bluuebunny/crossref_metadata_2025 huggingface dataset:
Compliance of recommendations with French clinical practice in the management of thromboembolism in patients with cancer: The CARMEN study.
Authors: Sevestre Marie-Antoinette , Belizna Cristina , Durant Cecile , Vedrine Lionel , Desruennes Eric , Debourdeau Philippe , Bonnet Isabelle , Pernod Gilles , Stoppa Anne-Marie , Berremili Toufik , Connault Jerome , Kriegel Irene , Mahe Isabelle , Camuset Juliette , Barrellier marie-Therese , Gerotzafias Grigoris , Cajfinger Francis , Terriat Beatrice , Bosson Jean-Luc , Farge Dominique ,   Groupe Francophone Thrombose et Cancer
Published: March 2020

1580

Background: Long-term treatment with low-molecular-weight heparin (LMWH) is recommended for treatment of venous thromboembolism (VTE) in cancer patients. Few data are available on compliance in this population. Our study measured whether the management of VTE in patients with cancer was consistent with French recommendations. Methods: Compliance with recommendations (CR+) was analysed according to malignancy and VTE from a 500-patient cross-sectional observational study run between May and October 2010. CR+ was defined as the compliance to initial 10-day treatment followed by long-term LMWH for at least 3 months, avoiding LMWH in patients with renal insufficiency (SRI). All inpatients with a diagnosis of cancer and VTE of less than 6 months were included in the study. Results: Of 500 patients included in 47 centers, 242 (49%) were male, 81 (18%) had local (T+), 83 (18%) had loco-regional (N+) and 287 (64%) had metastatic malignancies. Malignancies were gastro-intestinal (25%), gynaecologic (23%), pulmonary (21%), haematological (14%), urologic (10%) or other (8%). Twelve patients had SRI. Overall, treatment was CR+ in 289/500 patients (58% [95% CI 53%-62%]). Out of 12 patients with SRI only 3 (25%) were treated long-term with vitamin K antagonists (VKA), as usually recommended. Tumour site influenced CR+ (p=0.02). Treatment for haematological malignancy was poorly compliant with recommendations (32%) while patients with lung malignancy had the best compliance (68%). TNM stage and VTE location had no influence on treatment compliance. Conclusions: In French practice, treatment of cancer-related VTE is CR+ in 58% of cases. TNM stage and VTE location do not influence compliance which remains insufficient, especially in patients with haematological malignancy. [Table: see text]
MGMT promoter methylation as a predictive biomarker for response to radiotherapy versus chemotherapy in malignant astrocytomas in the elderly: The NOA-08 trial.
Authors: Wick Wolfgang , Meisner Christoph , Platten Michael , Simon Matthias , Nikkhah Guido , Papsdorf Kirstin , Sabel Michael , Braun Christian , Reifenberger Guido , Weller Michael
Published: March 2020

2000

Background: In a few years more than half of the patients with glioblastoma will be older than 65 years of age and thus be classified as elderly. The current standard of care in elderly patients with glioblastoma (GB) or anapestic astrocytoma (AA) is resection or biopsy followed by involved-field radiotherapy (RT). The role of primary chemotherapy is poorly defined. The NOA-08 trial compared efficacy and safety of RT to temozolomide (TMZ) in patients with newly diagnosed AA or GB. Methods: Patients (N=412; 39 AA, 373 GB) > 65 years with a Karnofsky performance score > 60 were randomized to receive RT or TMZ. The primary endpoint was overall survival (OS). The trial sought to demonstrate the non-inferiority of TMZ compared with RT. Results: Patient characteristics in the intention-to-treat population [N=373 (178 patients RT, 195 patients TMZ)] were balanced. All histologic diagnoses (11% AA and 89% GB) were centrally confirmed. Median OS [HR=1.09 (95% CI: 0.84-1.42)] and event-free survival (EFS) [hazard ratio (HR)=1.15 (0.92-1.43)] of TMZ versus RT did not differ between both arms. Non-inferiority of TMZ compared with RT was significant (p<0.05). Extent of resection, but not age or diagnosis of AA were associated with prolonged EFS and OS. DNA repair protein O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation in tumor tissue was associated with prolonged OS [HR=0.67 (0.38-1.29)]. Patients with MGMT promoter methylation had longer EFS when treated with TMZ (8.4 months [5.5-11.7] versus RT (4.6 [4.2-5] months) whereas patients without MGMT promoter methylation had longer EFS when treated with RT (4.6 [3.7-6.3] versus 3.3 [3-3.5] months). This effect persisted for OS. Conclusions: NOA-08 demonstrates the non-inferiority of TMZ compared with RT in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ.
Chemotherapy plus radiotherapy (CT-RT) versus RT alone for patients with anaplastic oligodendroglioma: Long-term results of the RTOG 9402 phase III study.
Authors: Cairncross J. Gregory , Wang Meihua , Shaw Edward G. , Jenkins Robert B. , Scheithauer Bernd W. , Brachman David , Buckner Jan C. , Fink Karen L. , Souhami Luis , Laperriere Normand , Curran Walter J. , Mehta Minesh P.
Published: March 2020

2008b

Background: Anaplastic oligodendrogliomas, pure (AO) and mixed (AOA), are chemosensitive tumors, especially if co-deleted for chromosomes 1p and 19q, but whether addition of CT to RT prolongs overall survival (OS), is unknown. Methods: In the RTOG 9402 Phase III trial, patients (pts) with AO/AOA were randomly assigned to PCV [procarbazine, CCNU (lomustine) and vincristine] followed by immediate RT vs. immediate RT alone. Early analysis showed no OS benefit for the PCV+RT group but combined therapy was associated with a longer progression-free survival (PFS). It also showed that the finding of 1p/19q co-deletion was associated with a longer OS independent of treatment. The current analysis has a median follow up of 11.3 years (yrs). Results: Two hundred ninety-one patients were randomized, 148 to PCV+RT and 143 to RT. PCV+RT was associated with longer PFS [2.5 vs. 1.7 yrs, hazard ratio (HR) 0.68, 95% confidence interval (CI) (0.53, 0.88), P = 0.003] and the 1p/19q co-deletion with a longer Median Survival Time (MST) [8.7 vs. 2.7 yrs, HR 0.41, 95% CI (0.30, 0.55), P < 0.001]. For the entire cohort, there was no difference in MST by treatment [4.6 yrs for PCV+RT vs. 4.7 yrs for RT, HR 0.79, 95% CI (0.60, 1.04), P = 0.1]. However, patients with 1p/19q co-deleted tumors lived much longer after PCV+RT (n = 59) than after RT (n = 67) [14.7 vs. 7.3 yrs, HR 0.59, 95% CI (0.37, 0.95), P = 0.03]. There was no difference in MST by treatment in pts without the 1p/19q co-deletion [n=137; 2.6 vs. 2.7 yrs, HR 0.85, 95% CI (0.58, 1.23), P = 0.39]. Re-operation rates upon progression were similar between treatment arms in co-deleted pts (43%, PCV+RT vs. 54%, RT) but salvage CT rates were higher in the RT arm [57% vs. 81% (P = 0.04)]. Conclusions: PCV followed by immediate RT was a highly effective therapy for patients with 1p/19q co-deleted AO/AOA. In this setting, 1p/19q co-deletion was both prognostic and predictive, and the early PFS benefit in co-deleted cases was a harbinger of their longer OS. [This work was supported by RTOG grants U10 CA21661 and U10 CA32115, NCCTG grant U10 CA25224, ECOG grants CA17145 and CA21115, SWOG grant CA32102, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI)]
Phase II trial of sunitinib as adjuvant therapy after stereotactic radiosurgery (SRS) in patients with 1-3 newly diagnosed brain metastases.
Authors: Peereboom David M. , Chao Samuel T. , Suh John H. , Wang Ding , Mikkelsen Tom , Brewer Cathy J. , Smolenski Kathy N. , Parsons Michael W. , Elson Paul , Angelov Lilyana , Barnett Gene H. , Vogelbaum Michael A. , Weil Robert J.
Published: March 2020

2018

Background: For patients with 1-3 brain metastases, standard therapy after SRS is adjuvant whole brain radiotherapy (WBRT). SRS without WBRT carries a higher rate of brain relapse. Due to concerns about neurologic sequelae of WBRT, however, many patients and physicians opt to defer WBRT until the time of central nervous system (CNS) progression. This trial used sunitinib as an alternative to WBRT for post-SRS adjuvant therapy. Sunitinib inhibits vascular endothelial growth factor signaling, and we hypothesized that it would prevent growth of microscopic brain metastases presumed to be present. The objective was to use adjuvant sunitinib after SRS to prevent the emergence of new or progressive disease in the brain or at the site of SRS and to preserve neurocognitive function. Methods: Eligible patients had 1-3 newly diagnosed brain metastases, RTOG RPA class 1-2, and started sunitinib < 1 month after SRS and baseline neuropsychological testing (NPT). Patients with controlled systemic disease were allowed to continue chemotherapy for their primary disease according to a list of published regimens (therapy + sunitinib) included in the protocol. Patients received sunitinib 37.5 or 50 mg/d days 1-28 every 42 days until CNS progression. NPT and MRIs were obtained every 2 cycles. The primary endpoint was the rate of CNS progression at 6 months (PFS6) after SRS. Results: Fourteen patients enrolled. The median age was 59 (range 46-80). Main histologies: lung 36%, breast 21%, melanoma 14%. Toxicities: Grade 4: neutropenia [ANC] (1 pt); Grade 3: fatigue (5), ANC (2), rash (1). Dose reduction due to toxicity: 1 pt (to 37.5 mg/d). The CNS PFS6 and PFS12 were 50% + 13% and 43% + 13%, respectively. The median PFS was 6.6 months (95% C.I. 1.5-19). NPT results will be reported at the meeting. Conclusions: Sunitinib after SRS for 1-3 brain metastases was well tolerated with a PFS6 of 50%. The use of novel agents to prevent progressive brain metastasis after SRS requires the incorporation of chemotherapy regimens to control the patient’s primary disease. Future trials should continue to explore the paradigm of secondary chemoprevention of brain metastases after definitive local therapy (surgery or SRS).
Bevacizumab versus bevacizumab plus vorinostat in adults with recurrent malignant glioma: Results of a phase I part of a phase I/II trial.
Authors: Wu Jing , Groves Morris D. , Gilbert Mark R. , Hess Kenneth R. , Loch Carolyn Sue , Ictech Sandra , De Groot John Frederick , Conrad Charles A. , Yung W. K. Alfred , Puduvalli Vinay K.
Published: March 2020

2029^

Background: Antiangiogenic therapy using b evacizumab (Bev) has shown promising activity against recurrent glioblastoma (GBM). However, most patients have disease progression after striking but transient responses. Salvage therapies have been uniformly ineffective, suggesting development of resistance mechanisms including upregulation of other proangiogenic factors and increased activity of hypoxia inducible factors (HIF)-1a. Vorinostat, a histone deacetylase (HDAC) inhibitor has single agent activity against recurrent GBM and downregulates HIF-1a and other proangiogenic and invasive factors. We hypothesized that HDAC inhibition combined with Bev would result in improved clinical outcome. We report the results of the Phase I portion of the study preceding the initiation of the 2-arm adaptive randomized Phase II study. Methods: Adults with recurrent malignant glioma, KPS ≥ 60, normal hepatic, renal and marrow organ function and no prior exposure to Bev or Vorinostat were enrolled to the combination therapy after the confirmation of recurrent GBM. A conventional 3+3 Phase I design was used to determine the maximum tolerated dose (MTD) and the toxicity profile of the combination of Bev and Vorinostat. The starting dose was Bev at 10mg/kg administered on days 1 and 15 intravenously and Vorinostat 400 mg/day orally on days 1 to 7, and days 15 to 21 with each cycle being 28 days. Results: A total of 6 patients were enrolled and all 6 patients were evaluable. Three patients were enrolled in the first cohort at the starting dose of the combination and completed the first cycle. One patient experienced a grade 3 ALT elevation and grade 3 hyperglycemia, which were designated as possibly related to vorinostat and constituting a dose-limiting toxicity (DLT). No grade 4 toxicities were noted. The cohort was expanded by 3 more patients with none of these patients experienced a DLT in the first cycle. The starting dose level of Bev and v orinostat was declared the Phase II dose. Conclusions: Combination of Bev (10 mg/kg q 2 weeks) and of vorinostat (400 mg on days 1 to 7 and 15 to 21) has tolerable toxicity profile. This will be followed by a multicenter Bayesian adaptive randomized Phase II study.
Differences in outcome due to bevacizumab (BEV) discontinuation versus BEV failure in adults with glioblastoma.
Authors: Anderson Mark Daniel , Puduvalli Vinay K. , Hamza Mohamed Ali , Gilbert Mark R. , Yung W. K. Alfred
Published: March 2020

2030

Background: BEV is approved for use in recurrent glioblastoma. Patients (pts) who benefit from BEV therapy are often treated until tumor progression but fail to respond to salvage therapy suggesting that BEV may alter tumor biology. In a subset of pts who benefit from BEV, treatment is discontinued for reasons other than disease progression; the characteristics and outcomes of this subset are poorly defined. Methods: In this IRB approved retrospective study, our neuro-oncology longitudinal database was screened for pts treated with BEV for ≥ 6 months (mo) between 2005-2010 and 18 pts were identified in whom BEV was discontinued for reasons other than disease progression (BEV-D group). A cohort of 72 pts who received BEV until treatment failure due to progression was used as comparator (BEV-F group). Results: In the BEV-D group, 5 pts completed a planned treatment course and 13 stopped BEV due to toxicity; in this group, progression free survival at 12 mo (PFS12) was 83.3% (95% CI, 56.8-94.3) and median time to progression (TTP) 27.6 mo. Median TTP after BEV discontinuation was 7.0 mo. In contrast, in the BEV-F group, PFS12 was 24.6% (95% CI, 13.9-36.2) and median PFS 9.7 mo. Length of BEV therapy was not significantly different between the groups with a median time to discontinuation of 10.2 and 12 mo. In 12/18 pts in the BEV-D group who subsequently had tumor recurrence a predominantly local pattern of progression was seen unlike those in the BEV-F group who had more infiltrative or distant failures. Salvage therapy yielded a PFS-6 of 28.6% (95% CI, 4.1-61.2) with a median PFS of 17.1 wk compared with 6.8% (95% CI, 1.2-19.8) and 9 wk in the comparator group. Conclusions: Among pts who benefit from BEV therapy, the BEV-D group did not experience an immediate progression suggesting continued benefit after BEV cessation. This cohort also had a less invasive pattern of recurrence and a possibly improved response to salvage therapy compared with BEV-F group. Our results suggest that planned cessation of BEV therapy could potentially change patterns of progression and response to subsequent therapy. This strategy warrants further evaluation in prospective studies given the absence of effective salvage therapy after BEV failure.
A phase II trial evaluating tumor penetration of bortezomib in patients with recurrent malignant gliomas treated prior to surgery and then treated with bortezomib and temozolomide postoperatively.
Authors: Raizer Jeffrey J. , Grimm Sean Aaron , Levy Robert M. , Muro Kenji , Rosenow Joshua M. , Chandler James , Bredel Markus
Published: March 2020

2035

Background: NF-Kappa B is one of the mechanisms of resistance for malignant gliomas. A few trials have assessed bortezomib in the treatment of malignant gliomas with limited activity. This may in part be due to limitations in dose escalation from peripheral neuropathy. We performed a phase II trial with the goal of measuring bortezomib in tumor tissue and also its effects on NF-Kappa B. Methods: Patients felt to be surgical candidates were enrolled after signing an IRB approved consent. They were treated with bortezomib 1.7 mg/m2 IV on day 1, 4 and 8 and then had surgery on day 8 or 9. Approximately, 14 days post operatively, patients were started on temozolomide 75 mg/m2 PO on days 1-7 and 14-21; on day 7 and day 21 they received bortezomib 1.7 mg/m2 (1 cycle was 1 month). Treatment continued until progression. If <1 patient had a PFS at 6 months the trial would be stopped. Results: 10 patients were enrolled (8 M and 2 F). Median age and KPS were 50 (42-64) and 90% (70-90). All but 1 patient went to surgery, one had an intracranial hemorrhage. The median number of cycles post operatively was 2 (1-4), with two patients discontinuing for wound infection (post 3 cycles, not restarted due to prolonged delays) and meningitis (post 2 cycles then withdrew from trial). Six patients are deceased. Trial was stopped as no patient had a PFS-6. PK analysis revealed measurable drug levels in tumor tissue. Conclusions: Post operative treatment with temozolomide and Bortezomib did not have any activity. Bortezomib can achieve measurable drug levels in tumor but may not be sufficient for anti-tumor activity. Tissue will be assessed for bortezomib effects on NF-Kappa B.
Lenalidomide and irinotecan in adults with recurrent malignant gliomas: Phase I results of the phase I/II trial.
Authors: Puduvalli Vinay K. , Groves Morris D. , Gilbert Mark R. , Hess Kenneth R. , Kang Sanghee , Ictech Sandra , Conrad Charles A. , Loghin Monica Elena , De Groot John Frederick , Levin Victor A. , Yung W. K. Alfred
Published: March 2020

2036

Background: Patients with recurrent malignant gliomas have limited treatment options. We previously reported promising results using 6 month progression free survival [PFS6] endpoint combining irinotecan and thalidomide compared to historical controls. In this study, we tested the tolerability and efficacy of Irinotecan combined with Lenalidomide, a more potent thalidomide analogue with unique antiangiogenic and immunomodulatory properties. Methods: This phase I portion of the phase I/II study aimed to determine the maximum tolerated doses (MTD) of irinotecan and lenalidomide. Eligible patients were adults (>=18 y) with recurrent WHO Grade 3 or 4 gliomas who were not on EIAED, had failed prior radiation therapy, had a KPS>=60, had adequate marrow, renal and hepatic organ function, no major medical illnesses and no other concurrent malignancies. Each cycle was designated as 4 weeks in duration. Results: Two of the 4 patients enrolled at the starting dose level of Lenalidomide 10 mg/day on days 1-21 and irinotecan 200 mg/m2 q2 weeks developed rash as dose limiting toxicity (DLT). The trial was restarted with no change in irinotecan dose but with a lowered Lenalidomide dose of 7.5 mg/day for cycle 1 with escalation to 10 mg/day for cycle 2 and beyond. Of 3 eligible patients enrolled, no DLTs were noted even after cycle 2. The dose was hence escalated to Lenalidomide 10 mg/day with unchanged irinotecan dose. Only 1/6 patients experienced a DLT (pulmonary embolism); however, it was noted that 4/6 patients required dose reduction of irinotecan to 150 mg/m2 after cycle 1. One patient died during cycle 2 of unknown causes (autopsy declined) without reports of preceding toxicities. Non DLT toxicities included neutropenia, leukopenia, hypokalemia, diarrhea, fatigue and nausea/vomiting. Lenalidomide pharmacokinetic data, obtained by serial blood draws initially after one dose of the drug on day 0 and subsequently after irinotecan and lenalidomide dose on day 1 to examine drug interactions, will be presented. Conclusions: Based on these results, the maximum tolerated dose was Lenalidomide 10 mg/day on days 1-21 and irinotecan 150 mg/m2 q 2 weeks every 28 days which will be used in the phase II study that will open shortly.
Does pilocytic astrocytoma (PA) in adults have a different prognosis than PA in children?
Authors: Marques Daniel Fernandes , Santana Iuri amorim , Guindalini Rodrigo Santa Cruz , Neto Hugo Sterman , Crosara Marcela Alves Teixeira , Teixeira Manoel Jacobsen , Hoff Paulo Marcelo , Feher Olavo
Published: March 2020

2038

Background: Pilocytic astrocytoma (PA) accounts for up to 25% of all brain tumors in children. A 75% progression-free survival rate at 5 years and overall survival rates of 95.8% at 10 years have been reported after a complete resection. However, the incidence in adults is low and the outcome less well characterized. We conducted a retrospective analysis of adult PAs identified in order to review the clinical characteristics and outcome of this neoplasm in this age group. Methods: A descriptive, cross-sectional study was undertaken in patients over 16 y.o., diagnosed with PA between January 1990 and December 2010 at our center. Clinical characteristics, date and extent of surgery, tumor location, postoperative treatment, complications and recurrences were collected from hospital records. Results: From May, 1990 to December, 2010, 18 eligible adult patients (pts) with the diagnosis of PA were identified. Median age was 25,5 (16-52) years, 72,2% female and 83,3% had an ECOG performance status ≤ 2. The most frequent tumor sites were the cerebellum (44,4%), followed by the cerebral hemispheres (38%). All patients underwent surgery as primary treatment, 72% had a complete macroscopic resection (CMR) and 28% had a partial resection (PR). Two patients received postoperative radiotherapy: one following a PR and the other after tumor relapse following a CMR. Two patients relapsed five months and 44 months after initial complete gross resection. Salvage surgery achieved CMR in both. With a median follow-up of 89 months, all patients are alive, except for one who died in the postoperative period due to fungal meningitis. Of note, none of 5 pts undergoing a partial resection progressed and 3 are alive for more than 10 years. Conclusions: As it occurs in the pediatric population, PA in adults seems to carry a similarly favorable prognosis. It is conceivable that after initial surgical resection a watch and wait type of approach is appropriate, even following partial resection. The role of upfront radiotherapy is uncertain and it should probably be left for progressive tumors.
Use of a non-coplanar half-beam block on the lower spinal field to decrease the maximum bowel and cumulative dose in craniospinal irradiation.
Authors: Kathpal Madeera , Davis Rihan
Published: March 2020

2039

Background: To develop and compare a non-coplanar half beam block technique that can be used in both prone and supine treatment positions with conventional beam matching for craniospinal irradiation (CSI) in order to decrease the maximum cumulative dose and dose to the bowel, while maintaining the therapeutic dose to the spinal axis. Methods: Ten treatment plans from five patients who underwent CSI were analyzed. The bowel was contoured en bloc for each patient on their simulation cat scan. Two different geometric techniques for each patient were planned and analyzed. The first technique consisted of the conventional method for CSI utilizing two coplanar beams to cover the entire spinal axis. The other technique used a non-coplanar half beam block on the lower spinal beam to exactly match the upper spinal beam’s divergence. Four “featherings” between the two spinal beams for each technique were still necessary to minimize under and overdosing which occur at abutting beam fields. Maximum doses for the plan and the bowel were compared between the two techniques on the same patient. Results: The maximum bowel dose was decreased between 10 to 35 percent when the non-coplanar half beam block was used. The maximum doses for the conventional technique were 5 to 35 percent higher than the plans using a non-coplanar half beam block. The homogeneity of the dose to the spinal axis was not altered with the use of the non-coplanar half beam block. Conclusions: Use of a non-coplanar half beam block to match the two spinal fields in craniospinal irradiation significantly reduces the maximum dose to the bowel and of the entire plan possibly resulting in reduced gastrointestinal toxicity while maintaining therapeutic dose to the spinal axis.
Relationship of cognitive function, quality of life (QOL), and neuroimaging in primary CNS lymphoma (PCNSL) survivors.
Authors: Doolittle Nancy Diane , Korfel Agnieszka , Lubow Meredith A. , Schorb Elisabeth , Schlegel Uwe S. , Rogowski Sabine , Fu Rochelle , Dosa Edit , Illerhaus Gerald , Kraemer Dale F. , Calabrese Pasquale , Hedrick Nancy A. , Muldoon Leslie L. , Maron Leeza M. , Jahnke Kristoph , Butler Robert W. , Neuwelt Edward A.
Published: March 2020

2040

Background: Delayed treatment-related neurotoxicity in PCNSL is a significant problem since improved treatments have increased survival. The study purpose is to describe and correlate neuropsychologic (NP), QOL and neuroimaging outcomes as neurotoxicity indicators. Methods: Four centers in Germany and U.S. prospectively evaluated PCNSL patients (pts) in complete remission (CR) for 2 yrs or more, treated as shown in the Table. NP tests evaluated attention/executive function, verbal memory, motor skills, and QOL (Correa, Ann Oncol 2007). Brain MRI was obtained; the size of T2 abnormalities was determined using two perpendicular linear measurements where hyperintensities were largest and the sum of the measurements was calculated. Differences in total T2 among treatments were compared using analysis of variance; correlations between total T2 and NP or QOL results were assessed using Pearson’s correlation coefficient (r). Results: From Feb 2009 to Feb 2011, 80 pts were evaluated (43 male; median age, 59; median KPS, 80). Median follow-up from diagnosis to evaluation was 5.5 yrs. Total T2 abnormalities were significantly different among treatments (p = 0.0006). The mean area of total T2 in pts treated with WBRT was significantly higher and more than twice the mean of any of the other 3 treatments. Total T2 abnormalities were negatively associated with NP results ie. attention/executive function, r = -0.38 (p = 0.0006), verbal memory, r = -0.23 (p = 0.042), motor skills, r = -0.28 (p = 0.016), composite score, r = -0.34 (p = 0.002); and functional/global QOL (higher total T2 associated with lower QOL). Conclusions: This large PCNSL series in long-term (LT) CR reveals higher total T2 abnormalities in pts treated with WBRT, which are associated with poorer cognitive performance and lower QOL at LT follow-up. Enhanced chemotherapy results in exciting LT survival and function. [Table: see text]
The effect of the addition of chemotherapy to radiotherapy on cognitive function in patients with low-grade glioma: Secondary analysis of RTOG 98-02.
Authors: Prabhu Roshan Sudhir , Won Minhee , Shaw Edward G. , Wang Meihua , Brachman David , Mehta Minesh P.
Published: March 2020

2047

Background: The addition of PCV chemotherapy to radiotherapy (RT) for patients with WHO grade II glioma improves progression free survival (PFS) and overall survival (OS), for patients surviving at least 2 years (Shaw, J Clin Oncol 26: 2008). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long term survival. Methods: 251patients with WHO grade II glioma and age > 40 with any extent of resection, or age < 40 with subtotal resection/biopsy were randomized to RT (54Gy) or RT + PCV. 111 patients with age < 40 and gross total resection were observed. CF was assessed by mini-mental status exam (MMSE)at baseline and years 1, 3, and 5 for patients without progression. Change in MMSE score from baseline of > 3 points was considered clinically significant. Results: Overall, very few patients experienced significant decline in MMSE score, with a median follow-up time of 9.7 years for alive patients. There were no significant differences in the proportion of patients experiencing MMSE decline between study arms at any time point. The table below summarizes MMSE change from baseline over time. Neither baseline MMSE score nor change in MMSE at year 1 significantly predicted for OS or PFS, but there was a trend towards worse OS for patients with MMSE loss of ≥ 2 points [HR 1.73, 95% CI (0.86, 3.47), p=0.12]. Conclusions: The MMSE is a relatively insensitive tool that has not been validated in patients receiving cranial RT, and subtle changes in CF may have been missed. However, the addition of PCV to RT for low grade glioma did not result in significantly higher rates of MMSE decline than RT alone or observation. There was a trend towards an MMSE decline of ≥ 2 points at year 1 predicting for worse OS.    [Table: see text]
First results of radiotherapy after hyperbaric oxygenation with temozolomide for high-grade gliomas.
Authors: Khelif David Hamid , Kintzinger Clement , Taha Said , Gauchez Philippe , Bintner Marc , Chirpaz Emmanuel , Harms JAN-Dirk , Magnin Valerie Florence
Published: March 2020

2048

Background: The outcome of patients with high-grade gliomas remains poor despite modern therapeutic arsenal. The objective of this study was to assess the feasibility and efficacy of radiotherapy (RT) given immediately after hyperbaric oxygenation (HBO) with Stupp protocol. Methods: All patients with histologically confirmed high-grade gliomas from 2008 till 2011 coveraged at GHSR hospital were enrolled. Patients underwent Stupp protocol consisting in 60 Gy RT with a daily dose of 2 Gy for 5 days per week administrated immediately after HBO. Temozolomide (TMZ) was administrated at the daily dose 75 mg/m², 7 days per week followed by 6 cycles of TMZ 150 to 200 mg/m² for 5 days each 28 day-cycle. HBO schedule was approximately 15 min of compression with air, 60 min of 100% oxygen inhalation and 10 min of decompression with oxygen. Results: A total of 21 patients were diagnosed and histologically confirmed high grade gliomas. Five were excluded because of HBO contraindications. Twelve patients (75%) had undergone debulking surgery. The time interval from completion of decompression to start of irradiation was less than 15 minutes (mean 14.25, range 8-18). Twelve patients (75%) received the complete dose of RT and TMZ. HBO was completed for 7 (43.75%). Five (31.25%) were temporarily stopped and 4 (25%) were definitively stopped. One patient (6.25%) suffered from pancytopenia with grade 4 thrombopenia and grade 3 neutropenia. The median follow up was 46.95 weeks (range 5.7-108.3). Nine patients (56.25%) are still alive. Four (25%) have a survival more than 16 months. Conclusions: HBO with Stupp protocol is feasible and promising but requiring a large multicentric study.
Natural history of glioblastoma in the modern era: Longitudinal results from a large prospective Italian register.
Authors: Brandes Alba Ariela , Franceschi Enrico , Ermani Mario , Depenni Roberta , Poggi Rosalba , Pisanello Anna , Marcello Norina , Valentini Antonella , Albani Fiorenzo , Faedi Marina , Guiducci Graziano , Urbini Benedetta , Crisi Girolamo , Dascola Isabella , Mucciarini Claudia , Dazzi Claudio , Cavanna Luigi , Bartolini Stefania , Cavallo Michele , Baruzzi Agostino
Published: March 2020

2057

Background: The role of temozolomide (TMZ) concurrent with and adjuvant to radiotherapy (RT) in the treatment of glioblastoma (GBM) has been demonstrated by the EORTC 22981/26981-NCIC CE.3 (EORTC/NCIC) randomized trial, and has been widely accepted as the standard treatment. The impact of RT/TMZ in the general patient population was assessed in the context of the Registry of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), that represents the first italian prospectic observational population-based study in neuro-oncology. Methods: Approvals from local Ethical Committees were obtained by 8 participating centres. Patients (pts) who met the following inclusion criteria were evaluated: age ≥18 years; PS 0-3; histologically confirmed GBM, no previous or concomitant non glial tumoral disease, resident in Emilia Romagna region. The data were prospectively collected. Results: From January 2009 to January 2011, 194 GBM pts were enrolled. The median age was 62.5, with 26% of pts over 70 years. After surgery pts received RT/TMZ (73%), RT alone (19%), TMZ alone (5%) or no further treatment (3%); 22% were included in clinical trials. Median overall survival (OS) was 12.9 months. Pts <70 years received RT/TMZ in 85% of cases. In this group of pts mOS was 17 months (95%CI: 15.4–18.6). Interestingly, pts <70 years included in experimental clinical trials showed a significant OS improvement (p=0.04). In multivariate analysis, only extent of surgery (p=0.047), KPS (p=0.01) and RT/TMZ (p<0.001) were associated with OS in pts <70 years. Conclusions: Our population data reproduces the beneficial effect of RT/TMZ from the EORTC/NCIC randomized trial, confirming how this successful approach as been widely incorporated in daily practice. Interestingly, our data suggest that the survival of GBM pts treated with RT/TMZ could be greater than patients treated with RT/TMZ in the EORTC/NCIC trial at the beginning of this century.
Quality of life in patients with malignant brain tumors.
Authors: Choucair Ali K. , Shields Lisa B.E.
Published: March 2020

2058

Background: A positive quality of life (QOL) serves as an important outcome priority in patients with malignant brain tumors whose survival is limited by tumor resistance to treatment. The FDA and ASCO have designated QOL as an outcome secondary in importance to survival. We conducted a prospective longitudinal collection of QOL measures (EORTC QLQ-C30, EORTC QLQ-BN20, and Hospital Anxiety and Depression Scale [HADS]) coupled with clinical standards of care (brain MRI and clinical history and physical examinations) in patients with newly diagnosed primary brain tumors (PBT). We also examined the QOL measures over time as related to tumor progression. Methods: Under an IRB-approved protocol, we reviewed the validated QOL measures and standard clinical measures from patients who were newly diagnosed with PBT. The patients were followed every 3 months over 2 years. No proxies were allowed. A total of 52 patients were enrolled in the study. Survey responses were compared between two tumor groups of patients: patients with tumor recurrence and/or died and patients without a recurrence (n=26 each group). A total of 17 patients succumbed to a tumor-related death. Statistical analysis utilizing non-parametric t-tests and Wilcoxon sign tests assessed QOL responses. Results: Significant group differences were noted in the questions of the QOL measures surveys with more negative responses in the recurrence group. The questions with significant group differences on the EORTC QLQ-C30 ranged from symptoms of dyspnea (p<.05) and difficulty sleeping (p<.05) as well as a poor QOL (p<.005) and pain interfering with daily activities (p<.05). Significant group differences of questions on the EORTC QLQ-BN20 included weakness of the legs (p<.05), coordination difficulties (p<.005), and unsteady gait (p<.05). Significant group differences of questions on the HADS reflected a patient who is "slowed down" (p<.01) and "frightened" (p<.05). Conclusions: Our analysis of questions answered by patients with newly diagnosed PBT may shed light on the impact of cancer and its treatment and potential recurrence on a patient's QOL. Further research is warranted to incorporate QOL measurements into improvement of patient care and their use in clinical trials and as a prognostic indicator.
Tolerance and feasibility of chemotherapy by procarbazine, lomustine, and vincristine (PCV) for oligodendroglial anaplastic gliomas (OAG).
Authors: Daros Marine , Tabouret Emeline , Barrie Maryline , Matta Mona , Autran Didier , Boucard Celine , Wertz Marie , Figarella Dominique , Honoré Stéphane , Chinot Oliver L.
Published: March 2020

2060

Background: Chemosensitivity of OAG has been documented although their role as part of adjuvant treatment combined to radiotherapy is debated. Beside temozolomide still under investigation, several studies have underlined activity of PCV regimen in this setting. However, significant toxicity has been described and dose intensity and schedule duration are not clearly reported. Methods: This monocentric retrospective analysis included all pts with OAG treated with at least 1 cycle of PVC (lomustine 110mg/m2 every 6 weeks) at our institution from August 2007 to August 2011 (pharmacy charter). Toxicities data were collected from clinical observations and blood investigations. Results: 40 pts were identified (M/F: 23/17). Median age was 45y (20 – 72). At the time of analyses, 32 pts were still alive. Histologies were oligodendroglioma (73%) or oligoastrocytoma (27%). Codeletion 1p19q was observed in 30 % of pts. PCV was administered in first or second line of chemotherapy for 60 % and 40 % of pts respectively. Seventy five percent and 52.5% of pts completed at least of 4 and 6 cycles respectively. Discontinuation of PCV occurred in 45% of pts for toxicity (10%), progression (30%), or other reason (5%). Because of toxicity 38/196 (19%) PCV cycles were delayed. Dose was adapted for 73% of pts and decreased under 60% of theoretical dose in 30% of pts at cycle 4 and in 57% of pts at cycle 6 (table1). Grade III or IV toxicity occurred in 28% of pts and only grade I-II in 50%. Neuropathies occurred in 43 % of pts. Conclusions: Despite activity of PCV regimen, significant toxicity is associated to this schedule, that impact feasibility and compliance. PVC schedule should be redefined taking into account dose intensity applied in toxicity observed. [Table: see text]
Pediatric glioblastoma: Results with adjuvant chemoradiation using temozolomide.
Authors: Joshi Nikhil Purushottam , Mallick Supriya , Gandhi Ajeet , Goyal Shikha , Puri Tarun , Julka Pramod Kumar , Sharma Dayanand , Rath Goura Kishor
Published: March 2020

2072

Background: Paediatric glioblastoma patients are underrepresented in major trials for this disease. The value of concurrent and adjuvant temozolomide is not known in this subset of patients. Methods: We retrospectively analysed our database between 2004 and 2010. All patients were treated with maximally safe surgical resection. This was followed by a uniform treatment schedule of post-operative radiation according to RTOG guidelines with concurrent daily temozolomide at 75 mg per meter square. The radiation dose was 60 Gy in 30 fractions planned by 3 dimensional conformal radiotherapy. 4 weeks later, adjuvant temozolomide was started at 150 mg per meter square, day 1 to 5 every 28 days and escalated to 200 mg per meter square if well tolerated. Log-rank test was used to compare survival distribution. The data was analysed using SPSS 16. Results: 23 patients were analysed. The median age was 11 years (range: 5 to 19 years). 15 males and 8 females were noted. 4 patients had seizures at presentation while 19 did not. 13 patients underwent a gross total resection while 10 underwent a subtotal resection. 5 patients received only concurrent temozolomide while 18 received concurrent and adjuvant temozolomide. The median number of adjuvant temozolomide cycles were 6 (range 2 to 12). The median follow up was 11.9 months (range: 1.6 to 30.1 months). 6 patients were dead and 17 were alive at the time of analysis. The median overall survival was not reached. The median survival for patients receiving only concurrent temozolomide was 13 months while that for patients receiving concurrent and adjuvant temozolomide was not reached and the difference was statistically significant (p=0.0009). The overall survival was not statistically different for age less or more than 10 years, gender, and type of surgery or the number of adjuvant cycles of temozolomide (less or more than 6). Conclusions: Temozolomide may have a role in paediatric Glioblastoma. Both concurrent and adjuvant temozolomide seem to be important for superior overall survival in this group of patients.
MRI-based vessel function maps for high-resolution differentiation between tumor and nontumoral tissues in brain tumor patients.
Authors: Zach Leor , Goez David , Grober Yuval , Last David , Daniels Dianne , Hoffmann Chen , Nass Dvora , Nissim Ouzi , Spiegelmann Roberto , Cohen Zvi R , Mardor Yael
Published: March 2020

2078

Background: Changes in enhancement seen in post treatment brain MRIs in primary and secondary brain malignancies often mimic tumor progression (pseudoprogression, radiation necrosis). Conventional MRI cannot differentiate tumor progression from treatment related effects resulting in suboptimal patient management. Methods: The application of delayed contrast extravasation MRI for depicting unique vessels characteristics with high resolution and high sensitivity to subtle BBB disruption is demonstrated in 17 GBM and 15 brain metastases patients undergoing standard chemoradiation and radiosurgery respectively. Results: 2 primary vessel function populations were defined: a slow population where contrast clearance from the tissue was slower than accumulation, and a fast population where clearance was faster than accumulation. Ten stereotactic biopsies acquired from GBM patients showed complete correlation with the maps, confirming the discrimination between fast population regions, reflecting morphological active tumor and slow regions reflecting necrosis/treatment-induced changes. Typical fast population vessel morphology consisted of proliferating endothelial cells, dilated lumen, peri vascular fibrosis and glumeroloid vessels, while slow regions consisted of necrotic vessels, in agreement with the observed MRI vessel function. The fast component volume 3 weeks post treatment was significantly correlated with the fast volume 4 (r2=0.84, p<0.0005) and 6 months (r2=0.84, p<0.01) later, suggesting early prediction of response. Brain metastases histology showed similar results: 5 brain metastases with a fast population component were confirmed histologically to contain morphologically active tumor. One metastasis consisting of the slow population only significantly decreased in volume in the following MRIs. Conclusions: These results demonstrate the feasibility of applying our delayed contrast extravasation high resolution function vessel maps for improving patient management by clearly depicting tumor and non-tumoral tissues in patients with primary and secondary brain malignancies undergoing standard chemoradiation or radiosurgery.
Primary central nervous system lymphoma: The Cleveland Clinic experience.
Authors: Ahluwalia Manmeet Singh , Xie Hao , Patel Mital , Chao Samuel T. , Suh John H. , Peereboom David M.
Published: March 2020

2092

Background: Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma that involves the brain, leptomeninges, eyes, or spinal cord without evidence of systemic disease. Untreated PCNSL has a rapidly fatal course, with survival of approximately 1.5 months from the time of diagnosis. In this study, we sought to describe the demographics, diagnoses, management, and outcomes of patients with PCNSL at a single institution. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify patients with histologically proven PCNSL at the Cleveland Clinic between 1986 and 2010. Data were subjected univariate and multivariate analysis followed by recursive partitioning analysis in order to generate a prognostic model. Results: 153 patients were diagnosed with PCNSL with a median age of 61 and Karnofsky performance status (KPS) of 70. The progression-free survival (PFS) was 9.3 months; the overall survival (OS) was 27 months. The treatment regimen included methotrexate-based chemotherapy (MTX) or a combination of methotrexate-based chemotherapy and whole brain radiation therapy (WBRT). Patients treated with the MTX regimen had an OS of 65 months; those treated with the MTX + WBRT regimen had an OS of 74 months. The Cox proportional hazards regression identified age and KPS as the only prognostic indicators to OS and PFS. Recursive partitioning analysis categorized the patients into three groups according to these prognostic factors. Patients with KPS ≥ 70 had a favorable outcome compared to patients with KPS < 70. This held true especially for patients age 60 and younger, whose median OS was 100 months. Conclusions: The survival and prognostic indicators approximate those reported previously and provide independent validation for a simple yet powerful prognostic model that uses age and KPS to predict survival. [Table: see text]
Low-grade gliomas in older patients.
Authors: Fawole Adewale Alade , Robles Irizarry Lizbeth , Hashemi-Sadraei Neda , Patel Mital , Ahluwalia Manmeet Singh
Published: March 2020

2093

Background: Low grade gliomas account for 10-20% of all primary brain tumors. The outcomes of older patients with low-grade glioma (LGG) are not well known. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify older patients defined as those >55 years of age 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<.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 61 patients diagnosed between 1991 and 2010 were included for final analysis. In contrast to patients ≤55 years, older patients are more likely to be male (p=.06), have poorer performance status at presentation (p<.0001), more comorbid conditions (p<.0001), present with more neurologic symptoms (p<.0001), have a prior history of cancer (p<.0001). They are more likely to have astrocytic histology (p=.008) and present with multifocal tumors more frequently (p=.001). Older patients received radiation (RT) upfront more frequently (p=.07) and undergo gross total resection less frequently (p=.003). Median Progression free survival (PFS) and median overall survival (OS) was 1.9 and 4.3 years, respectively in these patients. On univariate analysis, patients with poor performance status have worse PFS (p=.01) and OS (p=.003). Patients with memory impairment have worse PFS (p=.009) and OS (p=.0001). Patients treated with adjuvant chemotherapy had better OS (p=.01). Tumor related characteristics associated with poor survival included, "pure" or mixed astrocytoma histology (OS, p=.06), multifocal tumors (OS, p=.08), left-sided tumors (p=.07). In multivariable analysis, performance status was the only independent predictor of either PFS or OS. Conclusions: Older patients with low grade gliomas have less favorable outcomes as compared to younger patients. They have more comorbid conditions and symptoms at presentation. Use of chemotherapy in this patient group was associated with improved survival. Performance status was the only independent predictor of either PFS or OS.