bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurocognitive function (NCF) outcomes in patients with glioblastoma (GBM) enrolled in RTOG 0825.
Authors: Wefel Jeffrey Scott , Pugh Stephanie L. , Armstrong Terri S. , Gilbert Mark R. , Won Minhee , Wendland Merideth M , Brachman David , Komaki Ritsuko , Crocker Ian R. , Robins H. Ian , Lee R. Jeffrey , Mehta Minesh P. 
Published: March 2020

2004 Background: RTOG 0825 evaluated overall survival (OS) and progression-free survival (PFS) differences in patients with newly diagnosed GBM treated with standard chemoradiation, maintenance temozolomide and placebo (Arm 1) or bevacizumab (Arm 2). While OS was equivalent, PFS was longer in Arm 2. Longitudinal NCF testing was performed to evaluate clinical benefit. Methods: NCF was evaluatedat baseline and while on study and progression free with the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT) and Controlled Oral Word Association (COWA). Change in NCF from baseline was categorized using the reliable change index. Differences between treatment arms were compared at follow-up evaluations. Additionally, baseline (B) and early changes (EC) (B to week 10) in NCF were examined as prognostic factors. Results: 542 patients consented and 507 randomized patients participated, with test completion rates at weeks 0 (B), 10, 22, and 34 of 94-97, 69-73, 59-64, and 53-58%, respectively. Mean test performance at B was equivalent between arms and ranged from -0.8 to -4.8 SDs below healthy population norms with global NCF on a composite variable at -2.0 SDs. There were no statistically significant between arm differences in frequency of improvement through week 34. Decline on COWA (verbal measure of executive function) at week 34 relative to baseline was more common (16.1 vs 5.7%) in patients in Arm 1 (p<0.05); whereas, there were trends for more decline in Arm 2 on a visuomotor measure of executive function (TMT B, p< 0.06; 22.2 vs 35.4%). B performance and EC in global NCF, memory, executive function and processing speed were prognostic for OS. At B, global NCF was prognostic for PFS. EC in global NCF, memory and executive function were prognostic for PFS. Conclusions: There was a statistically significant difference in the frequency of decline on a verbal test of executive function at week 34 favoring Arm 2. However, this was not found at earlier time points and was not found on a visuomotor test of executive function. B and EC in NCF were prognostic for OS and PFS. Longitudinal modeling is ongoing to further evaluate the impact of treatment on patients’ NCF. Support: U10 CA21661, U10 CA37422 and Genentech, Inc. Clinical trial information: NCI-2009-01670.
Temozolomide chemotherapy versus radiotherapy in molecularly characterized (1p loss) low-grade glioma: A randomized phase III intergroup study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033).
Authors: Baumert Brigitta G , Mason Warren P. , Ryan Gail , Bromberg Jacoline E , Van Den Bent Martin J. , Hoang-Xuan Khê , Brandes Alba Ariela , Kantor Guy , Taphoorn Martin JB , Ben Hassel Mohamed , Rees Jeremy , Wick Wolfgang , Von Deimling Andreas , Hartmann Christian , Kros Johan M , Hegi Monika E. , Dif Nicolas , Lacombe Denis A. , Gorlia Thierry , Stupp Roger 
Published: March 2020

2007 Background: Outcome of low-grade glioma (LGG) is highly variable. We investigated whether primary chemotherapy in comparison to standard radiotherapy (RT) prolongs progression-free (PFS) and overall survival (OS), and whether prognostic molecular factors could be defined. Methods: Progressive, symptomatic or high-risk patients with a LGG requiring treatment other than surgery were randomized (after stratification for 1p-status) to either conformal RT (50.4 Gy/28 fractions) or dose-dense temozolomide [TMZ] (75 mg/m² daily x 21 days, q28 days, max. 12 cycles). Primary endpoint was PFS, secondary analyses included OS and impact of 1p status. Results: 477 patients were randomized (2005-2012, median FU 45.5 months). Analysis was performed after 246 progression events. Hematological toxicity ≥ grade 3 was observed in 9.4% of TMZ patients. PFS was not significantly different, median OS not reached. 1p deletion was a positive prognostic factor irrespective of treatment (p-value stratified by treatment (PFS: 0.0003;HR=0.59 95% CI(0.45-0.78)/OS: 0.002;HR=0.49 95% CI (0.32-0.77)). Conclusions: First-line treatment with TMZ compared to RT did not improve PFS in high-risk LGG patients. Although interaction test was not significant, there was a trend for inferior PFS in patients treated by TMZ with 1p intact, while OS may be better when 1p-deleted patients receive TMZ upfront. Survival analysis requires further maturation of the data. Clinical trial information: EudraCT number 2004-002714-11. [Table: see text]
A phase II study of a temozolomide-based chemoradiotherapy regimen for high-risk low-grade gliomas: Preliminary results of RTOG 0424.
Authors: Fisher Barbara Jean , Lui Jeff , Macdonald David R. , Lesser Glenn Jay , Coons Stephen , Brachman David , Ryu Samuel , Werner-Wasik Maria , Bahary Jean-Paul , Hu Chen , Mehta Minesh P. ,   Radiation Therapy Oncology Group
Published: March 2020

2008 Background: The primary endpoint of RTOG 0424 was to compare the 3-year survival (OS) of a regimen of concurrent and adjuvant temozolomide (TMZ) and radiotherapy (RT) in a high-risk low-grade glioma (LGG) population to the 3 year (yr) OS rate of the high risk EORTC LGG patients (pts) reported by Pignatti et al (J Clin Oncol 2002;20(8):2076-84). Secondary endpoints were: progression-free survival (PFS), toxicity, neurocognitive and quality of life data and molecular analysis. Methods: Pts with LGG's and >=3 high risk factors (age> = 40, astrocytoma dominant histology, tumor crossing midline, tumor > = 6 cm or preoperative neurological function status >1) were eligible and treated with conformal RT (54 Gy/30 fractions) plus concurrent TMZ 75 mg/m2 /day for 6 weeks and post-RT TMZ 150-200 mg/m2/day days 1-5 q28 days for up to 12 cycles. The study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months, and a 20% improvement in 3 yr OS rate from 54% to 65%, at a 10% significance level (1 sided) and 96% power. Results: Between January 2005-August 2009 136 pts were accrued, 129 (75 males, 54 females) were evaluable. Median age was 49 years, 91% had a Zubrod score 0-1 and 69%, 25% and 6% of pts had 3,4 and 5 high risk factors respectively. With a median follow-up time of 4.1 yrs, minimum follow-up of 3 yrs, MST has not yet been reached. Three year OS rate was 73.1% (95%CI:65.3-80.8%), significantly improved from historical control with a p-value <0.0001. No difference in OS rates for pts with 3, 4 or 5 high risk factors was seen. 3 year PFS was 59.2% (95% CI:50.7-67.8%). Grade 3 adverse events (AE) occurred in 43% of pts and grade 4 AE in 10%, primarily hematologic, constitutional or gastrointestinal (nausea, anorexia) toxicity. One patient died of herpes encephalitis. Secondary analyses are ongoing. Radiation Quality Assurance was per protocol/ acceptable in 95% and 74% of pts completed chemotherapy per protocol. Conclusions: The 3 year OS rate of 73.1% for these high risk LGG pts is significantly higher than those reported for historical controls (54%, p < 0.0001, one-sided) and the study-hypothesized 65%. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI and Merck Clinical trial information: NCT00114140.
Temozolomide plus bevacizumab in elderly patients with newly diagnosed glioblastoma and poor performance status: An Anocef phase II trial.
Authors: Reyes-Botero German , Honnorat Jerôme , Chinot Oliver L. , Taillandier Luc , Catry-Thomas Isabelle , Barriere Jerome , Guillamo Jean Sebastien , Fabbro Michel , Frappaz Didier , Benouaich Amiel Alexandra , Le Rhun Emilie , Campello Chantal , Tennevet Isabelle , Ghiringhelli François , Tanguy Marie-Laure , Mokhtari Karima , Delattre Jean-Yves ,   ANOCEF: Association des Neuro-Oncologues d'Expression Française
Published: March 2020

2020 Background: The optimal treatment of glioblastoma multiforme (GBM) in elderly patients (age ≥70 years) with impaired functional status (Karnofsky performance status, KPS<70) remains to be established. A previous study using temozolomide (TMZ) alone suggested an increase in median overall survival (OS) compared to supportive care (25 weeks vs. 12-16 weeks, respectively). Median progression-free survival (PFS) was 16 weeks and 26% of patients became transiently capable of self-care (IK>70) (J Clin Oncol. 2011; 29: 3050-5). The present clinical trial evaluated the efficacy and safety of the combination of TMZ with bevacizumab (BV) as an initial treatment for elderly patients with GBM and KPS<70. Methods: Patients aged ≥ 70 years with KPS < 70 and a newly supratentorial GBM diagnosed by biopsy were eligible for this multicentric, prospective and non-randomised phase II trial. The primary endpoint was the OS and secondary endpoints included median PFS, quality of life, safety and cognition. Treatment consisted of TMZ 130-150 mgs/m2/d for 5 days every 4 weeks plus BV 10mgs/kg every 2 weeks, until 12 cycles or tumoral progression. Neither surgical resection nor radiotherapy was performed. Follow-up included clinical assessment every 2 weeks and brain MRI every 8 weeks. Results: Between October 2010 and March 2012, 66 patients (median age, 77 years; median KPS, 60) were enrolled. Median OS was 24 weeks (95% CI, 19-27.6) and median PFS was 16 weeks (95% CI, 13.1–19.3). Twenty-five patients (38%) became transiently capable of self-care (IK>70). Grade 3 and 4 haematological toxicity occurred in 13(19.6%) cases, whereas non-haematological toxicities were reported in 21(32%), including high blood pressure in 7(10%), thromboembolic events in 3(4.5%), intracerebral haemorrhage in 2(3%) and intestinal perforation in 2(3%) cases. Conclusions: This study confirms that TMZ-based treatment is of help in elderly GBM patients with poor KPS. However, the addition of bevacizumab does not appear to be of benefit in term of PFS and OS.
Long-term survival in primary glioblastoma revisited: The contribution of isocitrate dehydrogenase mutations.
Authors: Weller Michael , Hentschel Bettina , Simon Matthias , Westphal Manfred , Schackert Gabriele , Tonn Joerg Christian , Loeffler Markus , Reifenberger Guido , Pietsch Torsten , von Deimling Andreas , Hartmann Christian ,   German Glioma Network
Published: March 2020

2027 Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival > 36 months (LTS-36), including 33 patients surviving > 60 months (LTS-60), with 259 patients surviving < 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.
Association of VEGFA SNP rs2010963 with prognosis and prediction of vascular toxicity of bevacizumab in recurrent glioblastomas.
Authors: Di Stefano Anna Luisa , Lombardi Giuseppe , Gallego Perez-Larraya Jaime , Boisselier Blandine , Labussiere Marianne , Ducray Francois , Zagonel Vittorina , Cheneau Caroline , Delattre Jean-Yves , Sanson Marc 
Published: March 2020

2028 Background: VEGFA has become an attractive target in high grade gliomas but there is no predictor of response or toxicity to anti-VEGF therapy. We investigated here the association between functional single nucleotide polymorphism (SNP) +405 G>C (rs2010963), located in 5’ untranslated terminal region of VEGFA gene, survival, response to bevacizumab (BVZ), and vascular toxicity. Methods: The rs2010963 was analyzed in blood DNA using a Taqman SNP Genotyping Assay and confronted to Progression Free Survival (PFS), Overall Survival (OS) in the general population of gliomas, and -for the glioblastomas (GBM) treated with BVZ at recurrence- with Response, PFS, and thrombo-hemorragic events. Results: In the general population of 954 gliomas stratified per grade (362 grade 2, 269 grade 3, 323 grade 4) there was no association between rs2010963 and OS or PFS. In the population of 123 recurrent GBM treated with BVZ, we observed a favourable trend in PFS associated with the C allele of rs2010963 (5.4 vs 4.2 months, p = 0.07). Most importantly the CC genotype was associated with the occurrence of thrombo-hemorragic events (6/16 vs 2/107 in CG+GG, p <0.0001). Conclusions: Our data suggest that rs2010963 status has not prognostic significance in gliomas, but is associated with vascular events in recurrent GBM treated with BVZ. The impact of rs2010963 on response to BVZ needs to be further investigated.
High-dose methotrexate with and without rituximab for the treatment of newly diagnosed primary CNS lymphoma: Johns Hopkins Hospital experience.
Authors: Holdhoff Matthias , Sarai Guneet , Abdelaziz Ahmed , Bonekamp David , Grossman Stuart A. , Ye Xiaobu 
Published: March 2020

2034 Background: The current institutional standard for treatment of patients with newly-diagnosed primary CNS lymphomas (PCNSL) at Johns Hopkins Hospital (JHH) consists of treatment with high-dose methotrexate plus rituximab (hd-MTX/R) every 2 weeks until complete response (CR), progression or unacceptable toxicities. Once CR is achieved, this is followed by monthly treatments for a total of up to one year for consolidation. Prior to 2008, the institutional standard had been treatment with hd-MTX alone. The benefit of adding rituximab to hd-MTX has not been formally evaluated. Methods: This is a retrospective study of HIV-negative adult patients with newly-diagnosed PCNSL treated at JHH with either hd-MTX or hd-MTX/R as initial therapy. Patients were identified using the cancer center registry (1995-2012) and were included if they had received at least one cycle of therapy (intention-to-treat). Primary objectives were CR rate (patients with sufficient imaging data; centrally reviewed) and overall survival (OS, all patients included). Results: A total of 81 patients were analyzed (median age of 65 yrs; 52% male). 54 patients received hd-MTX alone (median age, 65 yrs) and 27 patients received hd-MTX/R (median age, 66 yrs). 37 and 24 patients in the two groups were evaluable for response, respectively. Among these, the CR rate was 51% in patients treated with hd-MTX alone (overall response rate, ORR, 76%) and 79% in patients treated with hd-MTX/R (ORR 96%). The median number of cycles to CR was 5 and 4.5, respectively. Median OS among all patients (both groups combined) was 26 months (95% CI: 11-44). Conclusions: These data show potential clinical benefit from the addition of rituximab to hd-MTX for newly diagnosed patients with PCNSL based on a higher CR rate. Analysis of OS benefit between patients treated with hd-MTX and hd-MTX/R is pending maturation of further survival data.
A prospective phase II study to determine the efficacy of GDC 0449 (vismodegib) in adults with recurrent medulloblastoma (MB): A Pediatric Brain Tumor Consortium study (PBTC 25B).
Authors: Gajjar Amar J. , Gururangan Sridharan , Qaddoumi Ibrahim A , Packer Roger , Goldman Stewart , Prados Michael , Desjardins Annick , Fouladi Maryam , Takebe Naoko , Li Shaoyi , Ellison David W. , Curran Tom , Gilbertson Richard J. , Boyett James M. 
Published: March 2020

2035 Background: Almost 80% of adult medulloblastoma are of the SHH subtype. Second line therapy for adult MB is limited; therefore we tested the efficacy of vismodegib, a small molecule inhibitor of Smoothened (SMO) among patients with this disease. Methods: Adult patients with refractory or recurrent MB and who had measureable disease were enrolled on the study. Immunohistochemistry (IHC) was used to stratify patients to Stratum A (non-SHH group); Stratum B (SHH tumors) and Stratum C (indeterminate). All patients were treated with vismodegib at 150 mg/day PO daily. Tumor response, which had to be maintained for 8 weeks to meet protocol definition of sustained response, was assessed using RECIST criteria and central imaging review. Separate but identical Simon 2-stage MinMax designs (α = 0.10) were used in strata A and B to test for evidence that sustained response rates exceeded 5% with 90% power to detect 25% sustained response rates. Thus, 3/20 sustained responses were needed to declare potential activity of vismodegib. Results: 32 patients with a median age of 30 years (range 22.4-51.9) were enrolled on the study [Stratum A (n = 8); Stratum B (n = 20); Stratum C (n = 4)], including 18 males and 14 females. No responses were observed in Strata A or C and the median duration of treatment was 1.5 months (range 0.66-2.33). Three of 20 patients enrolled on Stratum B had sustained responses. The median duration of therapy for Stratum B patients was 2.76 months (range 0.33- 13.61). Six patients were on treatment for ≥6.44 months and 3 remain on treatment after 5.42, 9.34 and 13.61 months. During course 1, 2 patients experienced grade 3 decrease in lymphocytes; 1 experienced a grade 4 thromboembolic event; and 2 experienced grade 3 toxicities (back pain & syncope). During course 2, 3 patients experienced grade 3 toxicities (decrease in lymphocytes; myalgia & seizure). One other patient experienced grade 3 hypophosphatemia in courses 1 and 2. Conclusions: Vismodegib has activity against recurrent or refractory adult ‘SHH-subtype’ medulloblastoma and should be considered as a therapeutic option for newly diagnosed patients with this disease. Clinical trial information: NCT00939484.
A phase I clinical trial of veliparib and temozolomide in children with recurrent central nervous system tumors: A Pediatric Brain Tumor Consortium report.
Authors: Su Jack M. , Thompson Patrick Andrew , Adesina Adekunle , Li Xiao-Nan , Kilburn Lindsay Baker , Onar-Thomas Arzu , Kocak Mehmet , Chyla Brenda , McKeegan Evelyn Mary , Warren Katherine E. , Goldman Stewart , Pollack Ian , Fouladi Maryam , Chen Alice , Smith Malcolm A. , Giranda Vincent L. , Boyett James M. , Blaney Susan , Kun Larry E. ,   Pediatric Brain Tumor Consortium
Published: March 2020

2036 Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to: 1) estimate the maximum tolerated doses (MTD) or recommended phase II doses (RP2D) of veliparib and TMZ using the Continual Reassessment Method; 2) describe the toxicities of this regimen; and 3) evaluate plasma pharmacokinetics (PK) and peripheral blood mononuclear cell (PBMC) PARP inhibition after veliparib treatment. Methods: TMZ was given once daily and veliparib twice daily for 5 days, every 28 days. Five veliparib/TMZ dose levels were studied: 20/180; 15/180; 15/150; 20/135; and 25/135 mg/m2/dose, respectively. Baseline and serial veliparib PK samples were obtained on days 1 and 4. PBMC poly(ADP-ribose) (PAR) levels were also measured using an ELISA assay. A total of 12 subjects were enrolled at the RP2D. Results: Thirty-one patients (29 evaluable) with a median age of 7.0 years (range 1.3-19.8) were enrolled. Dose-limiting toxicities (DLT) included grade 4 neutropenia and thrombocytopenia at the 20/180 and 15/180 mg/m2/dose levels. Based on the toxicity profile, PKs and PBMC PAR results, the RP2D were veliparib, 25 mg/m2 BID, and TMZ, 135 mg/m2/day, for 5 days every 28 days. No objective responses were observed, although 4 subjects had SD > 6 months duration, including one patient each with glioblastoma multiforme, anaplastic ependymoma, pilocytic astrocytoma, and optic pathway glioma. At the veliparib RP2D, the PK parameters included: Cmax, 1.2 ± 0.7 µM; AUC0-12 hr, 1.53 ± 0.61 µg•hr/mL; and Cl/F, 173 ± ml/min/m2. PARP inhibition was observed in PBMC but did not correlate with veliparib dose levels. Conclusions: The combination of veliparib and TMZ was well tolerated in children with recurrent CNS tumors. Veliparib PK parameters at RP2D are similar to those in adults. PBMC PARP inhibition did not correlate with veliparib dose levels, perhaps due to the smaller number of patients at each dose level and the technical limitations of specimen collection/processing and the ELISA assay. A phase II trial of veliparib/TMZ in children with recurrent primary brain tumors is planned. Clinical trial information: NCT00946335.
Survival outcome of early versus delayed bevacizumab treatment in patients with recurrent glioblastoma.
Authors: Hamza Mohamed Ali , Mandel Jacob , Conrad Charles A. , Gilbert Mark R. , Yung W. K. Alfred , Puduvalli Vinay K. , De Groot John Frederick 
Published: March 2020

2042 Background: Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma (GB). Differences in outcome between early versus delayed BEV treatment of recurrent GB are not well defined. We examined the relationship between the time of start of BEV treatment and outcomes in patients with recurrent GB. Methods: In this retrospective chart review derived from our longitudinal database, we identified patients with recurrent GB between 2001 and 2011, who were treated with BEV alone or BEV-containing regimens. Data was analyzed to determine overall survival (OS) from time of diagnosis and progression free survival (PFS) from time of BEV start. Early BEV was defined as start of BEV treatment at first recurrence, while delayed BEV was defined as start of treatment at second recurrence or later. Results: A total of 298 patients with recurrent GB who received BEV were identified, of whom 149 patients received early BEV, 134 patients received delayed BEV, and 15 patients who were excluded because they received BEV upfront. There were no significant differences in the age, sex, performance status and extent of resection between patients treated with early BEV and those treated with delayed BEV. The median time from diagnosis to first recurrence was more than 6 months (mos.) for both groups (6.5 mos. for early BEV and 7.6 mos. for delayed BEV, p = 0.01). The median time from diagnosis to start of BEV was 7.9 mos. for patients with early BEV and 15.6 mos. for patients with delayed BEV (p<0.001). There was no significant difference in PFS between patients that received early BEV and those that received delayed BEV (5.73 mos. vs. 4.33 mos., p = 0.07). Patients who were treated with delayed BEV had longer OS when compared to those treated with early BEV (25.9 mos. vs. 19.7 mos., p = 0.0002). Conclusions: In patients with recurrent GB, there was no significant difference in PFS between early and delayed BEV; however, patients treated with delayed BEV have longer OS when compared to those treated with early BEV. These results indicate that delaying treatment with BEV is not detrimental and may be associated with a favorable survival outcome.