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Background Glioblastomas comprise heterogeneous cell populations with dynamic, bidirectional plasticity between treatment-resistant stem-like and treatment-sensitive differentiated states, with treatment influencing this process. However, current treatment protocols do not account for this plasticity. Previously, we generated a mathematical model based on preclinical experiments to describe this process and optimize a radiation therapy fractionation schedule that substantially increased survival relative to standard fractionation in a murine glioblastoma model. Methods We developed statistical models to predict the survival benefit of interventions to glioblastoma patients based on the corresponding survival benefit in the mouse model used in our preclinical study. We applied our mathematical model of glioblastoma radiation response to optimize a radiation therapy fractionation schedule for patients undergoing re-irradiation for glioblastoma and developed a first-in-human trial (NCT03557372) to assess the feasibility and safety of administering our schedule. Results Our statistical modeling predicted that the hazard ratio when comparing our novel radiation schedule with a standard schedule would be 0.74. Our mathematical modeling suggested that a practical, near-optimal schedule for re-irradiation of recurrent glioblastoma patients was 3.96 Gy × 7 (1 fraction/day) followed by 1.0 Gy × 9 (3 fractions/day). Our optimized schedule was successfully administered to 14/14 (100%) patients. Conclusions A novel radiation therapy schedule based on mathematical modeling of cell-state plasticity is feasible and safe to administer to glioblastoma patients.

BackgroundVenous thromboembolism is common in patients with solid malignancies and brain metastases. Whether to anticoagulate such patients is controversial given the possibility of intracerebral haemorrhage (ICH). We evaluated the added risk of ICH in patients with brain metastases receiving therapeutic anticoagulation.MethodsWe performed a matched, retrospective cohort study of 291 patients (100 receiving therapeutic anticoagulation vs 191 controls) with brain metastases managed at Brigham and Women’s Hospital/Dana-Farber Cancer Institute between 1998 and 2015. For each patient, all MRI studies of the brain were reviewed to identify ICH. Propensity score matching and multivariable Cox regression were used to mitigate confounding.ResultsThe risk of ICH was comparable in patients receiving anticoagulation versus controls preanticoagulation. Postanticoagulation, we observed significant or borderline-significant associations between anticoagulation and development of any ICH (HR 1.31, 95% CI 0.96 to 1.79, p=0.09), ICH as identified by gradient echo/susceptibility-weighted imaging (HR 1.46, 95% CI 1.06 to 2.01, p=0.02), symptomatic ICH (HR 1.80, 95% CI 1.01 to 3.22, p=0.05), extralesional ICH (HR 5.82, 95% CI 1.56 to 21.7, p=0.009) and fatal ICH (HR 5.68, 95% CI 0.60 to 54.2, p=0.13). Anticoagulation was associated with differentially higher ICH risk in patients with prior ICH versus no prior ICH (HR 2.20 vs 0.68, respectively, p interaction ConclusionsAnticoagulation is associated with clinically significant ICH in patients with brain metastases, especially those with melanoma or prior ICH. The indication for anticoagulation and risk of intracerebral bleeding should be considered on an individual basis among such patients.

Background During the ongoing COVID-19 pandemic, contact with the health care system for cancer treatment can increase risk of infection and associated mortality. Treatment recommendations must consider this risk for elderly and vulnerable cancer patients. We reanalyzed trials in elderly glioblastoma (GBM) patients, incorporating COVID-19 risk, in order to provide a quantitative framework for comparing different radiation (RT) fractionation schedules on patient outcomes. Methods We extracted individual patient-level data for 1321 patients from Kaplan–Meier curves from 5 randomized trials on treatment of elderly GBM patients including available subanalyses based on O6-methylguanine-DNA methyltransferase (MGMT) methylation status. We simulated trial data with incorporation of COVID-19–associated mortality risk in several scenarios (low, medium, and high infection and mortality risks). Median overall survival and hazard ratios were calculated for each simulation replicate. Results Our simulations reveal how COVID-19–associated risks affect survival under different treatment regimens. Hypofractionated RT with concurrent and adjuvant temozolomide (TMZ) demonstrated the best outcomes in low and medium risk scenarios. In frail elderly patients, shorter courses of RT are preferable. In patients with methylated MGMT receiving single modality treatment, TMZ-alone treatment approaches may be an option in settings with high COVID-19–associated risk. Conclusions Incorporation of COVID-19–associated risk models into analysis of randomized trials can help guide clinical decisions during this pandemic. In elderly GBM patients, our results support prioritization of hypofractionated RT and highlight the utility of MGMT methylation status in decision making in pandemic scenarios. Our quantitative framework can serve as a model for assessing COVID-19 risk associated with treatment across neuro-oncology. Key Points • Re-analysis of randomized controlled trials in COVID-19 era gives insight on optimal treatment of GBM. • Hypofractionated RT or temozolomide alone may be reasonable options in high risk pandemic settings. • A quantitative framework incorporating COVID-19 risks can be applied across neuro-oncology.

Brain metastases from breast cancer are frequently managed with brain-directed radiation but the impact of subtype on intracranial recurrence patterns after radiation has not been well-described. We investigated intracranial recurrence patterns of brain metastases from breast cancer after brain-directed radiation to facilitate subtype-specific management paradigms. We retrospectively analyzed 349 patients with newly diagnosed brain metastases from breast cancer treated with brain-directed radiation at Brigham and Women’s Hospital/Dana-Farber Cancer Institute between 2000 and 2015. Patients were stratified by subtype: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−), HER2+ positive (HER2+), or triple-negative breast cancer (TNBC). A per-metastasis assessment was conducted. Time-to-event analyses were conducted using multivariable Cox regression. Of the 349 patients, 116 had HR+/HER2− subtype, 164 had HER2+ subtype, and 69 harbored TNBC. Relative to HR+/HER2− subtype, local recurrence was greater in HER2+ metastases (HR 3.20, 95% CI 1.78–5.75, p

Background Brain metastases commonly manifest in patients with cancer, with ∼20%–50% presenting with 1 intracranial lesion. Among patients with 1, small brain metastasis and controlled or absent extracranial disease, it remains unclear whether aggressive intracranial management using neurosurgical resection plus cavity stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) rather than SRS/SRT alone is beneficial. In patients with controlled or absent extracranial disease and 1 brain metastasis ≤2 cm in size, we evaluated the effect of surgery plus SRS/SRT compared with SRS/SRT on oncologic outcomes, including overall survival. Methods We retrospectively identified 86 patients with controlled or absent extracranial disease and 1 brain metastasis ≤2 cm in size who had been treated from 2000 to 2015 at our institution. We examined differences in the rates of local and distant failure, use of salvage treatment, and other oncologic outcomes, including all-cause mortality. Results The baseline characteristics were similar between the 2 cohorts. The median follow-up period for the surviving patients was 38 months. On multivariable analysis, surgical resection plus cavity SRS/SRT was associated with a lower risk of all-cause mortality (hazard ratio, 0.44; 95% confidence interval, 0.19–1.00; P = 0.05) compared with SRS/SRT alone. The 1- and 2-year rates of overall survival were 100% and 88% versus 74% and 52% for surgery plus cavity SRS/SRT versus SRS/SRT alone, respectively. Conclusions Aggressive, local therapy, including neurosurgical resection, might benefit patients with 1 brain metastasis in the context of controlled or absent systemic disease, even if the lesion in question is small. Further studies are needed to evaluate these associations.

BACKGROUND The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial with Bayesian adaptive randomization and deep genomic profiling to more efficiently test experimental agents in newly diagnosed glioblastoma and to prioritize therapies for late-stage testing. METHODS In the ongoing INSIGhT trial, patients with newly diagnosed MGMT-unmethylated glioblastoma are randomized to the control arm or one of three experimental therapy arms (CC-115, abemaciclib, and neratinib). The control arm therapy is radiotherapy with concomitant and adjuvant temozolomide, and primary endpoint is overall survival. Randomization has been adapted based on Bayesian estimation of biomarker-specific probability of treatment impact on progression-free survival (PFS). All tumors undergo detailed molecular sequencing, and this is facilitated with the companion ALLELE protocol. To evaluate feasibility of this approach, we assessed the status of this ongoing trial. RESULTS Since INSIGhT was activated 4.3 years ago, it has expanded to include 12 sites across the United States. A total of 247 patients have been enrolled. Randomization probabilities have been repeatedly adjusted over time based upon early PFS results to alter the randomization ratio from standard 1:1:1:1 randomization. All three arms have completed accrual and efficacy estimates are available based upon comparison to the common control arm in context of relevant biomarkers. There are 87 patients alive and in follow-up, and there are ongoing plans to add additional arms to evaluate further treatments in the future. CONCLUSION The INSIGhT trial demonstrates that a multi-center Bayesian adaptive platform trial is a feasible and effective approach to help prioritize therapies and biomarkers for newly diagnosed GBM. The trial has maintained robust accrual, and the simultaneous testing of multiple agents, sharing a common control arm and adaptive randomization serve as features to increase trial efficiency relative to traditional clinical trial designs.

Purpose/objective(s) Relapsed or refractory central nervous system lymphoma (CNSL) after high-dose methotrexate-based therapy is a challenging clinical entity with limited treatment options. Salvage systemic therapy and whole brain radiation therapy (WBRT) are commonly employed but are associated with significant toxicity and poor outcomes. Prior studies have shown that primary CNSLs frequently exhibit increased expression of PD-L1, and immune checkpoint inhibitor (ICI) therapy may be active in this setting. We assessed the safety and efficacy of concurrent ICI therapy and hypo-fractionated stereotactic radiation therapy (SRT) in patients with relapsed or refractory CNSL. Materials/methods We retrospectively analyzed the records of patients with relapsed or refractory CNSL treated with SRT + ICI at our institution from 2017 to 2020. ICI therapy included pembrolizumab 200 mg IV q3weeks or nivolumab 3 mg/mg IV q2weeks. Linac-based SRT was delivered in 5 daily fractions of 5 Gy. CTVs included all grossly enhancing disease on T1 weighted post-contrast MR scans, with 3 mm uniform PTV expansions. Patients were followed for symptomatic and radiographic response. Progression-free survival (PFS) and overall survival (OS) were calculated via Kaplan-Meier analysis. Results Seven consecutive patients with relapsed or recurrent CNSL were analyzed: 6 with primary CNSL, 1 with secondary CNSL. Patients presented at a median age of 72.2 years (range: 40.9 - 89.9) after a median of 2 prior courses of systemic therapy. Five patients had a solitary intracranial lesion and 2 had multiple lesions. None had active extracranial disease. Median pre-SRT Karnofsky Performance Status (KPS) was 60 (range 50 - 90). All 7 patients completed SRT and received concurrent and adjuvant ICI therapy. Median follow-up after completion of SRT was 9.1 months. Acute toxicities of SRT and ICI therapy were minimal, including fatigue (3 patients), diarrhea (2), and adrenal insufficiency requiring oral steroids (1). Five patients (71.4%) achieved symptomatic improvement after SRT including 2 patients (28.5%) with a clinical complete response (CR). Median post-SRT KPS was 70 (range: 60 - 100). Six patients had follow-up imaging, and all had an objective response including 3 (50%) with a radiographic CR. The median time to best radiographic response was 2.0 months (range 0.3 - 3.7 months), and all treated lesions remained controlled on all subsequent imaging. Three patients (42.9%) experienced out-of-field intracranial recurrence. Median PFS was 7.7 months (95% CI: 4.0 - 11.4 months) and median OS was 12.6 months (95% CI: 7.5 - 12.7 months) post-SRT. Conclusion Among patients with relapsed or refractory CNSL, SRT + ICI appears to be well tolerated and offers excellent symptomatic and radiographic local control. Further studies are needed to identify appropriate candidates for salvage SRT + ICI, and to evaluate the clinical efficacy and neurocognitive impact of this approach.

PURPOSE/OBJECTIVE(S) While glioblastoma (GBM) is known to have increased incidence in males, recent work has identified possible sex-specific molecular differences that could be associated with improved clinical outcomes for female GBM patients. We evaluated sex-based differences in patient and tumor characteristics, and clinical outcomes in newly diagnosed GBM patients. MATERIALS/METHODS We reviewed 665 newly diagnosed adult IDH-wild type GBM patients with Karnofsky Performance Status (KPS) ≥60 who were treated at our institution from January 1, 2010 to May 30, 2019. Patient, tumor and treatment details were obtained from the electronic medical record. An unpaired t-test, Fisher's exact test and univariable/multivariable Cox proportional hazards modeling were used to evaluate associations, including progression free survival (PFS) and overall survival (OS). RESULTS In our GBM cohort, 384 (57.7%) were male and 281 (42.3%) were female. There were no significant differences in age (60.6 years in males vs. 60.0 years in females, P = 0.16), KPS (KPS ≥90 in 46.1% in males vs. 43.4% in females, P = 0.53), extent of resection (gross total resection in 44.8% in males vs. 47.7% in females, P = 0.48), or prevalence of MGMT methylation (37.8% in males vs. 43.4% in females, P = 0.11). There were also no differences in receipt of temozolomide (95.1% of males vs. 95.7% of females, P = 0.71), radiation dose (≥59.4 Gy in 85.2% in males vs. 87.5% in females, P = 0.43), or clinical trial enrollment (24.7% males vs. 21.0% females, P = 0.27). Median OS was 22.5 months for females and 19.3 months for males (hazard ratio [HR] 0.81, 95% CI 1.03-1.48, P = 0.02). On multivariable analysis adjusted for age (adjusted hazard ratio [AHR] 1.04, 95% CI [1.03-1.05], P < 0.001), KPS ≥90 (AHR 0.73, 95% CI [0.60-0.89], P = 0.002), extent of resection (AHR 1.12, 95% CI 0.92-1.37, P = 0.26), and MGMT methylation status (AHR 0.38, 95% CI [0.31-0.47], P < 0.001), female sex (AHR 0.78, 95% CI [0.64-0.95], P = 0.015) was associated with improved OS. Superior OS in females was observed in MGMT unmethylated patients (HR 0.69, 95% CI [0.54-0.90], P = 0.005) but not in MGMT methylated patients (HR 0.85, 95% CI [0.64-1.14], P = 0.28). While age (AHR 1.02, 95% CI [1.02-1.03], P < 0.001), KPS ≥90 (AHR 0.79, 95% CI [0.66-0.95], P = 0.01), and MGMT methylation (AHR 0.40, 95% CI [0.33-0.49], P < 0.001) were associated with PFS, biologic sex was not associated with PFS (AHR 0.94, 95% CI [0.78-1.12], P = 0.49). CONCLUSION Female sex was associated with improved survival after adjustment of known clinical covariates in newly diagnosed GBM patients. Further study is necessary to understand biologic mechanism for sex-based differences in clinical outcome given implications for therapy development and clinical trial design. AUTHOR DISCLOSURE D.D. Shi: None. M. Lim-Fat: None. G.C. Youssef: None. S. Whorral: None. M. Allen: None. D.N. Cagney: None. S. Tanguturi: None. D. Haas-Kogan: Research Grant; Novartis; Cellworks. A.A. Aizer: Research Grant; Varian. Consultant; Novartis. Advisory Board; Seattle Genetics. J. McFaline-Figueroa: None. U.N. Chukwueke: None. E.Q. Lee: None. D.A. Reardon: Research Grant; Celldex, Inovio, Midatech. Consultant; Amgen. Speaker's Bureau; Merck/Schering, Roche/Genentech. Advisory Board; AbbVie, Bristol Myers Squibb, Cavion, Celldex, EMD Serono, Juno Pharmaceuticals, Momenta Pharmaceuticals, Novartis, Novocure, Oxigene, Regeneron, Roche/Genentech, Stemline. L. Nayak: None. W.L. Bi: Research Grant; The Leukemia and Lymphoma Society, NIH/NCI.R. Beroukhim: Independent Contractor; Scorpion Therapeutics. Stock; Scorpion Therapeutics. K.L. Ligon: None. B.M. Alexander: Research Grant; Puma Biotechnology, Eli Lily, Celgene. Stock; Hoffman-La Roche. P.Y. Wen: None. R. Rahman: Research Grant; Project Data Sphere, LLC.

Key Points Question How is the COVID-19 pandemic associated with risks and benefits of standard cancer therapy? Findings In this comparative effectiveness study reanalyzing data from 8 randomized trials across oncology, radiation fractionation was not associated with outcomes in low COVID-19–risk scenarios. In higher-risk scenarios, aggressive hypofractionation was associated with a survival benefit, whereas moderate hypofractionation was not. Meaning These findings suggest that the expected benefit of altering radiation therapy during the COVID-19 pandemic is associated with local pandemic factors and the specifics of treatment modification, and can be estimated using a quantitative framework based on completed randomized trials to support treatment decision-making., This comparative effectiveness study investigates how the COVID-19 pandemic is associated with the benefits and risks of standard radiation therapy in simulated patients., Importance During the COVID-19 pandemic, cancer therapy may put patients at risk of SARS-CoV-2 infection and mortality. The impacts of proposed alternatives on reducing infection risk are unknown. Objective To investigate how the COVID-19 pandemic is associated with the risks and benefits of standard radiation therapy (RT). Design, Setting, and Participants This comparative effectiveness study used estimated individual patient–level data extracted from published Kaplan-Meier survival figures from 8 randomized clinical trials across oncology from 1993 to 2014 that evaluated the inclusion of RT or compared different RT fractionation regimens. Included trials were Dutch TME and TROG 01.04 examining rectal cancer; CALGB 9343, OCOG hypofractionation trial, FAST-Forward, and NSABP B-39 examining early stage breast cancer, and CHHiP and HYPO-RT-PC examining prostate cancer. Risk of SARS-CoV-2 infection and mortality associated with receipt of RT in the treatment arms were simulated and trials were reanalyzed. Data were analyzed between April 1, 2020, and June 30, 2020. Exposures COVID-19 risk associated with treatment was simulated across different pandemic scenarios, varying infection risk per fractions (IRFs) and case fatality rates (CFRs). Main Outcomes and Measures Overall survival was evaluated using Cox proportional hazards modeling under different pandemic scenarios. Results Estimated IPLD from a total of 14 170 patients were included in the simulations. In scenarios with low COVID-19-associated risks (IRF, 0.5%; CFR, 5%), fractionation was not significantly associated with outcomes. In locally advanced rectal cancer, short-course RT was associated with better outcomes than long-course chemoradiation (TROG 01.04) and was associated with similar outcomes as RT omission (Dutch TME) in most settings (eg, TROG 01.04 median HR, 0.66 [95% CI, 0.46-0.96]; Dutch TME median HR, 0.91 [95% CI, 0.80-1.03] in a scenario with IRF 5% and CFR 20%). Moderate hypofractionation in early stage breast cancer (OCOG hypofractionation trial) and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19 (eg, OCOG hypofractionation trial median HR, 0.89 [95% CI, 0.74-1.06]; CHHiP median HR, 0.87 [95% CI, 0.75-1.01] under high-risk scenario with IRF 10% and CFR 30%). More aggressive hypofractionation (FAST-Forward, HYPO-RT-PC) and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios (eg, FAST-Forward median HR, 0.58 [95% CI, 0.49-0.68]; HYPO-RT-PC median HR, 0.60 [95% CI, 0.48-0.75] under scenario with IRF 10% and CFR 30%). Conclusions and Relevance In this comparative effectiveness study of data from 8 clinical trials of patients receiving radiation therapy to simulate COVID-19 risk and mortality rates, treatment modification was not associated with altered risk from COVID-19 in lower-risk scenarios and was only associated with decreased mortality in very high COVID-19–risk scenarios. This model, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the potential impact of treatment modifications and supports the continued delivery of standard evidence-based care with appropriate precautions against COVID-19.

BACKGROUND CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents. METHODS Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used. RESULTS Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade > 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to < 10% at time of the trial arm closure. CONCLUSION Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.

Purpose Among patients with brain metastases, hippocampal avoidance whole brain radiation (HA-WBRT) preserves neurocognitive function relative to conventional WBRT but the feasibility of hippocampal sparing in patients with metastases in/near the hippocampus is unknown. We identified the incidence of hippocampal/perihippocampal metastases and evaluated the feasibility of HA-WBRT in such patients. Materials/Methods Dosimetric data from 34 patients randomized to HA-WBRT (30 Gy/10 fractions) in a phase III trial (NCT03075072) comparing HA-WBRT to stereotactic radiation in patients with 5 to 20 brain metastases were analyzed. Patients with metastases in/near the hippocampi received HA-WBRT with prioritization of tumor coverage over hippocampal avoidance. Target coverage and hippocampal sparing metrics were compared between patients with targets in/near the hippocampus versus not. Results In total, 9 of 34 (26%) patients had targets in the hippocampus and an additional 5 of 34 (15%) patients had targets in the hippocampal avoidance zone (HAZ, hippocampus plus 5 mm expansion) but outside the hippocampus. Patients with targets within the hippocampus and those with targets in the HAZ but outside the hippocampus were spared 34% and 73% of the ipsilateral mean biologically equivalent prescription dose, respectively. Of the latter cohort, 88% and 25% met conventional hippocampal sparing metrics of Dmin ≤ 9 Gy and Dmax ≤ 16 Gy, respectively. Among 11 patients with unilateral hippocampal/perihippocampal involvement, the uninvolved/contralateral hippocampus was limited to Dmin ≤ 9 Gy and Dmax ≤ 17 Gy in all cases. Conclusions In this study, a substantial percentage of patients with 5 to 20 brain metastases harbored metastases in/near the hippocampus. In such cases, minimizing hippocampal dose while providing tumor coverage was feasible and may translate to neurocognitive protection.

OBJECTIVEMetastatic spinal cord compression (MSCC) imposes significant impairment on patient quality of life and often requires immediate surgical intervention. In this study the authors sought to estimate the impact of surgical intervention on patient quality of life in the form of mean quality-adjusted life years (QALY) gained and identify factors associated with positive outcomes.METHODSThe authors performed a retrospective chart review and collected data for patients who had neurological symptoms resulting from radiologically and histologically confirmed MSCC and were treated with surgical decompression during the last 12 years.RESULTSA total of 151 patients were included in this study (mean age 60.4 years, 57.6% males). The 5 most common metastatic tumor types were lung, multiple myeloma, renal, breast, and prostate cancer. The majority of patients had radioresistant tumors (82.7%) and had an active primary site at presentation (67.5%). The median time from tumor diagnosis to cord compression was 12 months and the median time from identification of cord compression to death was 4 months. Preoperative presenting symptoms included motor weakness (70.8%), pain (70.1%), sensory disturbances (47.6%), and bowel or bladder disturbance (31.1%). The median estimated blood loss was 500 mL and the average length of hospital stay was 10.3 days. About 18% of patients had postoperative complications and the mean follow-up was 7 months. The mean pre- and postoperative ECOG (Eastern Cooperative Oncology Group) performance status grades were 3.2 and 2.4, respectively. At follow-up, 58.3% of patients had improved status, 31.5% had no improvement, and 10.0% had worsening of functional status. The mean QALY gained per year in the entire cohort was 0.55. The mean QALY gained in the first 6 months was 0.1 and in the first year was 0.4. For patients who lived 1–2, 2–3, 3–4, or 4–5 years, the mean QALY gained were 0.8, 1.4, 1.7, and 2.3, respectively. Preoperative motor weakness, bowel dysfunction, bladder dysfunction, and ASA (American Society of Anesthesiologists) class were identified as independent predictors inversely associated with good outcome.CONCLUSIONSThe mean QALY gained from surgical decompression in the first 6 months and first year equals 1.2 months and 5 months of life in perfect health, respectively. These findings suggest that surgery might also be beneficial to patients with life expectancy < 6 months.

Background Pemetrexed is a folate antimetabolite used in the management of advanced adenocarcinoma of the lung. We sought to assess the impact of pemetrexed on intracranial disease control and radiation-related toxicity among patients with adenocarcinoma of the lung who received stereotactic radiation for brain metastases. Materials/Methods We identified 149 patients with adenocarcinoma of the lung and newly diagnosed brain metastases without a targetable mutation receiving stereotactic radiation. Kaplan–Meier plots and Cox regression were employed to assess whether use of pemetrexed was associated with intracranial disease control and radiation necrosis. Results Among the entire cohort, 105 patients received pemetrexed while 44 did not. Among patients who were chemotherapy-naive, use of pemetrexed (n = 43) versus alternative regimens after stereotactic radiation (n = 24) was associated with a reduced likelihood of developing new brain metastases (HR 0.42, 95% CI 0.22–0.79, p = 0.006) and a reduced need for salvage brain-directed radiation therapy (HR 0.36, 95% CI 0.18–0.73, p = 0.005). Pemetrexed use was associated with increased radiographic necrosis. (HR 2.70, 95% CI 1.09–6.70, p = 0.03). Conclusions Patients receiving pemetrexed after brain-directed stereotactic radiation appear to benefit from improved intracranial disease control at the possible expense of radiation-related radiographic necrosis. Whether symptomatic radiation injury occurs more frequently in patients receiving pemetrexed requires further study.

BACKGROUND We evaluated sex-based differences in clinical outcomes and tumor genomics in patients with newly-diagnosed GBM. METHODS We reviewed 665 IDH-wild type GBM patients with Karnofsky Performance Status (KPS) ≥60 treated at our institution from 2010-2019 including; 585 patients with targeted exome sequencing of 447 cancer associated genes (OncoPanel). Deleterious mutations were defined as homozygous deletions or loss of function mutations of known tumor suppressors (as reported in TCGA, ≥ 3 times in the COSMIC database, or predicted as “damaging” in SIFT and/or “probably damaging” in Polyphen 2) or known oncogenic mutations in proto-oncogenes (reported in TCGA or ≥ 3 times in COSMIC). RESULTS There were 384 (57.7%) males and 281 (42.3%) females. Median OS was 22.5 months for females and 19.3 months for males (hazard ratio [HR] 0.81, 95% CI 1.03-1.48, p = 0.02). On multivariable analysis adjusted for age, KPS ≥90, extent of resection, and MGMT methylation status, female sex (adjusted hazard ratio 0.78, 95% CI [0.64-0.95], p = 0.015) was associated with improved OS. Superior OS in females was observed in MGMT-unmethylated patients (HR 0.69, 95% CI [0.54-0.90], p = 0.005) but not MGMT-methylated patients. Thirteen genes were deleteriously altered in ≥5% of our cohort: CDK4 (12.1% male vs. 7.8% female), CDKN2A (46.5% vs. 45.7%), CDKN2B (41.8% vs. 43.3%), EGFR (34.7% vs. 40.0%, MTAP (18.2% vs. 18.8%), NF1 (11.5% vs. 9.4%), PTEN (28.2% vs. 29.8%), TP53 (28.2% vs. 30.2%), RB1 (5.6% vs. 6.5%), MDM4 (6.2% vs. 5.7%), ATM (5.9% vs. 3.7%), MDM2 (7.4% vs. 4.1%), PIK3R1 (6.2% vs. 4.1%). There were no differences in frequency of mutations in these individual genes between males and females (χ 2 [1, N=585] = 0.05-2.86, p = 0.09-0.86). CONCLUSIONS Female sex is associated with improved survival. We did not identify sex-based differences in deleterious genomic alterations amongst commonly altered genes in GBM.

BACKGROUND Glioblastoma (GBM) patients are treated with chemotherapy, radiation therapy (RT) and often corticosteroids, which can all contribute to lymphopenia. We examined lymphopenia with respect to incidence, predictors, and association with progression-free survival (PFS) and overall survival (OS). METHODS We reviewed 349 newly diagnosed adult GBM patients treated at our institution in the temozolomide (TMZ) era with available lymphocyte and RT records. Data was reviewed from diagnosis through the chemoradiation (CRT) phase, defined as the period upto 6 weeks after RT. Linear regression and Cox proportional hazards modeling were used to evaluate outcomes. RESULTS Median age was 60 years (range, 19-90); 86% had KPS ≥ 70, 30% had gross total resection (GTR), and 91% received TMZ. Prior to RT, 60% (205/341) patients had a lymphocyte measurement < 1.0 x 1000 cells [K]/μL and 15% (50/341) had < 0.5 K/μL. During the CRT phase of therapy, 83% (270/324) had at least one lymphocyte measurement < 1.0 K/μL, 42% (135/324) < 0.5 K/μL, and 5% (16/324) < 0.2 K/μL. Older age was associated with lower lymphocytes pre-RT, while subtotal resection, TMZ use, and RT dose was associated with lower lymphocyte counts during CRT (p< 0.05). On multivariable analysis (MVA), age (AHR 1.03, p< 0.01), KPS > 70 (AHR 0.35, p< 0.01), MGMT status (AHR 0.47, p< 0.01), GTR (AHR 0.67, p=0.03), TMZ (AHR 0.27, p< 0.01) and lymphopenia during CRT (AHR 1.80, p< 0.01) were significantly associated with OS. Pre-RT lymphocyte level was associated with PFS on UVA (HR 0.81, p=0.03) but not on MVA (p=0.27). Lymphocyte count during CRT was not associated with PFS (p=0.24). CONCLUSION Lymphopenia is common in GBM, and chemoradiation-related lymphopenia was associated with inferior OS relative to patients without lymphopenia. Further characterization of the mechanism and optimal treatment of patients with lymphopenia are warranted to improve outcomes.

For patients with breast cancer who develop brain metastases, radiation therapy (RT) provides local control. Here, we review the current role for central nervous system RT, particularly focusing on the evolving role for stereotactic radiosurgery (SRS). SRS treats only known CNS disease as opposed to whole-brain radiation therapy (WBRT), which treats the entire brain parenchyma. SRS has been found to cause less neurocognitive decline than WBRT. SRS is currently utilized in patients with four or fewer brain metastases, but several ongoing trials are examining the use of SRS for greater than four metastases. For patients requiring WBRT, hippocampal avoidance WBRT and memantine concurrent with and adjuvant to WBRT have been found to reduce the risk of neurocognitive decline. Both SRS and WBRT are used as a local therapy for brain metastases. SRS is increasingly preferred given fewer long-term neurocognitive side effects.

Brain metastases can be radiographically cystic or solid. Cystic metastases are associated with a greater intracranial disease burden and poorer oncologic outcomes, but the impact of cystic versus solid appearance on local control after radiation remains unknown. We investigated whether cystic versus solid nature is predictive of local control after management with stereotactic or whole brain radiation (WBRT) and whether the radiation modality utilized is an effect modifier. We identified 859 patients with 2211 newly-diagnosed brain metastases managed with upfront stereotactic radiation or WBRT without preceding resection/aspiration at Brigham and Women’s Hospital/Dana-Farber Cancer Institute between 2000 and 2015. Multivariable Cox regression with an interaction term and sandwich covariance matrix was used to quantify local failure. Cystic lesions were more likely to recur than solid ones when managed with stereotactic radiation (HR 2.33, 95% CI 1.32–4.10, p = 0.004) but not WBRT (HR 0.92, 95% CI 0.62–1.36, p = 0.67), p-interaction = 0.007. 1 year local control rates for cystic versus solid metastases treated with stereotactic radiation were 75% versus 88%, respectively; estimates with WBRT were 76% versus 76%, respectively. However, no significant differences were noted between the two cohorts in post-radiation outcomes including all-cause mortality and neurologic death (p > 0.05). Among patients with brain metastases, stereotactic radiation yields improved local control and less morbidity than WBRT, and consequently for many patients the cystic versus solid designation does not impact treatment selection. However, our results suggest that in patients with a large number of cystic brain metastases, a lower threshold to consider WBRT, as opposed to stereotactic radiation, should be employed. If our results can be confirmed, further investigation into the underlying mechanism(s) would be warranted.

Background: Cancer therapy may put patients at risk of mortality from COVID-19. The impact of abbreviated treatment courses on outcomes in the setting of COVID-19 is unknown. We incorporated COVID-19-associated risks in re-analysis of practice-defining randomized trials in oncology that compared different radiation therapy (RT) regimens. Methods: We extracted individual patient level data (IPLD) from published survival curves from randomized trials in rectal cancer (Dutch TME, TROG 01.04), early stage breast cancer (CALGB 9343, OCOG hypofractionation trial, FAST-Forward, NSABP B-39), and localized prostate cancer (CHHiP, HYPO-RT-PC). Trials were simulated with incorporation of varying risk of SARS-CoV-2 infection and mortality associated with receipt of therapy. Results: IPLD from 14,170 patients were re-analyzed. In scenarios with low COVID-19-associated risks (0.5% infection risk per fraction [IRF], 5% case fatality rate [CFR]), fractionation did not significantly affect outcomes. In locally advanced rectal cancer, short-course RT appeared preferable to long-course chemoradiation (TROG 01.04) or RT omission (Dutch TME) in most settings. While moderate hypofractionation in early stage breast cancer (OCOG hypofractionation trial) and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19, more aggressive hypofractionation (FAST-Forward, HYPO-RT-PC) and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios (≥5% IRF; ≥ 20% CFR). In settings where RT can be omitted, such as favorable early stage breast cancer in the elderly (CALGB 9343), RT was associated with worse survival in higher risk pandemic scenarios (≥5% IRF, ≥ 20% CFR). Conclusions: Our framework, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the impact of treatment recommendations across oncology. The magnitude of potential benefit from abbreviated RT courses depends on the degree of hypofractionation and local COVID-19-associated risk. Abbreviated RT courses should be prioritized when possible and are increasingly beneficial in higher risk pandemic settings. With increased understanding and precautions against COVID-19 that can minimize risks for patients, our results support the continued use of evidence-based treatments for cancer patients in the COVID-19 era. Citation Format: Shervin Tabrizi, Lorenzo Trippa, Daniel Cagney, Ayal A. Aizer, Shyam Tanguturi, Steffen Ventz, Geoffrey Fell, Jennifer R. Bellon, Harvey Mamon, Paul Nguyen, Anthony V. D'Amico, Daphne Haas-Kogan, Brian M. Alexander, Rifaquat Rahman. Re-analyzing randomized trials with incorporation of COVID-19 risk associated with cancer therapy [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P26.

Deep inspiration breath hold (DIBH) is used to decrease cardiac irradiation during radiation therapy (RT) for breast cancer. The patients most likely to benefit and the impact on treatment time remain largely unknown. We sought to identify predictors for the use of DIBH and to quantify differences in dosimetry and treatment time using a prospective registry.A total of 150 patients with left breast cancer were enrolled. All patients were simulated with both free breathing (FB) and DIBH. RT was delivered by either modality. Alternate scans were planned with use of deformable registration to include identical RT volumes. DIBH patients were monitored by a real-time surface tracking system, AlignRT (Vision RT, Ltd, London, United Kingdom). Baseline characteristics and treatment times were compared by Fisher exact test and Wilcoxon rank sum test. Dosimetric endpoints were analyzed by Wilcoxon signed rank test, and linear regression identified predictors for change in mean heart dose (∆MHD).We treated 38 patients with FB and 110 with DIBH. FB patients were older, more likely to have heart and lung disease, and less likely to receive chemotherapy or immediate reconstruction (all P.05). Treatment times were not significantly different, but DIBH patients had greater variability in times (P = .0002). Of 146 evaluable patients, DIBH resulted in20 cGy improvement in MHD in 107 patients but a20 cGy increase in MHD in 14. Both MHD and lung V20 were significantly lower in DIBH than in paired FB plans. On multivariate analysis, younger age (4.18 cGy per year; P.0001), higher body mass index (6.06 cGy/kg/m(2); P = .0018), and greater change in lung volumes (130 cGy/L; P = .003) were associated with greater ∆MHD.DIBH improves cardiac dosimetry without significantly impacting treatment time in most patients. Greater inspiratory lung volumes augment this benefit. Because the improvement with DIBH was not uniform, patients should be scanned with both FB and DIBH.

Cranial radiation therapy (CRT) is used to treat a wide range of malignant and benign conditions and is associated with a unique set of risks and complications. Early complications from CRT include fatigue, skin reaction, alopecia, headaches, anorexia, nausea/vomiting, exacerbation of neurologic symptoms, serous otitis media, parotitis, and encephalopathy. Delayed complications include pseudoprogression, radiation necrosis, neurocognitive changes, cerebrovascular effects, migrainelike disorders, cataracts, xerophthalmia, optic neuropathy, hearing loss, tinnitus, chronic otitis, endocrinopathy, and secondary malignancy. This article presents an overview of clinically relevant neurologic complications for CRT, basic pathophysiology of radiation injury, and risk factors for neurologic complications.

Older patients with newly diagnosed glioblastoma have poor outcomes, and optimal treatment is controversial. Hypofractionated radiation therapy (HRT) is frequently used but has not been compared to patients receiving standard fractionated radiation therapy (SRT) and temozolomide (TMZ).We conducted a retrospective analysis of patients ≥65 years of age who received radiation for the treatment of newly diagnosed glioblastoma from 1994 to 2013. The distribution of clinical covariates across various radiation regimens was analyzed for possible selection bias. Survival was calculated using the Kaplan-Meier method. Comparison of hypofractionated radiation (typically, 40 Gy/15 fractions) versus standard fractionation (typically, 60 Gy/30 fractions) in the setting of temozolomide was conducted using Cox regression and propensity score analysis.Patients received SRT + TMZ (n=57), SRT (n=35), HRT + TMZ (n=34), or HRT (n=9). Patients receiving HRT were significantly older (median: 79 vs 69 years of age; P.001) and had worse baseline performance status (P.001) than those receiving SRT. On multivariate analysis, older age (adjusted hazard ratio [AHR]: 1.06; 95% confidence interval [CI]: 1.01-1.10, P=.01), lower Karnofsky performance status (AHR: 1.02; 95% CI: 1.01-1.03; P=.01), multifocal disease (AHR: 2.11; 95% CI: 1.23-3.61, P=.007), and radiation alone (vs SRT + TMZ; SRT: AHR: 1.72; 95% CI: 1.06-2.79; P=.03; HRT: AHR: 3.92; 95% CI: 1.44-10.60, P=.007) were associated with decreased overall survival. After propensity score adjustment, patients receiving HRT with TMZ had similar overall survival compared with those receiving SRT with TMZ (AHR: 1.10, 95% CI: 0.50-2.4, P=.82).With no randomized data demonstrating equivalence between HRT and SRT in the setting of TMZ for glioblastoma, significant selection bias exists in the implementation of HRT. Controlling for this bias, we observed similar overall survival for HRT and SRT with concurrent TMZ among elderly patients, suggesting the need for a randomized trial to compare these regimens directly.

Background. Whole lung irradiation (WLI) is a standard treatment component for children with metastatic Ewing Sarcoma (ES), but data on WLI for adults are sparse.Design. An email survey was sent to expert sarcoma-dedicated oncologists worldwide:An adult with excellent performance status presents with primary ES in the leg and multiple pulmonary metastases. The patient achieves complete radiographic response after chemotherapy and resection of the primary. Would you give bilateral WLI to (1) this adult patient?, (2) this patient if 20 years old (yo)?, (3) this patient if 45 yo?, or (4) this patient if 60 yo? Results. 38 experts responded, including 24 adult, 1 adolescent young adult, and 13 pediatric oncologists. 63%, 63%, 62%, and 50% of respondents offered WLI to the adult, 20-year-old, 45-year-old, and 60-year-old, respectively. Pediatric oncologists more likely endorsed WLI across all ages including the adult (P=0.01), 20-year-old (P=0.005), 45-year-old (P=0.01), and 60-year-old (P=0.08). There were no significant differences between medical and radiation oncologists or between European/Australian and American providers.Conclusions. Almost two-thirds of experts surveyed supported WLI for adults with metastatic ES up to age 45 and half supported WLI for a 60-year-old. Continued collaboration across adult and pediatric oncology is needed to define evidence-based strategies across the age spectrum.

This study evaluated the efficacy and toxicity of proton therapy for functional pituitary adenomas (FPAs).We analyzed 165 patients with FPAs who were treated at a single institution with proton therapy between 1992 and 2012 and had at least 6 months of follow-up. All but 3 patients underwent prior resection, and 14 received prior photon irradiation. Proton stereotactic radiosurgery was used for 92% of patients, with a median dose of 20 Gy(RBE). The remainder received fractionated stereotactic proton therapy. Time to biochemical complete response (CR, defined as ≥ 3 months of normal laboratory values with no medical treatment), local control, and adverse effects are reported.With a median follow-up time of 4.3 years (range, 0.5-20.6 years) for 144 evaluable patients, the actuarial 3-year CR rate and the median time to CR were 54% and 32 months among 74 patients with Cushing disease (CD), 63% and 27 months among 8 patients with Nelson syndrome (NS), 26% and 62 months among 50 patients with acromegaly, and 22% and 60 months among 9 patients with prolactinomas, respectively. One of 3 patients with thyroid stimulating hormone-secreting tumors achieved CR. Actuarial time to CR was significantly shorter for corticotroph FPAs (CD/NS) compared with other subtypes (P=.001). At a median imaging follow-up time of 43 months, tumor control was 98% among 140 patients. The actuarial 3-year and 5-year rates of development of new hypopituitarism were 45% and 62%, and the median time to deficiency was 40 months. Larger radiosurgery target volume as a continuous variable was a significant predictor of hypopituitarism (adjusted hazard ratio 1.3, P=.004). Four patients had new-onset postradiosurgery seizures suspected to be related to generously defined target volumes. There were no radiation-induced tumors.Proton irradiation is an effective treatment for FPAs, and hypopituitarism remains the primary adverse effect.

Background Biomarkers can improve clinical trial efficiency, but designing and interpreting biomarker-driven trials require knowledge of relationships among biomarkers, clinical covariates, and endpoints. We investigated these relationships across genomic subgroups of glioblastoma (GBM) within our institution (DF/BWCC), validated results in The Cancer Genome Atlas (TCGA), and demonstrated potential impacts on clinical trial design and interpretation. Methods We identified genotyped patients at DF/BWCC, and clinical associations across 4 common GBM genomic biomarker groups were compared along with overall survival (OS), progression-free survival (PFS), and survival post-progression (SPP). Significant associations were validated in TCGA. Biomarker-based clinical trials were simulated using various assumptions. Results Epidermal growth factor receptor (EGFR)(+) and p53(-) subgroups were more likely isocitrate dehydrogenase (IDH) wild-type. Phosphatidylinositol-3 kinase (PI3K)(+) patients were older, and patients with O6-DNA methylguanine-methyltransferase (MGMT)-promoter methylation were more often female. OS, PFS, and SPP were all longer for IDH mutant and MGMT methylated patients, but there was no independent prognostic value for other genomic subgroups. PI3K(+) patients had shorter PFS among IDH wild-type tumors, however, and no DF/BWCC long-term survivors were either EGFR(+) (0% vs 7%, P = .014) or p53(-) (0% vs 10%, P = .005). The degree of biomarker overlap impacted the efficiency of Bayesian-adaptive clinical trials, while PFS and OS distribution variation had less impact. Biomarker frequency was proportionally associated with sample size in all designs. Conclusions We identified several associations between GBM genomic subgroups and clinical or molecular prognostic covariates and validated known prognostic factors in all survival periods. These results are important for biomarker-based trial design and interpretation of biomarker-only and nonrandomized trials.

Purpose Little is known about the risk of gallbladder toxicity from hypofractionated (HFXRT) and stereotactic body radiation therapy (SBRT). We report on gallbladder toxicity and attribution to treatment in a prospective series of patients with primary and metastatic liver tumors receiving ablative-intent HFXRT and SBRT with protons. Methods and materials We evaluated 93 patients with intact gallbladders enrolled in either of 2 trials investigating proton HFXRT and SBRT for primary and metastatic liver tumors from 2009 to 2014. Patients received 45 to 67.5 GyE in 15 fractions for primary liver tumors (n = 45) and 30 to 50 GyE in 5 fractions for metastatic tumors (n = 48). No gallbladder dose constraints were used at treatment, and gallbladder volumes and dose-volume histograms were created retrospectively. Attributable toxicity was defined as cholecystitis or perforation without preexisting gallbladder disease. Baseline factors were evaluated using Fisher exact test and the nonparametric K-sample test. Results At baseline, 25 patients had preexisting cholelithiasis and 15 underwent biliary stenting before or after RT. Median follow-up after treatment was 11.8 months (range, 0.1-59.2 months). Despite maximum gallbladder doses >70 GyE in 41%, >80 GyE in 31%, and >90 GyE in 13% (equieffective dose at 2 Gy [EQD2], α/β = 3), there were no attributable cases of gallbladder toxicity. Two patients developed grade 3 and 4 cholecystitis 16 and 2 months after treatment, respectively, and both had a strong history of preexisting cholelithiasis and biliary stenting. These patients received relatively low gallbladder doses with mean doses of 0.02 GyE and 5.1 GyE (EQD2, α/β = 3), well below the 17.1 GyE mean for the remaining cohort (range, 0-81.1 GyE, EQD2). Conclusions We identified no relationship between gallbladder dose and toxicity and did not reach the maximum tolerated gallbladder dose in this cohort treated with high-dose radiation. We recommend not constraining dose to the gross tumor volume to protect the gallbladder during ablative HFXRT and SBRT.

Despite the historically limited role of radiotherapy in the management of primary hepatic malignancies, modern advances in treatment design and delivery have renewed enthusiasm for radiation as a potentially curative treatment modality. Surgical resection and/or liver transplantation are traditionally regarded as the most effective forms of therapy, although the majority of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma present with locally advanced or unresectable disease on the basis of local vascular invasion or inadequate baseline hepatobiliary function. In this context, many efforts have focused on nonoperative treatment approaches including novel systemic therapies, transarterial chemoembolization, ethanol ablation, radiofrequency ablation, and stereotactic body radiation therapy (SBRT). This review aims to summarize modern advances in radiotherapy, particularly SBRT, in the treatment of primary hepatic malignancies.

Background We evaluated the efficacy and safety of risk-adapted, proton-based stereotactic body radiation therapy (SBRT) for liver metastases from solid tumors. Methods This single-arm phase II single institutional study (NCT01239381) included patients with limited extrahepatic disease, 800 mL or greater of uninvolved liver, and no cirrhosis or Child-Pugh A, who had received proton-based SBRT to one to four liver metastases from solid tumors. Treatment comprised 30 to 50 Gray equivalent (GyE) in five fractions based on the effective volume of liver irradiated. Sample size was calculated to determine if local control (LC) at one year was greater than 70%. The cumulative incidence of local failure was used to estimate LC. The association of tumor characteristics, including genetic alterations in common cancer genes such as BRAF, EGFR, HER2, KRAS, NRAS, PIK3CA, and TP53 with local tumor control, was assessed. All statistical tests were two-sided. Results Eighty-nine patients were evaluable (colorectal, n = 34; pancreatic, n = 13; esophagogastric, n = 12; other, n = 30). Median tumor size was 2.5 cm (range = 0.5-11.9 cm). Median dose was 40 GyE (range = 30-50 GyE), and median follow-up was 30.1 months (range = 14.7-53.8 months). There was no grade 3 to 5 toxicity. Median survival time was 18.1 months. The one- and three-year LC rates were 71.9% (95% confidence limit [CL] = 62.3% to 80.9%) and 61.2% (95% CL = 50.8% to 71.8%), respectively. For large tumors (≥6 cm), one-year LC remained high at 73.9% (95% CL = 54.6% to 89.8%). Mutation in the KRAS oncogene was the strongest predictor of poor LC (P = .02). Tumor with both mutant KRAS and TP53 were particularly radioresistant, with a one-year LC rate of only 20.0%, compared with 69.2% for all others (P = .001). Conclusions We report the largest prospective evaluation to date of liver SBRT for hepatic metastases, and the first with protons. Protons were remarkably well tolerated and effective even for metastases that were 6 cm or larger. KRAS mutation is a strong predictor of poor LC, stressing the need for tumor genotyping prior to SBRT and treatment intensification in this patient subset.

Background. High-grade gliomas with mutations in the isocitrate dehydrogenase (IDH) gene family confer longer overall survival relative to their IDH-wild-type counterparts. Accurate determination of the IDH genotype preoperatively may have both prognostic and diagnostic value. The current study used a machine-learning algorithm to generate a model predictive of IDH genotype in high-grade gliomas based on clinical variables and multimodal features extracted from conventional MRI. Methods. Preoperative MRIs were obtained for 120 patients with primary grades III (n = 35) and IV (n = 85) glioma in this retrospective study. IDH genotype was confirmed for grade III (32/35, 91%) and IV (22/85, 26%) tumors by immunohistochemistry, spectrometry-based mutation genotyping (OncoMap), or multiplex exome sequencing (OncoPanel). IDH1 and IDH2 mutations were mutually exclusive, and all mutated tumors were collapsed into one IDH-mutated cohort. Cases were randomly assigned to either the training (n = 90) or validation cohort (n = 30). A total of 2970 imaging features were extracted from pre- and postcontrast T1-weighted, T2-weighted, and apparent diffusion coefficient map. Using a random forest algorithm, nonredundant features were integrated with clinical data to generate a model predictive of IDH genotype. Results. Our model achieved accuracies of 86% (area under the curve [AUC] = 0.8830) in the training cohort and 89% (AUC = 0.9231) in the validation cohort. Features with the highest predictive value included patient age as well as parametric intensity, texture, and shape features. Conclusion. Using a machine-learning algorithm, we achieved accurate prediction of IDH genotype in high-grade gliomas with preoperative clinical and MRI features.

The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease.

SUMMARY Many patients with primary hepatic malignancies present with advanced disease that is not suitable for surgical resection, orthotopic liver transplantation, or radiofrequency ablation. Outcomes are particularly dismal in patients with large, unresectable tumors and/or tumor venous thrombosis. Liver-directed radiotherapy, including stereotactic body radiotherapy (SBRT), is able to treat a variety of tumor sizes and tumors with venous involvement and has demonstrated excellent safety and control outcomes. SBRT should be considered a standard option in patients with early-stage hepatocellular carcinoma who are not candidates for surgical resection, orthotopic liver transplantation or radiofrequency ablation. SBRT should be strongly considered in patients with larger tumors and/or tumors with tumor venous thrombosis who have adequate liver function. Radiotherapy should remain a focus of hepatocellular carcinoma research.

TPS2079 Background: Patient with glioblastoma (GBM) with unmethylated MGMT promoters derive limited benefit from temozolomide (TMZ) and have dismal outcome. Prioritizing the numerous available therapies and biomarkers for late stage testing requires an efficient clinical testing platform. INSIGhT (NCT02977780) is a biomarker-based, Bayesian adaptively randomized, multi-arm phase II platform screening trial for patients with newly diagnosed GBM and unmethylated MGMT promoters. Methods: INSIGhT compares experimental arms to a common control of standard concurrent TMZ and radiation therapy (RT) followed by adjuvant TMZ. The primary endpoint is overall survival (OS). Patients with newly diagnosed, unmethylated GBM that are IDH R132H mutation negative, and with genomic data available or who consent to whole exome sequencing through the ALLELE companion study for biomarker grouping are eligible. Two experimental arms consist of concurrent RT/TMZ followed by adjuvant neratinib (EGFR, HER2, and HER4 inhibitor) or abemaciclib CDK 4/6 inhibitor), respectively, in place of TMZ. The other experimental arm is CC-115 (TORC1/2 and DNA PK inhibitor), which replaces TMZ in both the concurrent and adjuvant phases. Biomarker groups include: EGFR + patients with EGFR amplification/mutation; PI3K + patients with PIK3CA mutation/amplification, PIK3R1 mutation, AKT3amplification, PIK3C2B > 1 copy gain, or PTEN dual loss; CDK: + patients with wild-type RB1 and CDK4 amplification, CDK6 amplification, or CDKN2A > 1 copy loss. Given the lack of pretrial biomarker data and the anticipated overlap of the groups, randomization will initially be equal. As the trial progresses, randomization probabilities will be adapted based on the Bayesian estimation of the probability of treatment impact on progression-free survival (PFS). These randomization probabilities can vary among the biomarker groups so predictive biomarkers will be identified and utilized if present. Treatment arms may drop due to low probability of treatment impact on OS, and new arms may be added. Experimental arms are compared only with control and should be thought of as discrete experimental questions, with INSIGhT being open to new investigators with proposed therapeutic hypotheses. Clinical trial information: NCT02977780.

Purpose. We investigated whether NS-RP increased risk of PSA failure and whether PSA should be included as a selection criterion for NS.Methods. We evaluated 357 consecutive men with screen-detected PC who underwent open RP without adjuvant radiotherapy between 9/11/2001 and 12/30/2008. Criteria for NS included Gleason score ≤3 + 4, percentage of positive biopsies (PPB) ≤50%, percentage of core involvement ≤50%, nonapical location, no perineural invasion, and no palpable disease on pre- or intraoperative exam but did not include a PSA threshold. Cox multivariable regression assessed whether increasing PSA or unilateral- or bilateral-NS versus non-NS-RP was associated with PSA failure adjusting for prognostic factors.Results. After a median follow-up of 3.96 years, 34 men sustained PSA failure (9.5%). Increasing PSA was significantly associated with increased risk of PSA failure in the interaction model (adjusted hazard ratio (AHR): 1.09 [95% CI: 1.03–1.16];P=0.005), whereas unilateral (AHR: 1.24 [95% CI: 0.36–4.34];P=0.73) or bilateral NS (AHR: 0.41 [95% CI: 0.06–2.59];P=0.34) versus non-NS RP was not.Conclusion. NS-RP in a screened cohort did not increase risk of PSA failure using NS criteria not including PSA.

2009Background: Malignant gliomas with mutations in the isocitrate dehydrogenase (IDH) gene family confer longer overall survival relative to their IDH wild-type counterparts. Accurately determinin...

Background Lenalidomide is an effective new agent for the treatment of patients with myelodysplastic syndrome (MDS), an acquired hematopoietic disorder characterized by ineffective blood cell production and a predisposition to the development of leukemia. Patients with an interstitial deletion of Chromosome 5q have a high rate of response to lenalidomide, but most MDS patients lack this deletion. Approximately 25% of patients without 5q deletions also benefit from lenalidomide therapy, but response in these patients cannot be predicted by any currently available diagnostic assays. The aim of this study was to develop a method to predict lenalidomide response in order to avoid unnecessary toxicity in patients unlikely to benefit from treatment. Methods and Findings Using gene expression profiling, we identified a molecular signature that predicts lenalidomide response. The signature was defined in a set of 16 pretreatment bone marrow aspirates from MDS patients without 5q deletions, and validated in an independent set of 26 samples. The response signature consisted of a cohesive set of erythroid-specific genes with decreased expression in responders, suggesting that a defect in erythroid differentiation underlies lenalidomide response. Consistent with this observation, treatment with lenalidomide promoted erythroid differentiation of primary hematopoietic progenitor cells grown in vitro. Conclusions These studies indicate that lenalidomide-responsive patients have a defect in erythroid differentiation, and suggest a strategy for a clinical test to predict patients most likely to respond to the drug. The experiments further suggest that the efficacy of lenalidomide, whose mechanism of action in MDS is unknown, may be due to its ability to induce erythroid differentiation.

2065 Background: No randomized trials among elderly GBM patients using HRT have compared efficacy to the Stupp regimen of SRT+T, and many elderly patients in the United States receive SRT+T. Method...