ACTR-70. INCREASING SURVIVAL IN BIOPSY-ONLY GBM PATIENTS
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ABSTRACT:
SUBMITTER: Gainer J
PROVIDER: S-EPMC6216489 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
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Project description:Abstract The standard of care for glioblastoma is neurosurgical resection followed by radiation therapy (RT) and temozolomide (TMZ) chemotherapy. Although RT is effective for glioblastoma, attempts to improve survival using RT dose escalation above 60 Gy have been largely unsuccessful. This may be because prior attempts have been targeted to resection cavity or enhancing tumor, which may not accurately predict areas at highest recurrence risk. To overcome the limitations of standard T1 and T2-weighted MRI in predicting tumor recurrence, we have shown that supplementation with 3D high-resolution spectroscopic MRI (sMRI) identifies actively proliferating tumor beyond areas of T1-enhancement by measuring endogenous metabolites and their ratios. Previously, we demonstrated that the choline to N-acetylaspartate ratio (Cho/NAA) best correlates with tumor cellularity in surgically resected tissue (?=0.82, p< 0.001) and, most importantly, areas of sMRI metabolic abnormalities predate disease recurrence in those same areas (Cordova et al, Neuro-Oncology 2016). Therefore, we seek to identify whether sMRI can be used by radiation oncologists to choose the optimal regions to target for RT dose escalation. To assess its feasibility and safety, we developed a web-based imaging platform designed specifically to incorporate sMRI into the RT planning clinical workflow and are using it in a multisite sMRI-guided dose escalation trial (NCT03137888; Emory, Johns Hopkins, U. Miami). Recently, we have completed full enrollment including 30 patients treated with sMRI-guided dose escalated RT across three institutions. We have demonstrated successful integration of sMRI into the RT planning workflow, and we have delivered sMRI-guided dose escalated RT plans to glioblastoma patients without severe adverse events to date. Follow-up data will be analyzed for overall and progression-free survival. Based on the feasibility and safety of this technique in the current trial, we plan to assess the efficacy of sMRI-guided dose-escalated RT on patient outcomes in a NCTN clinical trial.
| S-EPMC6846992 | biostudies-literature
Project description:Abstract AZD1775 is an oral small molecular inhibitor of the G2/M checkpoint regulator Wee1. The Adult Brain Tumor Consortium 1202 trial (NCT01849146) is a phase I, open label, multicenter dose-finding study of AZD1775 in combination with standard RT and TMZ followed by an IDD study for patients undergoing surgery for recurrent GBM. Dose of AZD1775 was increased in a 3 + 3 design M-F during concurrent RT/TMZ and x 5d/28d cycle with adjuvant TMZ in separate cohorts. A combination cohort with both concurrent and adjuvant AZD1775 at MTD and analysis of PK/PD and IDD at MTD in patients undergoing surgery for recurrent GBM followed. MTD was 200 mg for concurrent with 2/6 patients experiencing DLTs (grade 4 neutropenia, grade 3 ALT elevation). MTD for the adjuvant cohort was 425 mg with 1/6 patients experiencing DLT (grade 4 decrease in ANC). 6/12 patients experienced DLTs when cohorts were combined, however, five during the concurrent phase. Three patients had grade ≥3 ALT/AST elevation, one had grade 3 afib, and one had grade 4 neutropenia/thrombocytopenia, grade 3 dehydration/fatigue/muscle weakness. A sixth patient had grade 4 neutropenia in the first adjuvant cycle. Following amendment, an additional 6 patients were enrolled with 150 mg (concurrent) and 425 mg (adjuvant) combination and are in the observation period with one DLT currently. Drug concentration in contrast enhancing and non-enhancing brain tumor was 4–8 x and 0.5–2.6 x greater than plasma, respectively for patients on IDD portion. CONCLUSIONS AZD1775 in combination with RT/TMZ at 200 mg qd M-F with concurrent RT/TMZ and 425 mg qd x 5d/28d cycle in combination with adjuvant TMZ had unacceptable DLT rate in the concurrent phase. A cohort with 150 mg concurrent/425 mg adjuvant has competed accrual with acceptable rates of toxicity currently in observation. AZD1775 has good penetration to non-enhancing and enhancing tumor areas.
| S-EPMC6216169 | biostudies-literature
Project description:Abstract Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT gene, which confers a limited response to standard of care treatment with temozolomide (TMZ) resulting in a lower survival. VAL-083 is a novel bi-functional DNA targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. The study has 2 stages: Stage 1 is a dose-escalation and induction format to confirm the recommended dose of VAL-083 when administered concurrently with radiation therapy (RT) based on safety and tolerability. The subjects received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment. Stage 2 comprises an expansion phase to enroll up to 30 patients. The dose escalation stage is complete and 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. As of 17 May, 2019, 18 patients have been enrolled. Fifteen patients have completed their prospectively planned MRI scans and had their initial assessment for tumor progression. Of these 15 patients, seven were assessed as a complete response (CR), and eight patients as having stable disease (SD). Of the remaining three patients, one died prior to their post-cycle 3 MRI and two have not been on study long enough to reach their planned post-cycle 3 MRI. As of the data cutoff, 14 of the 18 patients were still alive. Consistent with our prior experience, myelosuppression was the most common adverse event. Three dose-limiting toxicities have been reported - one at the 40 mg/m2/day and two at the 30 mg/m2/day dose. Further enrollment, safety & study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.
| S-EPMC6847153 | biostudies-literature
Project description:BackgroundWith the coming of the aging society, the incidence of elderly nasopharyngeal carcinoma (NPC) has been increasing which may result in considerable disease burden; however, the optimal treatment strategy for elderly patients is still debatable.Methods and resultsClinical data on 294 elderly NPC patients aged ≥70 treated between 2009 and 2019 was analyzed. Kaplan-Meier method was used to estimate overall survival (OS) and cancer-specific survival (CSS) rates. With a median follow-up of 53.25 months, the 5-year estimated OS and CSS for the entire group were 59.5% and 69.8%, respectively. 146 patients died within the follow-up period, of which recurrence + metastasis (48%) and internal medical disease unrelated to NPC (32%) are the primary causes of death. On univariable analysis, (IMRT vs. 3D-CRT) (p = 0.001; p = 0.000), T stage (p = 0.001; p = 0.000), N stage (p = 0.013; p = 0.000) and clinical stage (p = 0.000; p = 0.000) were associated with OS and CSS; Charlson Comorbidity Index (CCI) (p = 0.016) was associated with OS. The addition of chemotherapy (CT) correlated with better CSS (p = 0.039), but did not improve OS (p = 0.056) for stage III-IV subgroup. On multivariate analysis, advanced clinical stage independently predicted poorer OS (p = 0.002) and CSS (p = 0.000). In addition, the application of IMRT was an independent protective factor on both OS (p = 0.028) and CSS (p = 0.030).ConclusionIMRT is a reasonable treatment strategy to improve survival for elderly NPC patients aged over 70 years; consideration of adding chemotherapy for elderly population should be weighed carefully.
| S-EPMC10587980 | biostudies-literature
Project description:Abstract BACKGROUND We sought to determine the efficacy and tolerability of hypofractionated radiotherapy (HFRT), 34Gy given over two weeks with concurrent and adjuvant temozolomide, in patients over 70 years old with newly diagnosed GBM. METHODS Patients ≥ 70 years of age with newly diagnosed GBM received HFRT to a dose of 34 Gy in 10 fractions over 2 weeks, delivered with concurrent and adjuvant TMZ. Quality of life (QOL) data using the validated functional assessment of cancer therapy-brain (FACT-BR) questionnaire was collected. Kaplan-Meier methods and log-rank tests were used for survival analyses. A random intercepts growth model with baseline and linear effect in time terms was used to assess QOL with relation to protocol treatment. RESULTS Eleven patients were enrolled from 12/1/2015 to 2/5/2018. Median age and KPS of the cohort was 74 years (range 70 -81) and 80 (range 60–100). Eight patients have died. Median follow-up of the cohort was 13.8 months (range 3 – 26 months). The median progression free survival (PFS) was 6.0 months (CI 4.7 months -not achieved (NA) and the median overall survival (OS) was 24.5 months (CI 10.2 months –NA). MGMT methylation status was significantly associated with both PFS (p =0.02) and OS (p =0.02). All patients completed HFRT with no patients developing ≥ grade 3 adverse treatment events. QOL did not significantly worsen over time with therapy (p =0.75). CONCLUSIONS This completed phase II trial suggest a HFRT schedule of 34Gy delivered over 2 weeks with concomitant and adjuvant TMZ is well tolerated in elderly GBM patients without compromising clinical outcomes. This result compares favorably to the longer HFRT regimen of 40Gy over 3 weeks. ClinicalTrials.gov identifier: NCT01985087
| S-EPMC6847443 | biostudies-literature
Project description:Abstract Pamiparib, an investigational, selective PARP1/2 inhibitor that has demonstrated potent PARP trapping and ability to cross the blood-brain barrier, showed synergistic cytotoxicity with TMZ preclinically. We report updated safety and antitumor effects from a phase 1b/2 study of pamiparib + RT and/or TMZ in patients with newly diagnosed or R/R GBM (SNO 2018, ACTR-30). The dose-escalation/expansion study has 3 arms: Arm A, pamiparib (2, 4, or 6 weeks) + RT in newly diagnosed GBM patients with unmethylated MGMT promoter (unmethylated-GBM); Arm B, pamiparib (6 weeks) + RT and increasing TMZ dosed in weeks 1 and 5 of RT in newly diagnosed, unmethylated-GBM patients; and Arm C, pamiparib + increasing TMZ doses in methylated/unmethylated R/R-GBM patients. Arm A and B patients receive maintenance treatment post-RT rest period at the Arm C expansion dose/schedule. As of 10 April 2019, accrual was completed for Arms A and C dose-escalation (A: n=20; C: n=17) and continues in the dose expansion (A: n=28/40; C: n=28/30); accrual was completed in dose escalation for B (n=9). Recommended phase 2 doses were established for Arms A (pamiparib 60 mg BID×6 weeks + 6–7 weeks RT) and C (pamiparib 60 mg BID d1–28 + TMZ 60 mg d1–7/28-d cycle). One dose-limiting toxicity (grade 3 febrile neutropenia) was reported in Arm B. Treatment-related adverse events (?10%) were (overall/grade 3 [no grade 4/5]): Arm A, nausea (23%/2%); B, decreased WBC count (11%/11%); C (none). Of patients with tumor assessment post-RT: Arm A (n=17), 1 had cPR, 1 uPR, and 9 SD (disease control rate, 64.7% [95% CI, 38.3–85.8]); C (n=26), 1 had cPR (sustained 12 cycles), 1 uPR, and 5 SD (objective response rate, 7.7% [95% CI, 0.9–25.1]). Pamiparib 60 mg BID + RT/TMZ was generally well tolerated in patients with newly diagnosed or R/R GBM. Clinical trial ID: NCT03150862
| S-EPMC6847934 | biostudies-literature
Project description:In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.
| S-EPMC5580273 | biostudies-literature
Project description:An important factor correlated with poor survival in glioblastoma (GBM) is the aberrant and persistent activation of STAT3, a critical transcription factor that regulates multiple genes with key roles in cell survival, proliferation, resistance to chemotherapy, and stem cell maintenance. The Interleukin-6 (IL6)-STAT3 signaling axis has been studied extensively in inflammation and cancer. However, it is not completely understood how high levels of activated STAT3 are sustained in tumors. Previously, we identified a novel mechanism of biphasic activation of STAT3 in response to gp130-linked cytokines, including IL6, in which activation of STAT3 is prolonged by circumventing the negative regulatory mechanisms induced by its initial activationTo target prolonged STAT3 activation, we used the small molecule inhibitor bazedoxifene (BZA), which blocks formation of the IL6 receptor-gp130 complex. Glioma stem-like cells (GSCs) are more tumorigenic and more resistant to therapy. STAT3 is a key driver of the expression of stem cell transcription factors, making it a therapeutically important target in GBM. We show that treating GSCs with BZA decreases their self-renewal capacity and the expression of GSC markers in vitro. Additionally, BZA crosses the blood-brain barrier and confers a survival advantage in an orthotopic syngeneic mouse model of GBM. Although IL6-STAT3 signaling is important for GSC survival, a therapeutic agent that inhibits this pathway without toxicity has yet to be identified. Our findings reveal a mechanism of sustained STAT3 signaling in GBM and reveal its role in GSC maintenance, and we identify BZA as a novel candidate for treating GBM.
| S-EPMC8353354 | biostudies-literature
Project description:BackgroundPatients with glioblastoma multiforme (GBM) who undergo radiation often require anticonvulsants during treatment. The aim of this study was to determine the effects of anticonvulsants on GBM clinical outcomes.MethodsA retrospective analysis was performed using the SEER-Medicare database. All patients with GBM who were treated with radiation and concurrently taking an anticonvulsant were included in final analysis. Each class of medication was further subdivided by mechanism of action. Descriptive statistics were performed for all variables. Kaplan Meier survival curves were generated for each class of medication and Cox regression analysis was performed to assess the effect of each individual variable on survival.ResultsThere were 1561 patients available for final analysis. On multivariate Cox regression analysis, GBM patients taking sodium/calcium (Na/Ca) channel blocker anticonvulsants during radiation therapy demonstrated both improved overall survival (OS) (HR, 0.799; 95% CI [0.716, 0.891]; P < 0.001) and cancer specific survival (CSS) (HR, 0.814; 95% CI [0.727, 0.911]; P < 0.001).ConclusionOS was significantly better in patients taking NA/Ca channel blockers among patients with GBM who were concurrently undergoing radiation therapy.
| S-EPMC9896587 | biostudies-literature
Project description:Study designRetrospective analysis of a registered cohort of patients treated and irradiated for metastases in the spinal column in a single institute.ObjectiveThis is the first study to develop and internally validate radiomics features for predicting six-month survival probability for patients with spinal bone metastases (SBM).Background dataExtracted radiomics features from routine clinical CT images can be used to identify textural and intensity-based features unperceivable to human observers and associate them with a patient survival probability or disease progression.MethodsA study was conducted on 250 patients treated for metastases in the spinal column irradiated for the first time between 2014 and 2016, at the MAASTRO clinic in Maastricht, the Netherlands. The first 150 available patients were used to develop the model and the subsequent 100 patient were considered as a test set for the model. A bootstrap (B = 400) stepwise model selection, which combines both the forward and backward variable elimination procedure, was used to select the most useful predictive features from the training data based on the Akaike information criterion (AIC). The stepwise selection procedure was applied to the 400 bootstrap samples, and the results were plotted as a histogram to visualize how often each variable was selected. Only variables selected more than 90 % of the time over the bootstrap runs were used to build the final model.A prognostic index (PI) called radiomics score (radscore) and clinical score (clinscore) was calculated for each patient. The prognostic index was not scaled, the original values were used which can be extracted from the model directly or calculated as a linear combination of the variables in the model multiplied by the respective beta value for each patient.ResultsThe clinical model had a good discrimination power. The radiomics model, on the other hand, had an inferior performance with no added predictive power to the clinical model. The internal imaging characteristics do not seem to have a value in the prediction of survival. However, the Shape features were excluded from further analyses in our study since all biopsies had a standard shape hence no variability.
| S-EPMC8777154 | biostudies-literature