non-adaptive methods were used, and selection criteria are described. Adaptive plans were based on pre-beam motion-averaged or mid-position images derived from respiratory-correlated 4D-MRI. Quantitative intravoxel incoherent motion diffusion-weighted imaging and T2 mapping were acquired during plan adaptation. Real-time motion monitoring using cine MRI was performed during beam-on. RESULTS: Median patient age was 68.2, five patients were female. Tumor types included liver metastatic lesions from melanoma and sarcoma, primary liver hepatocellular carcinoma (HCC), and regional abdominal tumors included pancreatic metastatic lesions from renal cell carcinoma (RCC) along with two cases of recurrent pancreatic cancer. Doses included 30 Gy in 6 fractions, 33 Gy in 5 fractions, 50 Gy in 5 fractions, 45 Gy in 3 fractions, and 60 Gy in 3 fractions, depending on the location and clinical circumstances. Treatments were feasible and were successfully completed in all patients without significant acute toxicity, technical complications, or need for back up CT based treatment plans. CONCLUSIONS: We present a first clinical series of patients treated for pancreatic tumors, primary liver tumors, and secondary liver tumors with a 1.5 Tesla MR Linear accelerator using adapt-to-position and adapt-to-shape strategies. Treatments were well tolerated by all patients. Acquisition of fully quantitative MR imaging was feasible during the course of the treatment delivery workflow without extending overall treatment times.

Therapeutic targeting of C-terminal binding protein in human cancer.

The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable therapeutic index for cancer therapy. In human colon cancer cell peritoneal xenografts, MTOB treatment decreased tumor burden and induced tumor cell apoptosis. To verify the potential utility of CtBP as a therapeutic target in human cancer, the expression of CtBP and its negative regulator ARF was studied in a series of resected human colon adenocarcinomas. CtBP and ARF levels were inversely-correlated, with elevated CtBP levels (compared with adjacent normal tissue) observed in greater than 60% of specimens, with ARF absent in nearly all specimens exhibiting elevated CtBP levels. Targeting CtBP may represent a useful therapeutic strategy in human malignancies.