Vora, Sujay A.

Background: Radiation necrosis (RN) is a clinically relevant complication of stereotactic radiosurgery (SRS) for intracranial metastasis (ICM) treatments. Radiation necrosis development is variable following SRS. It remains unclear if risk factors for and clinical outcomes following RN may be different for melanoma patients. We reviewed patients with ICM from metastatic melanoma to understand the potential impact of RN in this patient population. Methods: Patients who received SRS for ICM from melanoma at Mayo Clinic Arizona between 2013 and 2018 were retrospectively reviewed. Data collected included demographics, tumor characteristics, radiation parameters, prior surgical and systemic treatments, and patient outcomes. Radiation necrosis was diagnosed by clinical evaluation including brain magnetic resonance imaging (MRI) and, in some cases, tissue evaluation. Results: Radiation necrosis was diagnosed in 7 (27%) of 26 patients at 1.6 to 38 months following initial SRS. Almost 92% of all patients received systemic therapy and 35% had surgical resection prior to SRS. Patients with RN trended toward having larger ICM and a prior history of surgical resection, although statistical significance was not reached. Among patients with resection, those who developed RN had a longer period between surgery and SRS start (mean 44 vs 33 days). Clinical improvement following treatment for RN was noted in 2 (29%) patients. Conclusions: Radiation necrosis is relatively common following SRS for treatment of ICM from metastatic melanoma and clinical outcomes are poor. Further studies aimed at mitigating RN development and identifying novel approaches for treatment are warranted.

Abstract INTRODUCTION Glioblastomas (GBMs) are highly aggressive tumors. A common clinical challenge after standard of care treatment is differentiating tumor progression from treatment-related changes, also known as pseudoprogression (PsP). Usually, PsP resolves or stabilizes without further treatment or a course of steroids, whereas true progression (TP) requires more aggressive management. Differentiating PsP from TP will affect the patient's outcome. This study investigated using deep learning to distinguish PsP MRI features from progressive disease. METHOD We included newly diagnosed GBM patients who met the inclusion criteria, including a new or increasing enhancing lesion size within the original radiation field and who had clinical, medication, and any histopathology available. The interpretation of the MR images at the image inclusion time point had to be indeterminate. We labeled those who subsequently were stable or improved on imaging and clinically as PSP and those with clinical and imaging deterioration as TP. A subset of subjects underwent a second resection. We labeled these subjects as PSP or TP based on the histological diagnosis. We performed skull stripping, coregistered contrast-enhanced T1 MRIs with T2-weighted images for each patient and used them as input to a 3-D Densenet121 model. We used several augmentation techniques and five-fold cross-validation to achieve more robust predictions. RESULT We included 124 patients who met the criteria, and of those, 63 were PsP and 61 were TP. We trained a deep learning model that achieved 76.4% (ranged 70%-84%, SD 5.122) mean accuracy over the 5 folds, 0.7560(ranged 0.6553-0.8535, SD 0.069) mean AUROCC, 88.72% (SD 6.86) mean sensitivity, and 62.05%(SD 9.11) mean specificity. CONCLUSION We report the development of a deep learning model that distinguishes PsP from TP in GBM patients treated per the Stupp protocol. Further refinement and external validation are required prior to widespread adoption in clinical practice.

Abstract PURPOSE Though patients with glioblastoma generally have poor overall survival (OS), OS estimates range significantly. We sought to develop a radiomics-based model predictive of OS in glioblastoma using preoperative MRI scans to identify these differences and guide clinical care. METHODS The primary endpoint was OS, determined from the date of surgery to death or last follow-up. T1, FLAIR, T2, and post-contrast T1 (T1c) MRI sequences were obtained for all patients. Using HD-GLIO-AUTO, lesion segmentation yielded three masks corresponding to the regions of contrast enhancement, non-enhancement, and total volume. Radiomics features were extracted from each region from the T2 and T1c sequences independently (i.e. either from T2 or T1c) and in combination. Age at surgery and gender were also considered. The data was split into training (75%) and test (25%) sets, stratifying for age at surgery. Kaplan-Meier analysis and the Coxnet model were used. For Coxnet, Elastic Net was used as the penalty, with optimization of the L1 coefficient using 5-fold cross-validation and evaluation via the concordance index (C-index). RESULTS From 3 institutions, 383 patients were included. Median OS was 395 days: 346 patients died, and 37 were right-censored. Age > 65 years was predictive of decreased OS (p < 0.005), but gender was not (p=0.16). For the Coxnet model, the C-index was 0.67 (standard deviation: 0.01) considering T2 and T1c sequences for the total lesion volume, with a C-index of 0.65 for the test set. For the enhancing volume, the model had a C-index of 0.71 for the test set using T1c sequences. Overall, C-indices ranged from 0.62-0.71. CONCLUSIONS We present a novel radiomics-based model predictive of OS in glioblastoma across a multi-institutional dataset. Ongoing efforts will incorporate immediate postoperative imaging and IDH and MGMT status into the proposed model to further improve prognostic ability and help guide clinical decision-making.

AbstractBackgroundBoth dose and linear energy transfer (LET) could play a substantial role in adverse event (AE) initialization of cancer patients treated with pencil‐beam‐scanning (PBS) proton therapy. However, not all the voxels within the AE regions are directly induced from the dose and LET effect. It is important to study the synergistic effect of dose and LET in AE initialization by only including a subset of voxels that are dosimetrically important.PurposeTo perform exploratory investigation of the dose and LET effects upon AE initialization in PBS using seed spots analysis.MethodsA total of 113 head‐and‐neck (H&N) cancer patients receiving curative PBS were included. Among them, 20 patients experienced unanticipated CTCAEv4.0 grade ≥3 AEs (AE group) and 93 patients did not (control group). Within the AE group, 13 AE patients were included in the seed spot analysis to derive the descriptive features of AE initialization and the remaining 7 mandible osteoradionecrosis patients and 93 control patients were used to derive the feature‐based volume constraint of mandible osteoradionecrosis. The AE regions were contoured and the corresponding dose–LET volume histograms of AE regions were generated for all patients in the AE group. We selected high LET voxels (the highest 5% of each dose bin) with a range of moderate‐to‐high dose (≥∼40‐Gy relative biological effectiveness) as critical voxels. Critical voxels that were contiguous with each other were grouped into clusters. Each cluster was considered a potential independent seed spot for AE initialization. Seed spots were displayed in a 2D dose–LET plane based on their mean dose and LET to derive the descriptive features of AE initialization. A volume constraint of mandible osteoradionecrosis was then established based on the extracted features using a receiver operating characteristic curve.ResultsThe product of dose and LET (xBD) was found to be a descriptive feature of seed spots leading to AE initialization in this preliminary study. The derived xBD volume constraint for mandible osteoradionecrosis showed good performance with an area under curve of 0.87 (sensitivity of 0.714 and specificity of 0.807 in the leave‐one‐out cross‐validation) for the very limited patient data included in this study.ConclusionOur exploratory study showed that both dose and LET were observed to be important in AE initializations. The derived xBD volume constraint could predict mandible osteoradionecrosis reasonably well in the very limited H&N cancer patient data treated with PBS included in this study.

Abstract IntroductionRadiotherapy is considered standard of care for adjuvant peri-operative treatment of many spinal tumors, including those with instrumented fusion. Unfortunately, radiation treatment has been linked to increased risk of pseudoarthrosis. Newerfocused radiotherapy strategies with enhanced conformalitycould offer improved fusion rates for these patients, but this has not been confirmed.MethodsWe performed a retrospective analysis of patients at three tertiary care academic institutions withprimary and secondary spinal malignancies that underwent resection, instrumented fusion, and peri-operative radiotherapy. Two board certified neuro-radiologists used theLenke fusion score to grade fusion status at6 and 12-months after surgery. Secondary outcomes includedclinical pseudoarthrosis, wound complications, and the effect of radiation timing, radiobiological dose delivered, the use of photons versus protons, tumor type, tumor location,and use of autograft on fusion outcomes.ResultsAfter reviewof 1252 spinal tumor patients, there were 60 patients with at least 6 months follow-up that were included in our analyses. Twenty-five of these patients received focused radiotherapy,20 patients received conventional radiotherapy, and 15 patients were treated with protons. There was no significant difference between the groups for covariates such assmoking status,obesity, diabetes, intraoperative use of autograft, and use of peri-operative chemotherapy. There was a significantly higher rate of fusion for patients treated with focused radiotherapy compared to those treated with conventional radiotherapy at 6-months (64.0% versus 30.0%, Odds ratio: 4.15, p=0.036) and 12-months (80.0% versus 42.1%, OR: 5.50, p=0.022). There was a significantly higher rate of clinical pseudoarthrosis in the conventional radiotherapy cohortcompared to patients in the focused radiotherapy cohort (19.1% versus 0%,p=0.037). There was no difference in fusion outcomes for any of the secondary outcomes except for use of autograft. The use ofintra-operative autograft was associated with an improved fusion at 12-months (66.7% versus 37.5%, OR: 3.33, p=0.043). ConclusionFocused radiotherapy may be associated withan improved rate of fusion and clinical pseudoarthrosis when compared to conventional radiation delivery strategiesin patients with spinal tumors.Use of autograft at the time of surgery may be associated with improved 12-month fusion rates.Further large-scale prospective and randomized controlled studies are needed to better stratify the effects of radiation delivery modality in these patients.

OBJECTIVE The authors aimed to demonstrate the feasibility and advantages of carbon fiber–reinforced PEEK (CFRP) composite implants in patients with both primary and secondary osseous spinal tumors. METHODS Twenty-eight spinal tumor patients who underwent fixation with CFRP hardware were retrospectively identified in a Spine Tumor Quality Database at a single institution. Demographic, procedural, and follow-up data were retrospectively collected. RESULTS The study population included 14 females and 14 males with a mean age of 60 years (range 30–86 years). Five patients had primary bone tumors, and the remaining patients had metastatic tumors. Breast cancer was the most common metastatic tumor. The most common presenting symptom was axial spine pain (25 patients, 89%), and the most common Spine Instability Neoplastic Score was 7 (range 6–14). Two patients in this series had anterior cervical procedures. The remaining patients underwent posterior thoracolumbar fixation. The average fusion length included 4.6 vertebral segments (range 3–8). The mean clinical follow-up time with surgical or oncology teams was 6.5 months (range 1–23 months), and the mean interval for last follow-up imaging (CT or MRI) was 6.5 months (range 1–22 months). Eighteen patients received postoperative radiation at the authors’ institution (16 with photon therapy, 2 with proton therapy). Eleven of the patients (39%) in this series died. At the last clinical follow-up, 26 patients (93%) had stable or improved neurological function compared with their preoperative status. At the last imaging follow-up, local disease control was observed in 25 patients (89%). Two patients required reoperation in the immediate postoperative period, one for surgical site infection and the other for compressive epidural hematoma. One patient was noted to have lucencies around the most cephalad screws 3 months after surgery. No hardware fracture or malfunction occurred intraoperatively. No patients required delayed surgery for hardware loosening, fracture, or other failure. Early tumor recurrence was detected in 3 patients. Early detection was attributed to the imaging characteristics of the CFRP hardware. CONCLUSIONS CFRP spinal implants appear to be safe and comparable to conventional titanium implants in terms of functionality. The imaging characteristics of CFRP hardware facilitate radiation planning and assessment of surveillance imaging. CFRP hardware may enhance safety and efficacy, particularly with particle therapy dosimetry. Larger patient populations with longer-term follow-up are needed to confirm the various valuable aspects of CFRP spinal implants.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

6108 Background: This pilot study evaluated whether providing clinicians with patient(pt) QOL results and symptom management pathways linked to QOL domains at the time of clinical appointment would result in improvement in QOL and treatment (tx) satisfaction. The objective was to obtain preliminary effect size estimates and logistical evidence for design of a larger, definitive trial. Methods: Oncology pts receiving 5-7 weeks of radiotherapy (RT) electronically completed QOL assessments (LASA) at baseline and biweekly prior to seeing clinicians. Was It Worth It (WIWI) and Interpersonal Patient-Provider Relationship (IPPRS) were measured at tx end. Pt endpoints (pro-rated primary endpoint LASA area under the curve (AUC), LASA changes from baseline, and WIWI responses) and clinician endpoints (IPPRS) were compared between the control group (Phase 1: no QOL feedback) and the intervention group (Phase 2: QOL feedback) via Wilcoxon, Chi-square and Fisher Exact tests. There was 80% power to detect a 10 point difference in average AUC. Results: 148 pts enrolled (79 Phase 1, 69 Phase 2) from 11/28/2008 to 09/20/2011 (sites GI (27%), Lung (22%) and Head and Neck (52%)). 68% received RT and chemo. There were consistently moderate effect sizes observed but no statistically significant differences in any AUC nor end of tx change from baseline scores. 20% fewer pts in phase 2 reported clinical deficits in overall QOL (pain). In pts receiving 7 weeks of RT, end of tx average overall QOL, mental well-being (WB), physical WB and pain severity were significantly better in Phase 2 pts. WIWI results showed 76% found participation worthwhile, 95% would participate again, and 92% would recommend the study to others. No differences between groups were found in communication between clinicians and pts (IPPRS). Conclusions: Preliminary estimates indicate potentially clinically significant improvements of moderate effect size in mental and physical WB and pain severity when clinicians received QOL real time with symptom management pathways. Further study is warranted in larger trial setting.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.