bluuebunny/crossref_metadata_2025 huggingface dataset:
NCCTG N057K phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: A North Central Cancer Treatment Group trial.
Authors: Ma Daniel , Galanis Evanthia , Schiff David , Wu Wenting , Peller Patrick J. , Giannini Caterina , Brown Paul D. , Uhm Joon H. , McGraw Steven , Jaeckle Kurt A. , Flynn Patrick J. , Buckner Jan C. , Sarkaria Jann Nagina
Published: March 2020

2031

Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt pathway as a critical modulator of cell survival. Preclinical studies in GBM indicate that the combination of mTOR inhibitors, such as everolimus (RAD001), with either radiation therapy (RT) or temozolomide (TMZ) provide increased tumor cell killing. Methods: Newly diagnosed GBM pts were eligible for the study. RAD001 was dosed orally at 70 mg/week weekly, starting 1 week prior to RT/TMZ, and continued throughout RT/TMZ, adjuvant TMZ and then until progression. This was a single arm phase II design powered to detect a true overall survival at 12 months (OS12) of 73% (vs 58% in historical controls). Secondary endpoints were toxicity, response rate, and time to progression (TTP). A subgroup of patients with measurable residual disease were eligible for the PET imaging component of the study, consisting of an 18FLT-PET/CT scan performed before and after the initial two doses of RAD001 but before the first dose of RT or TMZ. Results: 103 patients were accrued to phase II of which 100 were evaluable. The median age was 60.5 years (23-81), median ECOG PS was 1, 46 patients had GTR, 33 STR, and the remainder had biopsy at diagnosis. Treatment tolerance was acceptable: 17% patient had at least one grade 3 hematologic toxicity; 14% had at least one grade 4 hematologic toxicity, 42% had at least one grade 3 non-heme toxicity, while 12% had at least one grade 4 non-heme toxicity. No increased incidence of infectious complications was observed and there were no treatment related deaths. Median PFS was 5.3 months (1.3-21.4), with 22 patients progression free. Mature OS data will be available at the meeting. MGMT methylation status analysis is ongoing. Of the pts who had evaluable FLT-PET data, three of eight (37.5%) had a drop in SUVmax >25% after two treatments of RAD001. Conclusions: RAD001 with standard of care chemoradiation had moderate toxicity. Serial 18FLT-PET was feasible for evaluating drug-induced changes in tumor proliferation following RAD001. Final outcome data and association of MGMT status with outcome will be reported at the meeting.
Phase I/randomized phase II trial of either dasatinib or placebo combined with standard chemoradiotherapy for newly diagnosed glioblastoma multiforme (GBM): Final results of phase I study.
Authors: Laack Nadia N. , Galanis Evanthia , Leinweber Clinton , Buckner Jan C. , Giannini Caterina , Geoffroy Francois J. , Jaeckle Kurt A. , Sarkaria Jann Nagina ,   Alliance for Clinical Trials in Oncology
Published: March 2020

2032

Background: Dasatinib is a potent oral ATP competitive multi-targeted kinase inhibitor of multiple members of the Src kinase family, known to be involved in gliomagenesis and invasion. N0877 is a phase I/randomized phase II trial evaluating the combination of dasatinib, radiation (RT) and temozolomide (TMZ) in newly diagnosed GBM. The phase I portion has been completed and is the focus of this report. Methods: A cohorts-of-3 design was used to assess the safety of dasatinib in combination with RT and concomitant TMZ, and establish the phase II dose of the combination. Dasatinib was given orally for 42 days, beginning with the first day of RT (total dose 60 Gy) and first dose of TMZ (75 mg/m2/d). A 24 - 42 day rest (cycle 2) followed the RT/TMZ/dasatinib. Patients (pts) were observed for DLT to the end of cycle 2. Patients then received 6 cycles (28 day cycles) of dasatinib (once daily) and TMZ (days 1-5). At the completion of 6 cycles of TMZ + dasatinib, pts stay on dasatinib only (28 day cycles) until progressive disease. Results: Phase I component is complete with 13 patients (3 at dose level 0, 3 at dose level 0-A, 7 at dose level 1). One patient in dose level 1 had to be replaced due to the development of unrelated medical issues. One DLT (grade 4 pancytopenia) was observed in 1 patient at dose level 0 (50mg bid) and one DLT (grade 3 rash) was observed in 1 patient at dose level 1 (150mg qd). MTD of dasatinib was determined to be 150mg daily. Most common adverse events throughout the entire study period were hematologic with the most common toxicity being lymphopenia (grade 3 in 69% of patients, grade 4 in 8%). Other toxicities attributed to treatment and occurring in > 10% of patients included anemia (31%), neutropenia (15%), and fatigue(15%). Best response was stable disease in 10 patients, progressive disease in 1 patient, and not evaluable in 2. Conclusions: MTD for dasatinib in combination with TMZ and RT in newly diagnosed GBM patients is 150mg daily. Toxicity was primarily hematologic with minimal non-hematologic events. This dose is currently being used in the ongoing placebo-controlled, randomized phase II trial.
Final results of a randomized phase III trial of nimotuzumab for the treatment of newly diagnosed glioblastoma in addition to standard radiation and chemotherapy with temozolomide versus standard radiation and temoziolamide.
Authors: Westphal Manfred , Bach Ferdinand
Published: March 2020

2033

Background: The receptor for epidermal growth factor (EGF-R) has consistently been found expressed or overexpressed in human malignant glioma disease. Therapeutic targeting of the EGF-R has shown mixed responses which appear to be restricted by specific features of the tumor cells.Nimotuzumab binds preferentially to highly over expressing cells, a phase III trial was initiated to test efficacy in glioma. Methods: Nimotuzumab was tested in an open label, randomized, multicenter Phase III trial in patients with histologically confirmed, newly diagnosed glioblastoma. 12 consecutive weekly infusions of 400mg during standard radiotherapy with Temozolomide followed by biweekly infusions of 400mg arm A was randomized against standard radio chemotherapy alone arm B. Primary endpoint was PFS as determined by centralized neuro-imaging review. OS as secondary endpoint with quality of life, safety as additional parameters.MGMT and EGF-R were assessed where sufficient materials could be retrieved as well as tumor hypoxia. Results: Between 2007 and 2010, 149 patients were randomized and 142 were available for analysis. Stratification according to resection status resulted in 40 pts in the treatment arm and 41 in the control arm with residual tumor and 31 vs 30 pts without residual tumor. PFS: 12 month was 25.5% arm A vs 20.3% in arm B (p = 0.78) and OS: 679 days vs 596 days. For non - methylated MGMT the difference was most notable: OS arm A 28 pats: 19.6 months vs arm B 28 pats 15.0 months EGF-R amplification, gave no clear signal, neither was there a statistically significant treatment effect between with or without residual tumor. Tumor hypoxia does not appear to have predictive value in the overall group but possibly in subgroups.AEs and SAEs did not reveal a new specific toxicity profile beyond the known side effects from glioma treatment with current standard. Conclusions: Nimotuzumab shows a clear trend towards efficacy in MGMT non-methylated glioblastoma patients. Safety profile and indications for subgroup efficacy potentially justify focused evaluation of antibody therapy against glioblastoma.
Toxicity profile of temozolomide in the treatment of 300 malignant glioma patients in Korea.
Authors: Kim Chae-yong , Bae So Hyun , Park Min-Jung , Lee Min Mi , Kim Tae Min , Kim Young-Hoon , Kim Yu Jung , Park Chul-Kee
Published: March 2020

2041

Background: Toxicity of temozolomide itself has been rarely reported in the field of neuro-oncology. In an attempt to explore the toxicity profiles of temozolomide we investigated the records of 300 glioma patients in two institutions in Korea. Methods: We reviewed the records of 300 glioma patients who were treated with temozolomide between Jan 2004 and May 2010 at two hospitals of our university at two medical centers in Seoul National University, Korea. The age range of patients was 17 ~ 84 years old with its median of 49 years old. Their pathologies were glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, gliomastosis cerebri, gliosarcoma and others. Temozolomide was used as only concurrent manner with radiotherapy in 46 patients, as both concurrent and adjuvant manner in 93 patients, and as only adjuvant or palliative manner in 161 patients. We classified the side effects by Common Terminology Criteria for Adverse Events version 3.0(CTCAE). Results: We found 603 events of side effects of temozolomide. Nonhematolgic toxicities were most common (n=482). Especially, nausea(n=135), vomiting(n=110), and anorexia(n=40) were common among all kinds of toxicities. Hematologic adverse events(n=121), for example, thrombocytopenia(n=43), anemia(n=33), and neutropenia(n=20) were the second common toxicities. Some patients suffered from fatigue(n=31). None of our patient presented fatal Pneumocystis jiroveci pneumonitis. In our series, 512 cases(84.9%) of toxicity were grade 1 or 2, and 91 cases(15.1%) were grade 3 or 4. Grade 3 or 4 toxicity were 140 cases(15.1%). Only 27 cases(2.9%) presented grade 4 toxicity. There was no mortality due to temozolomide. Only 4 patients (1.3%) presented leukopenia, which is different pattern compared with the incidence reported in prior studies from western countries. Conclusions: Temozolomide had many kinds of toxicities. However, most of the toxicity was tolerable. This profile could be used to prevent toxic reactions more effectively and improve the patient’s quality of life. Furthermore, we could use these lessons for education of patients during the treatment with temozolomide.
Use of tumor-targeting salmonella typhimurium to eradicate human glioma in an orthotopic model in nude mice.
Authors: Momiyama Masashi , Zhao Ming , Kimura Hiroaki , Tran Benjamin , Chishima Takashi , Bouvet Michael , Endo Itaru , Hoffman Robert M.
Published: March 2020

2044

Background: Prognosis remains poor for glioma and therefore requires new approaches. We have previously developed a genetically-engineered strain of Salmonella typhimurium, A1-R, that targets tumors without overt toxicity in mouse models (Proc. Natl. Acad. Sci. USA 102, 755-760, 2005; Cancer Research 66, 7647-7652, 2006; Proc. Natl. Acad. Sci. USA 104, 10170-10174, 2007; Expert Opinion on Drug Discovery 7, 73-83, 2012). In the present study, we demonstrated that Salmonella typhimurium A1-R can inhibit and eradicate human glioma in an orthotopic nude mouse model. Methods: S. typhimuirum A1-R was administered by injection through a craniotomy open-window or intravenously in nude mice. To establish the model, 2×105 U87 human glioma cells, expressing red fluorescent protein (RFP), were injected stereotactically into the mouse brain through the craniotomy open window. Two weeks after glioma-cell implantation, mice were treated with S. typhimurium A1-R (2×107 CFU / 200 μl intravenous injection [i.v.] or 1×106 CFU / 1 μl intracranial injection [i.c.]) once a week for 3 weeks. Results: Brain tumors were observed by fluorescence imaging through the craniotomy open window over time. S. typhimurium A1-R, administered i.c., inhibited brain tumor growth 7.6-fold compared with untreated mice (p = 0.009) and improved survival 73% (p = 0.001). Two of ten mice had their tumors eradicated. Intravenous administration of S. typhimurium A1-R was not effective. Conclusions: The results of the present study demonstrate that bacterial therapy of glioma is a novel, effective and safe treatment strategy in a highly treatment-resistance cancer in an orthothopic model, a first step toward clinical development.
A phase II multicentric study of sunitinib administered as upfront therapy in glioblastoma: A study by the GEINO group.
Authors: Balana Carmen , Gil Gil Miguel J. , Reynes Gaspar , Capellades Jaume , Ribalta Teresa , Gallego Oscar , Pérez Segura Pedro , Verger Eugenia
Published: March 2020

2045

Background: Sunitinib is a multitargeted tyrosine kinase inhibitor that has direct antitumor and antiangiogenesis activity through targeting VEGFR 1-2, PDGFR α-β, c-kit, bFGF, (CSF-1), FLT3 and RET. Experimental studies in GB mice showed angiogenic activity, prolonged survival and synergy with irradiation Methods: Eligible pts were ≤75 years with GB not amenable to resection, PS≥2, MMS ≥25. Treatment was sunitinib 37.5mg daily for 8 w before radiotherapy, during radiotherapy (60Gy, 6 w) and after radiotherapy until disease progression. Primary endpoint was overall response (OR) (RANO criteria) after 8 w of sunitinib treatment before radiotherapy. Secondary endpoints were % pts free of neurological deterioration before radiotherapy, % pts who completed radiotherapy, PFS, OS and 1-year survival. We used a Simon 2-stage design (12 →20) based on OR to calculate the number of patients needed to detect at least 10% of responses with α error of 0.05 and β error of 0.10. Twelve patients were included in the first phase and one response was needed to continue study accrual. Results: 12 pts were enrolled: 7 males, median age 65 years, PS≥1: 8pts, median MMS 26.5. Neurological deficit: 5pts, DXM treatment 10/12, non-EIDS 3/12. Treatment: 5 pts completed 8 w of therapy, 2pts completed 7 w, 4 pts ≤ 6w. Toxicity G3 and 4: diarrhea (1pt), asthenia (2pts), skin and EDDPP (2), mucositis (2), fatal CNS hemorrhage (1), hypercholesterolemia and hypertriglycemia (1). OR was 1/12 SD, 11/12 P; radiological response was SD in 5 pts but 4 pts progressed neurologically. Only 2 pts completed radiotherapy plus sunitinib. The only SD received treatment for 18 w. Median PFS was 7.5w (CI 95% 5.8-9.2), OS 16w (CI 95% 0.5-23.7), 1year OS: 0%. Conclusions: the trial was closed after the first stage due to lack of response. Sunitinib is an inactive agent in glioblastoma.
Anaplastic gliomas at first recurrence: Outcome analysis.
Authors: Franceschi Enrico , Bartolotti Marco , Dall'Occa Patrizia , Poggi Rosalba , Bartolini Stefania , Di Battista Monica , Marucci Gianluca , Ermani Mario , Brandes Alba Ariela
Published: March 2020

2061

Background: Although anaplastic gliomas show a more favorable response to postsurgical therapy than glioblastoma, when recurs, salvage therapies offer only temporary benefit. Moreover, due to the rarity of these entities, no study exists to evaluate the clinical outcomes of anaplastic gliomas at first recurrence. Methods: A retrospective analysis was made using a database on 249 anaplastic glioma patients (pts) followed prospectively between 01/2000 and 12/2011. Eligibility criteria: age ≥18 years; PS 0-2; histological diagnosis at first surgery of anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and anaplastic oligoastrocytoma (AOA); first recurrence after postsurgical treatments. Results: 163 pts (recurrent AA:52%, AOA:23%, AO: 25%, mean age: 45 years, range: 21–74) were enrolled. 1p deletion and MGMT methylation were found in 23% and 56% of evaluable specimens, respectively. At time progression, second surgery was performed in 51 pts (31%). Chemotherapy was delivered in 128 pts: temozolomide in 96 pts (75%), PCV regimen in 11 pts (9%), and other cytotoxic treatments in 21 pts (16%). Median PFS was 7.1 months (95% CI: 5.8–8.5), being PFS-6 57.8% (95%CI: 49.8%–65.8%), mOS: 18.3 months (95% CI: 13.9–22.8) and OS-12: 63% (95%CI: 55.4%-70.6%). 1p status was not significantly associated with PFS and OS measured from first recurrence to second progression or death, respectively (p=0.12 and p=0.08). In the Cox proportional hazard model, PFS at recurrence was significantly correlated with OS measured at the first disease recurrence (p<0.00001). Conclusions: our data represent the largest series that evaluated the outcome of anaplastic gliomas at first recurrence. In this setting, PFS should be considered as a worthy endpoint, being significantly correlated with OS.
Illness intrusiveness and subjective well-being in patients with glioblastoma multiforme.
Authors: Coate Linda E. , Edelstein Kim , Massey Christine , Jewitt Natalie C. , Mason Warren P. , Devins Gerald M.
Published: March 2020

2063

Background: Glioblastoma multiforme (GBM) is the most common adult CNS malignancy. The quality-of-life (QOL) impact of its neurological sequelae and poor prognosis is poorly understood. In this study we examined relations between disease severity and mood in GBM patients. Methods: GBM patients (n=73) completed validated questionnaires examining depression (CESD), positive affect (ABS), illness intrusiveness (II), and health-related QOL (EORTC-QLQ30, BN-20). Median age was 53 years (range 26-75), median time since diagnosis was 1.1 years (range 0.1-12.4). 88% were on temozolomide. Questionnaire scores were compared to normative data from GI, GU, Breast, Head and Neck, Lymphoma, and Lung cancer groups using t-tests. Hierarchical multiple regression analyses tested the impact of disease severity indicators (ECOG; Symptoms, derived from QLQ30, BN20) and potential moderators on mood and whether II mediates those effects. Results: GBM patients reported less positive affect, more depression and greater II than other cancer patients (p<.05). Increase in symptoms correlated with greater II (β=.59; 95% CI [.31, .87], p<.0001) and depression (β=.37; 95% CI [.20, .55], p<.0001) and less positive affect (β=-.04; 95% CI [-.08, -.01], p=.02). Surprisingly, higher ECOG (i.e., poorer performance status) was associated with less II (β=-3.58; 95%CI [-7.06, -.10], p=.04) and depression (β=-2.20; 95%CI [-4.21, -.19], p=.03). II partially mediated the relations between disease severity and mood, evidenced by the change in the disease severity coefficient when II was added to the models (mean change measured by bootstrap sampling: CESD=.23, 95% CI [.06, .43]; ABS=.21, 95%CI [.02, .44]). The occurrence of other stressful life events was associated with II (β=2.73; 95% CI [.43, 5.02], p=.02), but there was no evidence of a moderating effect on this or any other relationship (p>.05). Conclusions: GBM patients are more distressed than other cancer patients. GBM-induced lifestyle disruptions partially mediate the association between disease severity and subjective well-being. Efforts to engage patients in valued activities and interests, despite the constraints, can help to preserve QOL.
Health-related quality of life (HRQOL) in patients with glioblastoma (GBM) and their caregivers in the end-of-life phase: A retrospective study.
Authors: Flechl Birgit , Sax Cornelia , Ackerl Michael , Crevenna Richard , Gaiger Alexander , Keilani Mohammad , Preusser Matthias , Dieckmann Karin , Widhalm Georg , Oberndorfer Stefan , Calabek Bernadette , Reijneveld Jaap , Sizoo Eefje , Marosi Christine
Published: March 2020

2071

Background: Glioblastoma multiforme (GBM) still harbours an inevitably fatal prognosis. The specially course of this disease poses unique challenges in care provision to the relatives. We still lack data about the end-of-life phase of GBM patients to improve counseling and supporting GBM patients and their proxies. Methods: In this retrospecitve study we included 52 caregivers of deceased GBM patients treated in two hospitals in Vienna, Austria. We used a specially developed questionnaire by the Medical University of Amsterdam to explore and document the last three months of living of GBM patients. Results: Most of the included caregivers were the partners of the patients (88%) and two thirds were female. The most common symptom in GBM patients was fatigue (87%), followed by reduced consciousness (81%) and aphasia (77%). 22% of the patients were bedbound during their last three months increasing to 80% in the last week of life. 30% of the caregivers told that they felt incompletely informed for their task and about the illness of their loved one. They stated the quality of life (QOL) of the patients with 2.2 and their own with 2.8 on a scale of 1 to 7 whereas 7 displays the best possible answer. The majority of the patients (46%) died in hospitals and 38% at home, which was the most often expressed wish for place of death (45%)by patients. Regarding the caregivers’ symptoms, sadness (90%), fear (69%), burnout (60%), less interest in others (54%) and irritation (42%) were the leading ones and did not differ significantly in-between the places of death. Conclusions: The end-of-life phase of GBM patients is different from that of patients dying from other cancers. Most alarmingly, one thirds of their caregivers feels poorly informed. About two thirds of the caregivers fell overstrained and stresses thereby the urgent need for support and dedicated educational programs.
Adult low-grade gliomas: The Cleveland Clinic experience.
Authors: Robles Irizarry Lizbeth , Fawole Adewale Alade , Hashemi-Sadraei Neda , Patel Mital , Elson Paul , Tekautz Tanya M. , Murphy Erin Sennett , Recinos Violette , Chao Samuel T. , Suh John H. , Peereboom David M. , Stevens Glen , Weil Robert J. , Vogelbaum Michael A. , Barnett Gene H. , Ahluwalia Manmeet Singh
Published: March 2020

2076

Background: Low-grade gliomas account for 10-20% of all primary brain tumors. There is limited data on specific prognostic factors for patients with low-grade gliomas. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify patients with histologically confirmed grade 2 glioma at the time of diagnosis. Multivariable analysis was conducted with use of a Cox proportional hazards model and a stepwise selection algorithm that used p<0.10 as the criteria for entry and p<0.05 as retention in the model to identify independent predictors of survival. Results: Chart records of 478 patients (54% of whom were men) diagnosed between 1991 and 2010 were included for analysis. The median age at presentation was 41 years (range, 18-83 years). 42% of patients had biopsy only, 27% had gross total resection, 6% had near total resection, and 25% had subtotal resection. 22% of patients were initially treated with radiation, 30% with adjuvant chemotherapy, and 7% with concurrent chemotherapy. Median progression free survival and median overall survival (OS) were 5.1 years and 12.8 years, respectively. On multivariate analysis, independent of additional therapy, five factors were identified as independent predictors of OS: age at diagnosis (p=0.002), Karnofsky performance status (KPS, p<0.0001), histology (astrocytoma vs. other, p=0.001), hemispheric location (left or bilateral involvement vs. right, p=0.02) and gender (male vs. female, p=0.0003). Conclusions: Older age, male gender, poor performance status, astrocytic histology, and left hemispheric or bilateral involvement are associated with higher mortality. [Table: see text]
Utility of iron oxide nanoparticles in the radiographic diagnosis of CNS lymphoma and inflammatory diseases.
Authors: Farrell Brian T. , Hamilton Bronwyn E. , Dosa Edit , Rimely Endre , Nasseri Morad , Gahramanov Seymur , Lacy Cindy , Frenkel Eugene P. , Doolittle Nancy Diane , Jacobs Paula M. , Neuwelt Edward A.
Published: March 2020

2077

Background: Ferumoxytol, an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO), is approved for intravenous treatment of iron deficiency in chronic renal failure. The package insert warns of potential alterations of magnetic resonance imaging (MRI). Our initial animal studies provided evidence of USPIO uptake by macrophages and lymphoreticular cells suggesting its potential in CNS lymphoma (CNSL), post transplant lymphoproliferative disease, or CNS inflammation (i.e. multiple sclerosis). The mechanism of USPIO enhancement differs from gadolinium-based contrast agents (GBCA), which optimally image areas of increased vascular permeability. Methods: USPIO was administered as an MRI contrast agent to 20 patients with presumptive or de facto diagnosis of CNSL or CNS inflammation. Seventeen of 20 patients underwent both USPIO- and gadolinium-based MRI. Three patients received only USPIO due to risk of nephrogenic systemic fibrosis (NSF) with GBCA exposure. In the pilot phase of the study, patients were given the USPIO ferumoxtran-10 and subsequent patients were given a successor USPIO (ferumoxytol) which has improved pharmaceutical properties. All patients were monitored for adverse reactions. MRI scans were subsequently reviewed by a neuroradiologist. Results: No significant toxicities were seen. Thirteen of 17 patients who received both contrast agents showed equal numbers of enhancing lesions on postcontrast images. USPIO-based contrast revealed additional areas of enhancement in three of 17 patients that were not visible when GBCA was administered. In three patients more lesions were seen with GBCA. Examples of ferumoxytol utility include 1) improved targeting for surgical biopsy; 2) avoidance of NSF; 3) demonstrating enhancement related to macrophages within lesions; 4) correlating cerebral blood volume and CNS inflammation; 5) demonstrating pitfalls such as prolonged imaging changes (3 months) in one case due to intensive inflammation, which can simulate hemorrhage. Conclusions: These studies provide data about the utility and value of USPIO-based contrast imaging in CNSL and inflammatory CNS lesions that support a dual role for these agents beyond iron replacement.
Relationship between IDH1 mutation status and magnetic resonance imaging features in WHO grade II and III oligodendroglial tumors.
Authors: Toulgoat Frederique , Arrigoni Pierre Paul , Loussouarn Delphine , Leux Christophe , Frenel Jean-Sebastien , Denis Marc G. , Le loupp Anne-Gaelle , Aumont Maud , Campone Mario , Martin Stephane , Desal Hubert
Published: March 2020

2082

Background: In gliomas, relationship between radiological characteristics and several biomarkers was the subject of numerous publications. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been identified recently to play a key role in these tumors occuring in up to 75% of low-grade diffuse (WHO grade II) and anaplastic (WHO grade III) astrocytic, oligodendroglial and mixed oligodendroglial neoplasms. However, the correlation with magnetic resonance imaging (MRI) features has been little studied. Methods: Patients treated for WHO grade II and III oligodendroglial tumors between 2005 and 2011 were retrospectively identified. Each case has been reviewed by the same neuropathologist. IDH1 and IDH2 mutations were available. Preoperative MRI, including T1 weighted, T2 weighted, T1 contrast enhanced, FLAIR, T2* weighted, diffusion weighted (ADC ratio), perfusion weighted (CBV ratio) and MR spectroscopy, were analyzed by two radiologists blinded from molecular data. Logistic regression analysis and Fisher’s test were used to develop predictive models of genetic profile from imaging. Results: Sixty eight patients, WHO grade II (n= 37) and grade III (n=31) patients were identified. Mean age at diagnosis was 46 years; ratio male/female was 40/28. IDH1 mutations were identified in 42 patients (62 %), IDH2 in 4 patients (6 %). Analysis of tumor location, size, borders, morphological aspect, and signal did not shown any significant difference between IDH1 mutated group and IDH1 non mutated group neither in grade II nor in grade III oligodendroglial tumors. In the same way, MR spectroscopy (Choline/NAA ratio and detection of lipid and lactate) was not relevant to discern the two groups. As well, ADC ratio (1,5 versus 1,4; p=0,35) and CBV ratio (3,4 versus 4,2; p= 0,46) did not reveal any difference between mutated group and non mutated group. Conclusions: In our study, IDH1 mutations were not correlated with MRI features available during routine MRI. Nevertheless, recent studies suggest the ability of MR spectroscopy to detect 2-hydroxyglutarate as an MRI marker of IDH1 mutated tumors, which encourage carrying on research in molecular imaging.
The final report of a phase I trial of surgical resection with biodegradable carmustine (BCNU) wafer placement followed by vaccination with dendritic cells pulsed with tumor lysate for patients with glioblastoma.
Authors: Rudnick Jeremy , Hu Jethro Lisien , Luptrawan Anne , Mazer Mia , Wheeler Chris , Nuno Miriam , Chu Ray M , Phuphanich Surasak , Black Keith L. , Yu John
Published: March 2020

2084

Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers and have a modest impact to extend overall survival. We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu, and this is a presentation of the final results of our clinical trial. Methods: Patients with glioblastoma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis was used to isolate mononuclear cells which were differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Twenty three patient with glioblastoma received therapy including 8 with newly diagnosed disease (35%) and 15 with recurrent disease (65%) were evaluable. Immune response data is available for 20/23 patients although survival data is present for all. One grade 3 SAE of fever and chills was noted otherwise therapy was well tolerated. Within the newly diagnosed GBM cohort the median overall survival (OS) was 25.5 months (15,31+), and within the recurrent GBM cohort, the median OS was 16 months (8,23+). Among the recurrent GBM an increase of >1.5 X baseline interferon gamma production post vaccination was associated with a prolonged median OS 22 months (8,40) in 4/12 patients versus 17 months (9,27) in 8/12 patients. Conclusions: We were able to generate an immune response in 25% of patients which is lower than what we have seen in previous trials and suggests a limited synergy with local control. However, within the recurrent GBM cohort we did find prolonged survival in both groups with an increased survival noted in immune responders demonstrating the potential for this therapy.
Phase II study of bevacizumab plus irinotecan and carboplatin for recurrent WHO grade 3 malignant gliomas with no prior bevacizumab failure.
Authors: Desjardins Annick , Vredenburgh James J , Peters Katherine B. , Threatt Stevie , Herndon James Emmett , Sampson John Howard , Friedman Allan H. , Friedman Henry S. , Reardon David A.
Published: March 2020

2095^

Background: No standard treatment exists for recurrent WHO grade 3 malignant glioma patients. Bevacizumab (BV) with irinotecan has significant anti-tumor activity for recurrent glioblastoma. Carboplatin has anti-glioma activity and can potentiate the cytotoxicity of irinotecan. We evaluated the progression-free survival (PFS) of BV in combination to irinotecan and carboplatin in recurrent WHO grade 3 malignant gliomas, as well as its safety. Methods: Adult patients with measurable recurrent WHO grade 3 malignant glioma, ≥12 weeks after radiation therapy, ≥4 weeks after chemotherapy, with adequate organ function, KPS ≥70%, no prior failure or grade ≥3 toxicity to the agents, and no contraindications to BV were eligible for study. Patients received BV at 10 mg/kg with irinotecan on days 1 and 15 of a 28-day cycle. The dose of irinotecan was 125 mg/m2 for patients not on enzyme inducing anti-epileptics (EIAEDs) and 340 mg/m2 for patients on EIAEDs. All patients received carboplatin at an AUC of 4 on day 1 of each cycle. MRIs were obtained every 8 weeks. Results: As planned, 39 WHO grade III malignant glioma patients were enrolled on study. Median age was 47 (range, 26-71). At a median follow up of 14 months, the 6-month PFS is 69% and the median PFS is 11 months. A median of 8 cycles were given. Seven patients completed the planned course of treatment (12 cycles) with hypometabolic PET scan and nine patients remain on study. Fifteen patients came off study due to disease progression and eight due to toxicity. As of 1/25/2012, 22 patients are still alive and 17 have died. Grade 3-4 toxicities included: neutropenia (grade 3, n=12; grade 4, n= 1), thrombocytopenia (grade 3, n=6; grade 4, n=4), nausea (grade 3, n=7), diarrhea (grade 3, n=2), deep venous thrombosis (grade 3, n=2), febrile neutropenia (grade 3, n=1; grade 4, n=1), fatigue (grade 3, n=8; grade 4, n=1), cerebral infarction (grade 4, n=3), intracranial hemorrhage (grade 4, n=1), posterior reversible encephalopathy syndrome (grade 3, n=1). Conclusions: The combination of bevacizumab, irinotecan and carboplatin for WHO grade 3 malignant glioma patients is effective and with no more than expected toxicity.
Prognostic nomogram in elderly patients with glioblastoma.
Authors: Patel Mital , Hashemi-Sadraei Neda , Elson Paul , Ahluwalia Manmeet Singh
Published: March 2020

2096

Background: Glioblastoma (GBM) is the most common malignant primary brain tumor. More than half the cases occur in patients aged ≥65 years; however, there is limited data on specific prognostic factors in these patients and there is a lack of easy to use nomograms in elderly GBM patients to provide them prognostic information. Methods: The Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify elderly patients with GBM ( ≥65 years at the time of diagnosis). Multivariable analysis was conducted to identify independent predictors of survival using a Cox proportional hazards model and a stepwise selection algorithm with p=.10 as criteria for entry and retention. "Points" were assigned to each of these poor prognostic features and prognostic groups were formed based on the total number of calculated points. Results: 512 GBM patients with a median age of 73 years (range 65-96, 54% male) were included in the final analysis. On multivariable analysis six factors were identified as having an independent impact on overall survival after controlling for non-surgical treatment related factors like chemotherapy and radiation: age at diagnosis (p<.0001), surgery (p< .0001), multifocal disease (p=.0008), seizure at presentation (p=.02), hypertension (p=.05) and Karnofsky Performance Status (p<.0001). Prognostic groups were developed as summarized in the table. 28% of the patients had the most favorable profile which was associated with 56% one year survival and a 13.2 months median survival. In contrast, almost all patients in the least favorable group (27%) died within one year. Conclusions: This is an easy to use nomogram in elderly GBM patients to provide them prognostic information. [Table: see text]
Primary CNS lymphoma: A review of clinicopathologic characteristics, therapy, and outcomes of 54 patients with primary CNS DLBCL.
Authors: Hasija Nalini , Jaglal Michael , Duong Vu , Bello Celeste M. , Tomblyn Michael B. , Forsyth Peter A. J. , Sotomayor Eduardo M. , Pan Edward , Sokol Lubomir
Published: March 2020

2099

Background: Primary central nervous system lymphoma (PCNSL) is a rare aggressive variant of diffuse large B cell lymphoma (DLBCL) with a poor prognosis. Optimal therapeutic strategies have not yet been defined. High dose methotrexate (HD MTX) is an effective chemotherapeutic agent with superior outcomes compared to historical studies using whole brain radiation therapy (WBRT). Purpose: To review clinicopathologic characteristics, therapy and outcomes of 54 patients (pts) with primary CNS DLBCL. Methods: This was a single center retrospective review of pts with confirmed diagnosis of primary CNS DLBCL from 1999 to 2009. Data was extracted from the Moffitt Cancer Center (MCC) electronic records. Baseline demographics, clinical, pathological and treatment data were collected and analyzed. Pts were stratified according to their treatment regimens including HD MTX (8g/m2) alone or in combinations and WBRT alone or in combination with CT. Descriptive statistical analyses were utilized. Chi square analysis and t- test were performed to compare categorical and continuous variables. Kaplan-Meier method was used to estimate OS and log rank test was used to compare the groups. All data was analyzed using SPSS version 20.0 statistical software. Results: 54 pts who underwent CT and/or WBRT for PCNSL between 1999 and 2009 were identified. The age range at diagnosis was 19-85 years with median age of 63. 31 of 54 pts (57%) were ≥ 60 years old. Male to female ratio was 1.25 :1 (30:24). The median ECOG PS was 1. Only 2 pts had HIV. A majority of pts presented with motor deficits. The most common location of lymphoma was in the cerebral hemispheres. The median survival of the entire cohort was 42 months. 15 of 54 pts (23%) survived ≥ 60 months. In the cohort of pts that survived ≥ 60 months, a majority 11 of 15 (73%) received HD MTX. Pts treated with initial WBRT revealed inferior overall survival (OS) compared to pts treated with induction CT (OS 37 months vs. 50 months) (p=0.056). Conclusions: HD MTX was the most frequently utilized CT regimen in the cohort of pts surviving > 60 months. Administering WBRT as an initial modality was associated with worse outcomes in this retrospective analysis.
Phase IB study on combined intradermal (ID) and intravenous (IV) administration of autologous mRNA electroporated dendritic cells (DC) as a single-agent cellular immunotherapy or combined with ipilimumab.
Authors: Neyns Bart , Wilgenhof Sofie , Van Nuffel An M. T. , Benteyn Daphné , Corthals Jurgen , Heirman Carlo , Aerts Cindy , Van Riet Ivan , Bonehill Aude , Thielemans Kris
Published: March 2020

2507

Background: Autologous monocyte-derived DC electroporated with synthetic mRNA encoding CD40 ligand, a constitutively active TLR4, and CD70 (TriMix-DC) have superior T-cell stimulatory capacity. In a pilot clinical trial, ID administration of TriMixDC-MEL (a mixture of TriMix-DC co-electroporated with mRNA encoding a fusion of DC.LAMP and 1 of 4 melanoma associated antigens) was immunogenic but resulted in limited anti-tumor activity in patients (pts) with advanced melanoma. Ipilimumab (IPI) is a CTLA-4 blocking mAb with established activity in pts with advanced melanoma. Methods: TriMixDC-MEL by the IV and ID-route was investigated as a single-agent or in combination with IPI (10 mg/kg q3wks x4, allowing for maintenance with IPI-alone q12wks in pts PFS at >24 wks). Ratio of ID/IV administered DC: Cohort-1: 20.106/4.106 DC [2pts], -2: 12.106/12.106 DC [3pts], -3: 4.106/20.106 [6pts], and -4: 0/24.106 DC [4pts]; DC were administered 4x q2w, and a 5th administration on w16. in cohort-5, DC (4.106-ID/20.106-IV) were first administered alone and 2w thereafter in combination with IPI for a total of 4 administrations [6pts]. Results: Local skin reactions (gr1-2) were observed in all pts receiving DC ID, flu-like symptoms (< gr2) were observed in 12/21 pts, post IV-infusion chills (gr2) in 7/21 pts. Cytokines release (including a >2-fold rise in the serum levels of IL-1RA, IL-6, IL-8, IL-17, G-CSF, IFN-g, MIP-1a, MIP-1b, TNF-a) was documented during chills. Best objective tumor response: 2x PR + 2x CR (by RECIST) out of 15 pts (27%) treated with DC-only (ongoing after 10+, 14+, 19+, and 20+ mths) and 3 PR out of 6 pts (all stage IV-M1c) treated with DC+IPI (ongoing after 5+, 5+, 6+ mths). Conclusions: ID/IV-administration of TriMixDC-MEL as a single-agent cellular immunotherapy or combined with IPI is associated with distinct but manageable side-effects and has clinical activity against pretreated advanced melanoma. Activity compares favorably with TriMixDC-MEL by ID-administration-only. Combined ID/IV administration of TriMixDC-MEL with IPI is currently under further evaluation in a phase II trial.
Interim analysis of a phase II randomized clinical trial of samrium-153 (Sm-153) with or without PSA-TRICOM vaccine in metastatic castration-resistant prostate cancer after docetaxel.
Authors: Heery Christopher Ryan , Madan Ravi A. , Bilusic Marijo , Kim Joseph W. , Singh Nishith K. , Rauckhorst Myrna , Chen Clara , Dahut William L. , Stadler Walter Michael , DiPaola Robert S. , Stein Mark N. , Hodge James W. , Schlom Jeffrey , Gulley James L.
Published: March 2020

2526

Background: A prior randomized, placebo-controlled, multi-center phase 2 trial of PSA-TRICOM (PROSTVAC) demonstrated an overall survival benefit. Sm-153 is a radiopharmaceutical that targets osteoblastic bone lesions. Preclinical data indicated that Sm-153 could alter tumor phenotype, causing upregulation of Fas, MHC Class I, and tumor-associated antigens, making tumor cells more amenable to immune-mediated killing. Methods: This is a phase 2 multi-center trial design intended to randomize 68 patients (pts) to Sm-153 with or without PROSTVAC. Eligibility included castrate resistant prostate cancer bone metastases, no visceral disease, prior docetaxel, ECOG ≤2, and normal organ function. Sm-153 was given at 1mCi/kg IV on day 8 and then every 12 weeks. PROSTVAC was given on days 1, 15, 29, then every 4 weeks. The 1° endpoint is a comparison of progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA criteria. 68 patients will provide 80% power to detect a difference of 15% vs. 40% without progression at 4 mo with a one-tailed alpha = 0.10 assuming Fisher’s exact test comparing these fractions as the primary method of analysis. 2° endpoints are OS, ORR, PSA changes, immunologic, toxicity, and palliation. Reported here is the result of a pre-specified interim analysis, which required ≥20% conditional power to detect 15% vs. 40% without progression at 4 months for the trial to continue. Results: Of 37 enrolled pts, 3 were not evaluable for PFS. PFS and PSA findings are found below. Hematologic toxicities (anemia, thrombocytopenia, neutropenia, or lymphocytopenia) are most common, with grade 3 or 4 thrombocytopenia occurring in 22% and 26% of treatment cycles on Arms A and B, respectively. The conditional power for the comparison of fractions without progression at 4 mo is 77%. Conclusions: This interim analysis suggests the combination of PROSTVAC and Sm-153 is well tolerated with similar toxicity profile to Sm-153 alone. The early indication of improved TTP warrants continued study accrual. [Table: see text]
Response to epidermal growth factor vaccine in patients with metastatic non-small cell lung cancer (NSCLC) after progressing to first-line therapy.
Authors: Venegas Diego , Neninger Elia , Iberico Carlos , Oliva Claudia , Alarcon-Rozas Ashley E. , Lozada Claudia Patricia , Galvez Jose , Gonzalez Gisela
Published: March 2020

2531

Background: A direct correlation between anti–epidermal growth factor (EGF)antibody titers and survival was demonstrated in vaccinated patients with novel NSCLC advanced in Phase II studies. We show the results of treatment with anti-EGF vaccine in a cohort of patients with metastatic NSCLC after progressing to first line therapy. We evaluated immunogenicity, safety, treatment response and effect on survival. Methods: 12 patients with metastatic NSCLC after progressing to first-line therapy received anti EGF-vaccine alone or in combination with chemotherapy. Results: From October 2009 until August 2011, 12 patients started treatment with anti EGF vaccine; mean age 56.5 (42-79 y); 66.7% male; ECOG 0 and 1: 41.7% and 58,3% respectively. Adenocarcinoma (50%), bronchioloalveolar (33.3%), adenosquamous (16.7%). Metastatic sites: lung (41.7%), pleura (25%), CNS (16.7%), Kidney (8.3%). In addition to chemotherapy previous used: radiotherapy (50%), surgery (41.7%), erlotinib (41.7%), bevacizumab (25%). The 50% patients received vaccine alone. The 83.3% of patients had titers 1/4000 sera dilutions or more (good responders). According to RECIST 1.1: CR: 8.3%, PR: 16.7%, SD: 41.7%, PD 25%. Median overall survival was 18.8 months (95% CI: 13.3- 24.4 m). Median progression-free survival was 7.3 months (95% CI: 6.4 -8.2 m). We found no statistically significant differences in OS and PFS when comparing vaccine alone or combined (p = 0.181 and p = 0.801). 75% of patients had adverse effect: more frequently were: 42.4% application site pain, 15.1% fever and 10.38% chills, none of them serious. Conclusions: Vaccination anti EGF in patients with metastatic NSCLC after progressing to first line, alone or in combination, was safe and provoked an increase in anti-EGF antibody titers, produced clinical benefit, improved overall survival and progression free survival.
Effect of age on the pharmacokinetics of busulfan (Bu): An alliance study.
Authors: Beumer Jan Hendrik , Lewis Lionel D. , Owzar Kouros , Jiang Chen , Holleran Julianne L. , Christner Susan M. , Blum William G. , Devine Steven M , Kolitz Jonathan E. , Linker Charles A. , Larson Richard A. , Ratain Mark J. , Egorin Merrill J.
Published: March 2020

2533

Background: Older acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients (pts) have been excluded from myeloablative regimens including agents such as busulfan because of the potential for non-disease related morbidity and mortality. Busulfan, often used as part of myeloablative regimens, is cleared in part by glutathione–S-transferase and CYP3A4. We hypothesized that busulfan clearance (BuCL) in the elderly (> 60 years) would be reduced compared to that in young patients (< 60 years), thus potentially explaining differences in tolerability. Methods: AML and MDS pts in three CALGB bone marrow transplant studies across a wide age range (17-74) were treated with a conditioning regimen using IV busulfan, dosed at 12.8 mg/m2 in CALGB studies 10503 and 19808 and 6.4 mg/m2 in CALGB 100103. Blood samples were collected for determination of busulfan plasma pharmacokinetics (PK). Plasma busulfan was quantitated by LC-MS. BuCL was determined using non-compartmental modeling, and normalized to actual (ABW), ideal (IBW) and corrected (CBW) body weight (kg). Differences between age groups were examined using the Wilcoxon rank sum test. Results: A total of 185 pts were accrued and signed consent, of which 174 provided useable PK data. Twenty-nine pts ≥60 years old (median age 66.3) had a significantly higher mean BuCL vs those < 60 years old (median age 49.8); BuCL 263 vs 186 mL/min, p=0.0002; BuCL/ABW 3.22 vs 2.34 mL/min/kg, p=0.0001; BuCL/IBW 3.63 vs 2.91 mL/min/kg, p=0.0035; BuCL/CBW 3.50 vs 2.70 mL/min/kg, p=0.0005. Inter-patient variability in clearance (CV%) was up to 47% in the elderly and up to 48% in young patients. Phenytoin use, a potential confounder, did not affect BuCL, regardless of weight normalization (p=0.74). Conclusions: Contrary to our hypothesis, BuCL is significantly higher in pts ≥60 years old compared to younger patients and does not explain the previously reported increase in Bu toxicity observed in the elderly.