Background Patients with locally advanced non-small-cell lung cancer (NSCLC) who undergo concurrent chemotherapy and radiotherapy often experience synergistic toxicity, and local regional control rates remain poor. We assessed the activity and safety outcomes of primary tumour stereotactic body radiotherapy (SBRT) followed by conventional chemoradiotherapy to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced NSCLC. Methods In this multicentre, single-arm, phase 2 trial, patients aged 18 years and older were enrolled at eight regional cancer centres in North Carolina and South Carolina, USA. Patients were eligible if they had stage II-III, unresectable, locally advanced NSCLC (any histology), with peripheral or central primary tumours that were 7 cm or smaller, excluding central tumours within 2 cm of involved nodal disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients who had previously received systemic therapy or radiotherapy were excluded. Participants received SBRT to the primary tumour (50-54 Gy in three to five fractions) followed by standard radiotherapy (planned up to 60 Gy in 30 2 Gy fractions) to the involved lymph nodes with concurrent platinum doublet chemotherapy (either paclitaxel 50 mg/m2 intravenously plus carboplatin area under the curve mg/mL per min every 7 days for a total of six 1-week cycles or etoposide 50 mg/m2 intravenously on days 1-5 and days 29-33 plus cisplatin 50 mg/m2 intravenously on days 1, 8, 29, and 36 for two cycles of 4 weeks). An amendment to the protocol (Dec 11, 2017) permitted the administration of consolidation durvalumab at the discretion of the treating investigator. An additional protocol amendment on Jan 13, 2021, directed patients without disease progression after chemoradiotherapy to receive consolidation durvalumab (10 mg/kg intravenously on day 1 and day 15 of a 4-week cycle for up to 12 cycles or 1500 mg intravenously on day 1 of a 4-week cycle for up to 12 cycles). The primary endpoint was 1-year progression-free survival (per Response Evaluation Criteria in Solid Tumours version 1.1), assessed in all participants who received at least one fraction of SBRT and had radiological follow-up data up to 1 year. A 1-year progression-free survival rate of greater than 60% was required to reject the null hypothesis and show significant improvement in 1-year progression-free survival. One-sided exact binomial tests were used to compare the primary endpoint versus the historical control 1-year progression-free survival rate used to determine the sample size. Safety was assessed in all patients who received at least one fraction of SBRT. This study is registered with ClinicalTrials.gov, NCT03141359, and is closed to accrual. Findings Between May 11, 2017, and June 27, 2022, 61 patients were enrolled and received at least one dose of fractionated SBRT, of whom 59 were evaluable for the primary endpoint. Median age was 67 years (IQR 61-72), 28 (46%) of 61 were female, 33 (54%) were male, 51 (84%) were White, seven (11%) were Black, and three (5%) were of other or unknown race. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. As of data cutoff (July 12, 2023), median follow-up was 295 months (IQR 149-471). 1-year progression-free survival was 627% (90% CI 512-732; one-sided p=039, compared with the historical control rate), with 37 of 59 evaluable participants progression free and alive 1 year after enrolment (n=14 progressed, n=8 died). The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (nine [15%] of 61 patients), decreased white blood cell count (five [8%]), and anaemia (four [7%]). Treatment-related serious adverse events occurred in 11 (18%) of 61 patients, which included lung infection (three [5%]), pneumonitis (two [3%]), decreased neutrophil count (two [3%]), febrile neutropenia (two [3%]), and dyspnoea, hypoxia, respiratory failure, sinus tachycardia, bronchial infection, and acute kidney injury (each in one [2%] patient). Treatment-related deaths occurred in four (7%) of 61 patients (one each of respiratory failure, respiratory failure and dyspnoea, lung infection, and pneumonitis). Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Background: These are the efficacy and toxicity outcomes of a prospective phase II trial of primary tumor stereotactic body radiation (SBRT) followed by conventional chemoradiation to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced non-small cell lung cancer (LA NSCLC). Methods: Eligible patients included stages II-III LA NSCLC with peripheral primary tumors ≤7 cm or centrally-based tumors with ≥2 cm separation from involved nodal disease. Patients received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation (60 Gy in 30 fractions) to the involved lymph nodes with concurrent platinum-doublet chemotherapy. Trial amendment allowed patients without disease progression after chemoradiation to receive consolidation durvalumab. The primary endpoint was 1-year progression-free survival (PFS). Frequencies and proportions were used for reporting this primary endpoint, adverse events, and patterns of failure. Time to event endpoints, including PFS and overall survival (OS), were estimated using Kaplan Meier (KM) methods. Findings: 61 patients across 8 centers were enrolled, including 59 evaluable for the primary objective, with a median follow-up of 48.1 months. Overall grade 3 or higher toxicity related to SBRT and/or mediastinal radiation was 13·1%, with three patients (5%) developing grade 3 pneumonitis. KM-estimated PFS at 1-year for all patients was 62.8%, median PFS was 25·3 months (95% CI: 11·5, 54·1), and median OS was 47·1 months. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. The KM-estimated 1-year PFS for patients who received durvalumab was 69·6%. Interpretation: SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes and consolidation immunotherapy was well tolerated and showed improved 1-year PFS compared to prior conventional chemoradiation trials for inoperable LA NSCLC. These findings serve as the basis for the randomized phase III study NRG Oncology LU008 (NCT05624996).Trial Registration: The trial is registered with ClinicalTrials.gov, NCT03141359.Funding: This research was supported by AstraZeneca and Atrium Health Levine Cancer.Declaration of Interest: The authors have no potential competing interests to report.Ethical Approval: This was an open-label, single-arm, phase II study approved by our Institutional Review Board and monitored by our institutional data and safety monitoring committee. All participants provided written informed consent to participate. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice at eight different centers within North and South Carolina all within the Levine Cancer Institute Atrium Health network. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice and approved by the IRB of the Levine Cancer Institute Atrium Health network (IRB approval number Pro00021247).

Supplementary Figure 1. Encapsulation efficiency (drug loading/theoretical drug encapsulated) of candidate drugs into PLA-PEG NPs as a function of their solubility in DMSO; Supplementary Figure 2. PLA-PEG NP in vitro stability and uptake; Supplementary Figure 3. in vitro dose-dependent response of HR (L) and mNHEJ (R) pathway repair in the U2OS reporter assay to treatment with either free drug (red) or drug-NP (green) for each candidate radiosentizier; Supplementary Figure 4. dsDNA repair pathway activity levels in U2OS reporter cells; Supplementary Table 1. Results of Linear Regression Analysis and Correlation testing between drug properties and release properties; Supplementary Table 2. Summary of NP-drug formulations and established criteria for candidate drug-NP formulation selection.

PURPOSE:Stereotactic body radiation therapy (SBRT) has been used with high effectiveness in early-stage non-small cell lung cancer (NSCLC) but has not been studied extensively in locally advanced NSCLC. We conducted a phase 2 study delivering SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes for patients with node-positive locally advanced NSCLC. This manuscript serves as both a guide to planning techniques used on this trial and the subsequent phase 3 study, NRG Oncology LU-008, and to report patient dosimetry and toxicity results. METHODS AND MATERIALS:We initiated a phase 2 multicenter single arm study evaluating SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by conventionally fractionated chemoradiation to 60 Gy in 2 Gy fractions with doublet chemotherapy to the involved lymph nodes for patients with stage III or unresectable stage II NSCLC. Patients eligible for adjuvant immunotherapy received up to 12 months of durvalumab. We report a detailed guide for the entire treatment process from computed tomography simulation through treatment planning and delivery. The dosimetric outcomes from the 60 patients who completed therapy on study are reported both for target coverage and normal structure doses. We also report correlation between radiation-related toxicities and dosimetric parameters. RESULTS:Sixty patients were enrolled between 2017 and 2022. Planning techniques used were primarily volumetric modulated arc therapy for SBRT to the primary tumor and conventionally fractionated radiation to the involved nodes, with a minority of cases using dynamic conformal arc technique or static dynamic multileaf collimator intensity modulated radiation therapy. Grade 2 or higher pneumonitis was associated with lung dose V5 Gy > 70% and grade 2 or higher pulmonary toxicity was associated with lung dose V10 Gy > 50%. Only 3 patients (5%) experienced grade 3 or higher pneumonitis. Grade 2 or higher esophagitis was associated with esophageal doses, including mean dose > 20 Gy, V60 Gy > 7%, and D1cc > 55 Gy. Only 1 patient (1.7%) experienced grade 3 esophagitis. CONCLUSIONS:SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes is feasible with planning techniques as described. Radiation-related toxicity on this phase 2 study was low. This manuscript serves as a guideline for the recently activated NRG Oncology LU-008 phase 3 trial evaluating this experimental regimen.

SGRT provides a reliable technique for BH SBRT treatments of the lung. Minimal target displacements on mid treatment BH CBCT were observed. Higher 4D ROM on free breathing scans correlated with larger displacements in tumor position utilizing this technique.

Purpose: Previous trials have shown no benefit for radiation therapy (RT) dose escalation when RT is given as adjuvant monotherapy for infiltrative low-grade glioma (LGG). However, the current standard of care for high-risk LGG is RT with concurrent and/or adjuvant chemotherapy. The effect of RT dose escalation on overall survival (OS) in the setting of concurrent and/or adjuvant chemotherapy is not well established. Methods and Materials: We used the National Cancer Database to select records for adult patients with intracranial grade 2 LGG diagnosed between 2004 and 2015. Patients must have received adjuvant external beam RT with concurrent and/or adjuvant chemotherapy. RT dose level was categorized as standard (45-54 Gy) or high (>54-65 Gy). Multivariable and propensity score matched analyses were used. Results: The study cohort consisted of 1043 patients, of whom 644 (62%) received standard dose (median, 54 Gy) and 399 (38%) received high-dose RT (median, 60 Gy). RT dose level was not associated with OS (hazard ratio, 1.2; P = .1) in multivariable analysis. Propensity score matching yielded 380 matched pairs (n = 760). There was no difference in OS for high-dose versus standard-dose RT in the matched cohort (5-year OS 64% vs 69%; P = .14) or in the 2 prespecified subgroups of astrocytoma histology and 1p/19q noncodeleted. Conclusions: Adjuvant RT dose escalation above 54 Gy in the setting of concurrent and/or adjuvant chemotherapy was not associated with improved OS for patients with infiltrative LGG in this National Cancer Database retrospective study. This was also true for the subgroups with less chemotherapy-sensitive disease, including astrocytoma histology and 1p/19q noncodeleted, although these analyses were limited by small size. Methods to improve OS other than RT dose escalation in the setting of concurrent and/or adjuvant chemotherapy should be considered for patients with poor-prognosis LGG.

Background. Adult intracranial ependymoma is rare, and the role for adjuvant radiotherapy (RT) is not well defined. Methods. We used the National Cancer Database (NCDB) to select adults (age >= 22 years) with grade 2 to 3 intracranial ependymoma status postresection between 2004 and 2015 and treated with adjuvant RT vs observation. Four cohorts were generated: (1) all patients, (2) grade 2 only, (3) grade 2 status post-subtotal resection only, (4) and grade 3 only. The association between adjuvant RT use and overall survival (OS) was assessed using multivariate Cox and propensity score matched analyses. Results. A total of 1787 patients were included in cohort 1, of which 856 patients (48%) received adjuvant RT and 931 (52%) were observed. Approximately two-thirds of tumors were supratentorial and 80% were grade 2. Cohorts 2, 3, and 4 included 1471, 345, and 316 patients, respectively. There was no significant association between adjuvant RT use and OS in multivariate or propensity score matched analysis in any of the cohorts. Older age, male sex, urban location, higher comorbidity score, earlier year of diagnosis, and grade 3 were associated with increased risk of death. Conclusions. This large NCDB study did not demonstrate a significant association between adjuvant RT use and OS for adults with intracranial ependymoma, including for patients with grade 2 ependymoma status post-subtotal resection. The conflicting results regarding the efficacy of adjuvant RT in this patient population highlight the need for high-quality studies to guide therapy recommendations in adult ependymoma.

The management of locally advanced pancreatic cancer typically involves chemotherapy with or without a course of conventionally fractionated RT (CFRT). A Phase II study demonstrated the safety and efficacy of hypofractionated radiation therapy (HFRT) using a regimen of 36 Gy in 15 fractions with concurrent gemcitabine. The recently presented PREOPANC-1 trial used a similar regimen in borderline resectable disease. HFRT is an attractive option for the treatment of inoperable pancreatic cancer due to the relatively short duration of treatment and acceptable toxicity profile. In this retrospective study, we investigated clinical practice patterns and compared overall survival (OS) for patients receiving HFRT to those receiving CFRT in a large national cohort. Using the National Cancer Data Base, we identified adult patients with unresected Stage I-III pancreatic adenocarcinoma treated with either (1) HFRT (36 Gy in 15 fractions) or (2) CFRT (45-54 Gy in 25-30 fractions) from 2006-2012. Trends in HFRT use were analyzed. Multivariable logistic regression was performed to identify factors independently associated with receipt of each regimen. Analysis of OS for patients diagnosed in 2006-2011 was performed using the log-rank test and Cox proportional hazards regression. Propensity score matching (PSM) with 1:1 nearest-neighbor matching without replacement was performed using variables found to be significant on logistic regression. We identified 3,872 patients who met inclusion criteria, among whom 140 (3.6%) received HFRT while 3,732 (96.4%) received CFRT. Median age was 65. HFRT use increased slightly over the years studied ranging from 3.0% in 2006 to 4.1% in 2012. Chemotherapy was used in 99.3% of patients receiving HFRT and 95.5% of patients receiving CFRT. Factors associated with receipt of HFRT on logistic regression included white race, treatment at an academic center, and treatment in the Northeast (all P<0.05). In the un-matched cohort, OS was not different with HFRT vs CFRT on log-rank analysis (Median OS 13.3 vs 11.7 mos, P=0.32) or Cox regression (HR 0.91, P=0.32). Subset analysis also showed no difference in OS when the analysis was limited to patients receiving chemotherapy (HR 0.91, P=0.35), patients with N0 disease (HR 0.91, P=0.43), and both Stage I/II (HR 0.94, P=0.66) and Stage III disease (HR 0.86, P=0.33). PSM identified a well-matched cohort based on clinical and demographic factors of 186 patients, confirming no difference in survival for patients treated with HFRT vs CFRT (log-rank P=0.72). Our results suggest equipoise in survival outcomes for patients with unresected pancreatic cancer receiving HFRT compared to CFRT, suggesting that HFRT may be an attractive and convenient treatment option in this subset of patients. Prior studies have demonstrated safety of this regimen with concurrent chemotherapy. Randomized studies are necessary to confirm these findings.

Abstract INTRODUCTION: Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosurgery (SRS). We have previously risk stratified patients into high, intermediate, and low-risk BMV groups, which correlates with overall survival (OS). We sought to externally validate BMV in a multi-institutional setting. METHODS: Patients from nine academic centers were treated with upfront SRS; the validation cohort consisted of data from eight institutions not previously used to define BMV. Patients were classified by BMV into low (< 4 BMV), intermediate (4–13 BMV), and high-risk groups (>13 BMV). Time-to-event outcomes were estimated using the Kaplan-Meier method. Cox proportional hazards methods were used to estimate the effect of BMV and salvage modality on OS. RESULTS: Of 2829 patients, 2092 patients were included in the validation dataset. Of these, 921 (44.0%) experienced distant brain failure (DBF). Median OS from initial SRS was 11.2 mo. Median OS for BMV < 4, BMV 4–13, and BMV > 13 were 12.5 mo, 7.0 mo, and 4.6 mo (p < 0.0001). Compared to initial salvage with WBRT, salvage SRS was associated with improved OS following DBF for BMV < 4 (p = 0.05), BMV 4–13 (p = 0.002) and BMV > 13 (p = 0.0001). CONCLUSIONS: This multi-institutional dataset validates BMV as a predictor of OS following initial SRS. BMV is being utilized in upcoming multi-institutional randomized controlled trials as a stratification variable for salvage whole brain radiation vs salvage SRS after DBF.

Purpose: To review trends in the use of postoperative radiotherapy (PORT) in the modern era for N0-N1 margin-negative non–small cell lung cancer (NSCLC) following surgical resection and evaluate the association between PORT dose and overall survival. Materials and Methods: We performed a retrospective study of nonmetastatic stage II and III N0-N1 margin-negative NSCLC surgically treated patients within the National Cancer Data Base from 2003 to 2011. Cox proportional hazards regression was performed for multivariable analyses of overall survival and PORT dose. Radiation modalities included nonconformal beam radiation, 3-dimensional conformal radiation (3D-CRT), and intensity-modulated radiation therapy. Results: We identified 2167 (6.7%) and 30,269 (93.3%) patients with surgically resected stage II or III N0-N1 margin-negative NSCLC who were treated with and without PORT, respectively. The proportion of patients treated with PORT (dose range, 45 to 74 Gy) decreased from 8.9% in 2003 to 2006 to 4.1% in 2010 to 2011. Among patients receiving PORT, the use of high-dose (60 to 74 Gy) PORT rose throughout the study period, starting at 34.8% in 2003 to 2006 and rising to 49.3% in 2010 to 2011. Overall, patients who received PORT had worse survival (hazards ratio=1.30; 95% confidence interval, 1.20-1.40) compared with those not receiving PORT. This association was unchanged when limited to patients receiving modern treatment with 3-CRT or intensity-modulated radiation therapy (hazards ratio=1.35; 95% confidence interval, 1.10-1.65). Conclusions: The use of PORT for N0-N1 margin-negative NSCLC decreased from 2003 to 2011. We found no evidence of benefit from PORT for resected N0-N1 margin-negative NSCLC, regardless of dose or technique. PORT should be approached with caution in this group of patients, regardless of radiotherapy technique.

The hereditary cancer syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) are linked to germline loss-of-function mutations in genes encoding the Krebs cycle enzymes fumarate hydratase and succinate dehydrogenase, thus leading to elevated levels of fumarate and succinate, respectively(1-3). Here, we report that fumarate and succinate both suppress the homologous recombination (HR) DNA-repair pathway required for the resolution of DNA double-strand breaks (DSBs) and for the maintenance of genomic integrity, thus rendering tumor cells vulnerable to synthetic-lethal targeting with poly(ADP)-ribose polymerase (PARP) inhibitors. These results identify HLRCC and SDH PGL/PCC as familial DNA-repair deficiency syndromes, providing a mechanistic basis to explain their cancer predisposition and suggesting a potentially therapeutic approach for advanced HLRCC and SDH PGL/PCC, both of which are incurable when metastatic.

Background:In this study, we use a competing risks analysis to assess factors predictive of early-salvage whole brain radiotherapy (WBRT) and early death after upfront stereotactic radiosurgery (SRS) alone for brain metastases in an attempt to identify populations that benefit less from upfront SRS.Patients and methods:Patients from eight academic centers were treated with SRS for brain metastasis. Competing risks analysis was carried out for distant brain failure (DBF) versus death prior to DBF as well as for salvage SRS versus salvage WBRT versus death prior to salvage. Linear regression was used to determine predictors of the number of brain metastases at initial DBF (nDBF).Results:A total of 2657 patients were treated with upfront SRS alone. Multivariate analysis (MVA) identified an increased hazard of DBF associated with increasing number of brain metastases (P < 0.001), lowest SRS dose received (P < 0.001), and melanoma histology (P < 0.001), while there was a decreased hazard of DBF associated with increasing age (P < 0.001), KPS < 70 (P < 0.001), and progressive systemic disease (P = 0.004). MVA for first salvage SRS versus WBRT versus death prior to salvage revealed an increased hazard of first salvage WBRT seen with increasing number of brain metastases (P < 0.001) and a decreased hazard with widespread systemic disease (P = 0.002) and increasing age (P < 0.001). Variables associated with nDBF included age (P = 0.02), systemic disease status (P = 0.03), melanoma histology (P = 0.05), and initial number of brain metastases (P < 0.001).Conclusions:Patients with a higher initial number of brain metastases were more likely to experience DBF, have a higher nDBF, and receive early-salvage WBRT, while patients who were older, had lower KPS, or had more systemic disease were more likely to experience death prior to DBF or salvage WBRT.

11586 Background: 2-Hydroxyglutarate (2HG) exists as two enantiomers, R-2HG and S-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (aKG)-dependent dioxygenases. The former is an oncometabolite induced by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, while the latter is produced under pathologic processes such as hypoxia. Recurring IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML). Methods: Our group recently reported that IDH1/2 mutations induce a homologous recombination (HR) defect which renders tumor cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. Remarkably, this “BRCAness” phenotype can be completely reversed by mutant IDH1/2 inhibitors, and it can be entirely recapitulated by treatment with either 2HG enantiomer in cells with intact IDH1/2. We performed a comprehensive series of studies that directly implicate two aKG-dependent dioxygenases, KDM4A and KDM4B, as key mediators of the observed phenotype. Results: Using the methodology and preliminary data obtained above as a basis for further inquiry, here we have extended these findings to several related gene mutations, which similarly induce profound synthetic lethality with PARP inhibitors in these tumors, and our data suggest a similar mechanism of action via which HR is suppressed. Finally, we provide additional evidence that suppression of 2HG production with small molecule inhibitors of mutant IDH1/2 function does not lead to any detectable decreases in cell growth or viability in several unique models. Conclusions: Small molecule inhibition of oncogenic kinases is a pillar of precision medicine in modern oncology, and this approach has been extrapolated to treat IDH1/2-mutant and other oncometabolite-producing cancers with inhibitors blocking the neomorphic activity of the mutant proteins. The findings present here directly challenge this therapeutic strategy, and they instead provide a novel approach to treat these tumors with DNA repair inhibitors. Based on these findings, we are planning a multi-center Phase II trial testing the efficacy of olaparib for the treatment of recurrent IDH1/2-mutant tumors later this year.

2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This "BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.

Abstract 2-Hydroxyglutarate (2HG) exists as two enantiomers, R-2HG and S-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, while the latter is produced under pathologic process such as hypoxia. Recurring IDH1/2 mutations were first identified gliomas and acute myeloid leukemia (AML), and subsequently they were found in multiple other tumor types. Many IDH1/2-mutant tumors are known to be chemo- and radiosensitive, although the mechanisms underlying this enhanced sensitivity have been elusive. Here, we report that IDH1/2 mutations induce a homologous recombination (HR) defect which renders tumor cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. Remarkably, this “BRCAness” phenotype can be completely reversed by small molecule mutant IDH1/2 inhibitors, and it can be entirely recapitulated by treatment with either 2HG enantiomer in cells with intact IDH1/2. We performed a comprehensive series of studies directly implicate two αKG-dependent dioxygenases, KDM4A and KDM4B, as key mediators of the observed phenotype. In addition, we demonstrate that 2HG-induced HR suppression cannot be explained by mutant IDH1/2-associated alterations in NAD+ levels. We have demonstrated IDH1/2-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells and AML bone marrow cultures in vitro, as well as genetically-matched tumor xenografts in vivo. Finally, we have extended these findings to several structurally related and clinically relevant oncometabolites. We demonstrate profound synthetic lethality with PARP inhibitors in tumors which produce these other oncometabolites, and our data suggest a similar mechanism of action via which HR is suppressed. Small molecule inhibition of oncogenic kinases is a pillar of precision medicine in modern oncology, and this approach has been extrapolated to treat IDH1/2-mutant and other oncometabolite-producing cancers with small molecule inhibitors which block the neomorphic activity of the mutant proteins. The findings present here directly challenge this therapeutic strategy, and they instead provide a novel approach to treat these tumors oncometabolite-producing tumors with DNA repair inhibitors. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair and genetic instability. We previously reported that hypoxia suppresses HR, driving genetic instability and conferring a BRCAness phenotype in hypoxic tumor cells. It is tempting to speculate that the findings reported here provide a novel commonality between hypoxia and IDH1/2 mutations as mediating a “hit-and-run” mechanism for genetic instability and tumor progression through 2HG, but at the same time bestowing a vulnerability to PARP inhibition that can be therapeutically exploited. Based on these findings, we are planning a multi-center Phase II trial testing the efficacy of olaparib for the treatment of recurrent IDH1/2-mutant tumors, and we anticipate this trial will be open for enrollment later this year. Citation Format: Parker Sulkowski, Christopher Corso, Nathaniel Robinson, Susan Scanlon, Karin Purshouse, Hanwen Bai, Yanfeng Liu, Ranjini Sundaram, Denise Hegan, Nathan Fons, Gregory Breuer, Yuanbin Song, Ketu Mishra, Henk De Feyter, Robin de Graaf, Yulia Surovtseva, Maureen Kachman, Stephanie Halene, Murat Gunel, Peter Glazer, Ranjit S. Bindra. Oncometabolites induce a BRCAness state that can be exploited by PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-290. doi:10.1158/1538-7445.AM2017-LB-290

Objectives: Stereotactic body radiation therapy (SBRT) has become increasingly utilized over the last decade in the treatment of inoperable stage I non–small cell lung cancer (NSCLC) patients, although no standardized dosing guidelines exist. In this retrospective study, we investigated the dose prescription pattern use in the United States for patients receiving SBRT. Methods: Patients with stage I NSCLC treated with SBRT between 2004 and 2011 were identified within the National Cancer Database (NCDB). Trends in SBRT use and dose prescriptions were analyzed. Results: A total of 5246 patients met criteria as receiving SBRT. The overall mean and median BED10 were 134.5 and 132 Gy, respectively. Of these patients, 94.5% were prescribed a regimen with a BED10≥100 Gy. The most common prescriptions overall were 60 Gy in 3 fractions (24.1%), 48 Gy in 4 fractions (17.8%), 50 Gy in 5 fractions (13.0%), and 54 Gy in 3 fractions (12.8%). Analysis of prescription trends revealed decreased utilization of 54 to 60 Gy in 3 fractions (47.9% in 2006 to 27.9% in 2011, combined) and increased utilization of 50 Gy in 5 fractions (3.1% in 2006 to 20.4% in 2011). Conclusions: Our findings suggest increasing use of SBRT over the last decade with a majority of patients being treated with regimens employing a BED10≥100 Gy. Since 2006, there has been a decline in the use of 54 to 60 Gy in 3 fractions, with an increase in the use of 50 Gy in 5 fractions. Possible explanations include concern for increased toxicity with higher BED regimens and increasing treatment of centrally located tumors.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients’ DBF risk within the validation dataset (c-index = 0.631) and Heller’s explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.

AbstractHigh-grade gliomas, such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), are characterized by an aggressive phenotype with nearly universal local disease progression despite multimodal treatment, which typically includes chemotherapy, radiotherapy, and possibly surgery. Radiosensitizers that have improved the effects of radiotherapy for extracranial tumors have been ineffective for the treatment of GBM and DIPG, in part due to poor blood–brain barrier penetration and rapid intracranial clearance of small molecules. Here, we demonstrate that nanoparticles can provide sustained drug release and minimal toxicity. When administered locally, these nanoparticles conferred radiosensitization in vitro and improved survival in rats with intracranial gliomas when delivered concurrently with a 5-day course of fractionated radiotherapy. Compared with previous work using locally delivered radiosensitizers and cranial radiation, our approach, based on the rational selection of agents and a clinically relevant radiation dosing schedule, produces the strongest synergistic effects between chemo- and radiotherapy approaches to the treatment of high-grade gliomas. Mol Cancer Ther; 16(8); 1456–69. ©2017 AACR.

Glioblastoma (GBM) is an aggressive intracranial tumor characterized by nearly universal local relapse despite aggressive therapy. New treatments are necessary to improve local tumor control and extend survival. A promising strategy involves development of rationally designed radiosensitizers targeting specific pathways in glioma cells to enhance the cytotoxic effects of ionizing radiation while sparing normal adjacent tissue. In this review, developments in glioma radiosensitizers are discussed with a focus on agents targeting cell cycle and DNA repair pathways including the Wee1, ATM, and ATR pathways. A case study on a repurposed hypertension drug now in clinical Phase I testing as a novel radiosensitizer for GBM is also included.

The use of adjuvant therapy in T3N0 non-small cell lung cancer chest wall tumors is unclear. The results of the present retrospective analysis of 759 patients suggest that those with tumors <= 4 cm will benefit from adjuvant chemotherapy and those with tumors > 4 cm will benefit from adjuvant chemoradiation, implying that the treatment for these patients should be different from that of other stage IIB patients.Introduction: The present study investigated the effect of adjuvant chemotherapy and radiation on survival among patients undergoing chest wall resection for T3N0 nonesmall cell lung cancer (NSCLC). Materials and Methods: Patients with T3N0 NSCLC who underwent chest wall resection were identified in the National Cancer Data Base in 2004 to 2012. The cohort was divided into patients who had received adjuvant chemotherapy, radiation therapy, chemoradiation therapy, or no adjuvant treatment. Kaplan-Meier and log-rank tests were used to compare overall survival, and a bootstrapped Cox proportional hazards model was used to determine the significant contributors to survival. A subset analysis was performed with stratification by margin status and tumor size. Results: Of 759 patients identified, 42.0% underwent surgery alone, 23.3% underwent surgery followed by chemotherapy, 22.3% underwent surgery followed by chemoradiation therapy, and 12.3% underwent surgery followed by radiotherapy alone. Tumors > 4 cm benefited from adjuvant chemotherapy and radiation therapy in the multivariable analysis, and those <= 4 cm benefited only from adjuvant chemotherapy. The subgroup analysis by margin status identified that margin-positive patients with tumors > 4 cm benefited significantly from either adjuvant chemoradiation therapy or radiation therapy alone. Conclusion: T3N0 NSCLC with chest wall invasion requires unique management compared with other stage IIB tumors. An important determinant of management is tumor size, with tumors <= 4 cm benefiting from adjuvant chemotherapy and tumors > 4 cm benefiting from adjuvant chemotherapy if margin negative and adjuvant chemoradiation therapy or radiotherapy if margin positive.