bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bevacizumab for recurrent ependymoma
Authors: Green R. M. , Cloughesy T. , Stupp R. , DeAngelis L. M. , Woyshner E. A. , Ney D. E. , Lassman A. B. 
Published: August 2020

2060 Background: Ependymoma is a rare type of glioma, representing less than 5% of brain tumors in adults. Radiotherapy (RT) is commonly administered, but there is no standard chemotherapy. At recurrence ependymoma is notoriously refractory to therapy and the prognosis is poor. In recurrent glioblastoma, encouraging responses with bevacizumab have been observed. Therefore, we treated patients with recurrent ependymoma and anaplastic ependymoma with bevacizumab containing chemotherapy regimens. Methods: We retrospectively identified adults treated for recurrent ependymoma and anaplastic ependymoma with bevacizumab containing chemotherapy regimens. We determined radiographic response (Macdonald criteria) and estimated median time to progression (TTP) and overall survival (OS) by the Kaplan-Meier method. Results: There were six patients, four women and two men, with a median age of 29 years (range, 20–65). Prior treatment included RT in all and temozolomide in four. Bevacizumab (5–10 mg/kg) every other week was combined with cytotoxic agents: irinotecan (3), carboplatin (2), or temozolomide (1). Five patients achieved a partial response (83%); in one patient the disease was stable. Median TTP and OS were 6.5 (95% CI: 2.7–10.2) and 9.4 (95% CI: 6.3–12.6) months, respectively, with a median follow up of 18.7 months for the two surviving patients. One additional patient is initiating bevacizumab monotherapy (not included in this analysis). Conclusions: Bevacizuamb has efficacy in the treatment of recurrent ependymoma. Prospective study is warranted. [Table: see text]
Extraneural metastasis of medulloblastoma
Authors: Mazloom A. , Zangeneh A. H. , Teh B. S. , Paulino A. C. 
Published: August 2020

2065 Background: Medulloblastoma is the most common childhood intracranial tumor to spread extraneurally. Information regarding prognostic factors and best therapeutic approach of extraneural metastasis (ENM) of medulloblastoma is mostly limited to case reports. The purpose of this study was to perform a comprehensive literature review and analysis of reported cases dealing with ENM to identify the characteristics, prognostic factors, optimal treatment modalities, and survival of these patients. Methods: A PubMed search of English language articles from 1963–2007 was performed, yielding 47 articles with 119 patients. Factors analyzed included age, time interval to ENM, CNS involvement at the time of ENM, location of ENM, treatment, and outcome. Results: Location of ENM included bone in 84%, bone marrow in 27%, lung in 6%, liver in 6%, and lymph nodes in 15%. Of patients with available data regarding location of RT after ENM, 87% of patients received this treatment to the site of ENM. The 1-year disease free survival (DFS) and overall survival (OS) after the diagnosis of ENM was 35% and 42%, respectively. The 1-year OS for patients with and without radiotherapy (RT) after ENM was 58% and 35%, respectively (p = 0.019). For patients without CNS involvement at the time of ENM the 1-year OS for those treated with and without RT was 82% and 51%, respectively (p = 0.030), however RT did not significantly improve OS for those with CNS involvement. ENM in the lung or liver was found to be a negative prognostic factor (p = 0.002). 1-year OS of patients with time interval to ENM of <18 months was 25% while those with time interval greater than or equal to 18 months it was 61% (p = 0.001). Conclusions: Negative prognostic factors for patients with ENM include CNS involvement at the time of ENM, lung or liver involvement, and duration to ENM <18 months. Patients without CNS involvement who received RT after ENM had an OS and DFS benefit compared to those not receiving RT. No significant financial relationships to disclose.
Quantitative analysis of 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with low-grade gliomas
Authors: Ochsenbein A. F. , Schubert A. D. , Vassella E. , Mariani L. 
Published: August 2020

2069 Background: Loss of heterozygosity (LOH) on the chromosomes 1p and 19q is associated with sensitivity to alkylating agents like temozolomide (TMZ) in patients with low-grade gliomas; whether methylation of the MGMT-promoter, a predictive factor in glioblastoma patients, also correlates with tumor response to TMZ in low-grade gliomas is unclear. Methods: We performed a retrospective analysis of patients with histologically verified low-grade gliomas (WHO Grade II) who were treated with TMZ for tumor progression at our hospital between November 1999 and November 2007. Objective tumor response was assessed by MRI at 6-month intervals. LOH of microsatellite markers on chromosomes 1p and 19q was determined by polymerase chain reaction (PCR) amplification of the matched pairs of blood and tumor DNA. A methylation-specific, primer extension based PCR method was developed to quanitatively assess the MGMT methylation status in the tumour tissue. Results: Twenty-two patients with a median age of 53 years (range 27–72) were included in the study; 59% were male. Seven patients had prior surgical resection of the tumor. Histological classification revealed 10 oligodendrogliomas, 7 oligoastrocytomas, and 5 astrocytomas. All patients were treated with TMZ 200mg/m2 day1–5 in a 4 wk cycle. Grade 3–4 hematological toxicity occurred in 32% of the patients (9% leucopenia, 23% thrombocytopenia). The progression free survival was 32 months. Combined LOH 1p and 19q was found in 14 pts; 1 patient had LOH 1p alone and 1 patient LOH 19q alone. The LOH status could not be determined in two patients and was normal in the remaining four. MGMT promoter methylation was detectable in 20 pts by conventional PCR and quantitative analysis revealed a methylation status between 12%-100%. The volumetric response to chemotherapy analyzed after 6 months by MRI correlated with the level of MGMT promoter methylation (p = 0.012). Conclusions: Quantitative methylation-specific PCR of the MGMT promoter correlates with radiological response to chemotherapy with temozolomide in WHO grade II gliomas. No significant financial relationships to disclose.
Combination immunochemotherapy followed by reduced dose (rd) whole brain radiation therapy (WBRT) in an expanded cohort of patients with newly diagnosed primary central nervous system lymphoma (PCNSL)
Authors: Abrey L. E. , Correa D. , Yahalom J. , Raizer J. , Grimm S. , Lai R. , Schiff D. , Grant B. , DeAngelis L. M. , Morris P. G. 
Published: August 2020

2072 Background: High-dose methotrexate (M)-based chemotherapy combined with WBRT has improved survival in patients with PCNSL. However, disease recurrence and treatment-related neurotoxicity are significant problems. We conducted a prospective trial incorporating rituximab (R) and rdWBRT and previously demonstrated this was feasible. This study was extended to assess the long-term outcome of this approach in an expanded cohort. Methods: Patients were treated with R-MPV (d1 R 500mg/m2; d2 M 3.5gm/m2; vincristine 1.4mg/m2; d1–7 procarbazine 100 mg/m2/d on odd-cycles). Patients with a PR after five cycles received two additional cycles. Patients with a CR received rdWBRT (2340cGy), otherwise patients received standard WBRT (4500cGy). Patients then received two cycles of Ara-C 3gm/m2. Prospective neuropsychological evaluations were performed at baseline, before WBRT, and every 6 months thereafter. Results: From October 2002 to September 2008, 50 patients were enrolled (22 female, 28 male), median age 59.5 years (range 30–79 years). Due to neutropenia in two of the first five patients, all subsequent patients received G-CSF. 42 patients are assessable for response (4 patients died from progressive disease prior to completing the first cycle of treatment, 4 patients - treatment ongoing). 33 patients (79%) had a CR, of whom 29 received rdWBRT (3 refused, 1 died). At median follow-up of 3 years for survivors the median OS has not been reached and the estimated 2-year OS is 68%. Patients treated with rdWBRT have a median follow up of 38 months: 21 (72%) are alive with no evidence of disease, seven (24%) relapsed, and one died of unknown causes. Eight of 21 (38%) who are alive with no evidence of disease were age 60+ at diagnosis. The number of patients treated with rdWBRT alive with no evidence of disease at 3, 4, and 5 years is 12, 8, and 4 respectively. 9 patients have completed neuropsychological evaluations 24 months after rdWBRT with no significant cognitive decline detectable. Conclusions: Prolonged follow-up of an expanded cohort of patients treated with immunochemotherapy followed by rdWBRT for patients with an initial CR continues to support our initial conclusions that this approach results in excellent disease control with no observed treatment-related neurotoxicity. [Table: see text]
A placebo-controlled study investigating the dexamethasone-sparing effects of corticorelin acetate in patients with primary or metastatic brain tumors and peritumoral edema
Authors: Recht L. D. , Mechtler L. , Phuphanich S. , Hormigo A. , Hines V. , Milsted R. , O'Connor P. C. , Ryan R. P. , Wong E. T. 
Published: August 2020

2078 Background: The standard therapy for patients with peritumoral edema (PTE) associated with cerebral tumors is long-term dexamethasone (dex), which is associated with significant short- and long-term adverse events (AEs). Corticorelin acetate (CrA) is a synthetic peptide of corticotropin-releasing factor that may have the potential to allow such patients to reduce or stop dex therapy. This study investigated the steroid-sparing effect of CrA in patients with cerebral tumors and PTE. Methods: Patients were randomized to CrA 1.0 mg bid SC (n = 100) or placebo (PLA) SC (n = 100) for 12 weeks. The primary endpoint was the percentage of responders, defined as patients able to reduce their daily dex dose by ≥50% by week 2 and maintain this reduction until week 5, without deterioration in neurologic or performance status. Secondary endpoints included maximum percent dex dose reduction from baseline and proximal myopathy (Kendall Myopathy Scale). Steroid-specific treatment-emergent AEs (TEAEs) were also evaluated. Results: The groups were comparable at baseline. There were more responders in the CrA arm vs the PLA arm (62/100 vs. 47/100; p = 0.03). A maximum dex dose reduction of ≥75% was achieved by 42% of CrA patients vs 22% of PLA patients (p = 0.01). 15% of CrA patients were able to stop dex vs. 6% PLA (p = 0.04). At week 12 vs. baseline, proximal myopathy was improved in the CrA group vs the PLA group for upper limbs (p = 0.06) and lower limbs (p = 0.02). AE profiles in both groups were dominated by dex-associated side effects. The overall AE profiles of the treatment groups were generally similar. Emergent cushingoid signs were seen in 13 PLA vs 2 CrA patients (p = 0.01); 14 PLA patients reported skin/subcutaneous tissue disorders as TEAEs vs. 7 CrA patients (p = 0.07). Conclusions: CrA may benefit patients with symptoms of PTE associated with primary or metastatic cerebral tumors by allowing them to reduce/stop their dex treatment, so reducing the incidence of the steroid-related AEs of myopathy, cushingoid symptoms, and skin disorders. [Table: see text]
Interaction between sorafenib and erlotinib
Authors: Kuhn J. G. , Gilbert M. , Wen P. , Cloughesy T. , Cooper J. , Puduvalli V. , DeAngelis L. , Lieberman F. , Lamborn K. , Prados M. 
Published: August 2020

2500 Background: The combination of sorafenib plus erlotinib was evaluated in patients with recurrent glioblastoma (GBM). In addition to defining the maximum tolerated dose (MTD), pharmacokinetics (PKs) for single agent and combination were determined. Methods: Adults with recurrent GBM with the usual phase I inclusion/exclusion criteria were eligible. No enzyme inducing anti-epileptic agents were allowed. Starting doses for erlotinib and sorafenib were 100mg PO QD and 200 mg PO BID, respectively, for 28 days (a cycle). For cycle 1 PKs, erlotinib was started on day 1 followed on day 2 by sorafenib. Eight plasma samples were collected over 24hrs on days 1, 15 and 28. Sorafenib and its metabolite (N-oxide) were analyzed by HPLC and erlotinib and OSI-420 by LC/MS. PK parameters were characterized by standard non-compartmental methods. Results: The MTD was sorafenib 200 mg PO BID and erlotinib 100 mg PO QD. The PKs for erlotinib (OSI) are displayed below. Conclusions: The PKs for sorafenib are in agreement with previous reports and not affected by the co-administration of erlotinib. However, there is an apparent affect of sorafenib on the PKs of erlotinib. The expected accumulation of erlotinib's Cmax and AUC at steady-state was not observed. This interaction results in at least a 2+ fold decrease in exposure to erlotinib and its active metabolite. The interaction does not appear to be the classical enzyme induction due to the rapidity of the onset/offset. This same phenomenon has been reported with the co-administration of sorafenib with gefitinib (Clin Cancer Res 13:2684,2007). Increasing the maximal velocity (Vmax) of CYP3A4, not the quantity of enzyme, is suggested as a testable hypothesis (J Pharmacol Exp Ther 290:1.1998). The clinical relevance of this interaction with regard to toxicity and efficacy warrants further evaluation. [Table: see text] No significant financial relationships to disclose.
Population pharmacokinetic analysis of S-1 including the CYP2A6 genotype in patients with advanced cancer
Authors: Hirose T. , Nishimura K. , Fujita K. , Adachi M. , Sasaki Y. , Tanigawara Y. 
Published: August 2020

2507 Background: S-1 is an oral anticancer agent composed of tegafur, CDHP, and potassium oxonate. Tegafur is a prodrug of fluorouracil (5-FU), and CDHP prevents degradation of 5-FU by inhibiting dihydropyrimidine dehydrogenase and enhances the anticancer activity of 5-FU. The biotransformation of tegafur to 5-FU is demonstrated to be catalyzed by CYP2A6. CYP2A6 polymorphisms are seen more frequently in Japanese people than Caucasian. Therefore, we performed a population pharmacokinetic (PPK) analysis of S-1 including the CYP2A6 genotype in Japanese patients with advanced cancer and developed a model describing the disposition kinetics of tegafur, CDHP, and 5-FU after oral administration of S-1. Methods: Fifty-eight patients with advanced cancer were eligible if they had a performance status of 0 to 3 and had adequate organ function. A dose of 80 mg/m2 of S-1 was given orally twice daily for 28 consecutive days, followed by 14 days of rest. The PPK analysis was performed with plasma concentration data for tegafur, CDHP, and 5-FU. The CYP2A6 genotype was analyzed with the polymerase chain reaction-restriction fragment length polymorphism method or an allele-specific polymerase chain reaction-based method. On the basis of the CYP2A6 genotype, all patients were classified into 1 of 3 groups: wild type, 1 variant allele, and 2 variant alleles. Results: Creatinine clearance correlated with the individual clearance of CDHP. Body surface area correlated with the individual clearance and volumes of CDHP and tegafur. In patients with 2 variant alleles of CYP2A6, tegafur clearance was 58% less than that in patients with wild type or 1 variant allele of CYP2A6. In addition, in patients with a history of gastrectomy, the absorption rate constant of tegafur was 66% higher than that in patients with no history of gastrectomy. The time-varying concentration of CDHP was the most appropriate model component describing the inhibitory effect on 5-FU catabolism. The individual Bayesian predictions of CDHP, tegafur, and 5-FU concentrations based on the present PPK model were in good agreement with the observed data. Conclusions: This is the first PPK model of S-1 including the CYP2A6 genotype. No significant financial relationships to disclose.
Phase I dose-escalating study of PM02734 in a 24-hour infusion schedule every 21 days in advanced solid tumors
Authors: Evans T. R. , Oaknin A. , Jones R. J. , Vandermeeren A. , Coronado C. , Soto-Matos A. , Germa J. R. , Crawford D. , Frontelo P. , Salazar R. 
Published: August 2020

2511 Background: PM02734 is a chemically synthesized depsipeptide with a broad spectrum of activity against solid tumors in vitro (breast, colon, lung, neuroblastoma, prostate, sarcoma and thyroid) and in vivo (breast, prostate, melanoma); as well as an acceptable non-clinical toxicology profile. Methods: Patients (pts) with metastatic or advanced solid tumors were enrolled in a phase I, open-label, dose-escalating study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT) and recommended dose (RD) of PM02734 infused over 24 hours every 21 days (d). The starting dose was 0.48 mg/m2. Cohorts of 1–6 pts were treated at different dose levels. Results: Thirty seven pts were treated in this study. The median age was 55 years (40–75), sex: males/females 20/19. The median PS was 1 (range 0–2). The most frequent cancer types were colon/ gastric/ sarcoma (n=8/5/5). Most patients were heavily pretreated, with a median of prior therapy lines of 4 (1–12). Patients were treated at 8 dose levels (0.48, 0.72, 1.0, 1.6, 2.4, 3.6, 5.4, and 6.8 mg/m2), the MTD was 6.8 mg/m2 and the RD was 5.4 mg/m2 (10 mg flat dose).Common toxicities grade ≤ 2 included asthenia, nausea/emesis, lymphopenia, injection site reactions and asymptomatic elevated transaminases (TAs). DLT were grade 3 asymptomatic, reversible TA elevations at 6.8 mg/m2. Preliminary PK data is characterized by long half life (>100 h), a wide distribution and high inter-patient variability. Clearance was not correlated with dose or body surface area (BSA), therefore, flat dose was implemented and the RD was explored with this schedule. Efficacy data showed one complete response (CR) of +28 months observed in a pt with metastatic large cell esophageal carcinoma, and five more showed stable disease (SD) for more than 3 months in different histologies. Conclusions: PM02734 shows to be safe, well tolerated and with evidence of activity (1 CR and 5 SD > 3 months) in pts with advanced solid tumors. The DLT was grade 3 asymptomatic and reversible TA elevations, and the RD for further phase II studies is 10 mg. [Table: see text]
Is the maximal tolerated dose still the best primary endpoint? Analysis of 288 dose-seeking phase I trials
Authors: Bonneterre J. , Adenis A. , Dansin E. , Ferté C. , Clisant S. , Penel N. 
Published: August 2020

2513 Background: For decades, the phase-2-recommended dose (P2RD) depends on toxicity (especially ‘the maximal tolerated dose', MTD) experienced by patients enrolled in dose-escalating phase 1 trials. Recent studies suggest that this policy is not suitable for modern anti-cancer agents. Methods: We retrospectively studied288 recently (1997–2008) published phase-I-trials using the maximal tolerated dose (MTD) to define the P2RD. We analysed how the P2RD was actually defined and then identified the risk factors for failure to establish the P2RD. Results: Seventeen percent (37/288) of the trials failed to identify the P2RD: 13% of studies investigating cytotoxic agents, 23% of studies investigating molecular targeted therapies and 33% of studies investigating immunostimulant agents. The risk factors for this failure were: trials investigating immunostimulant agents (Relative risk (RR)=2.9 [1.1–8.0]) or molecular targeted therapy (RR=3.1 [1.6–6.0]), single-agent regimen (RR=2.5 [1.3–4.9]), dose increments using of Fibonacci-modified series (RR=3.0 [1.5–5.8]), other method of escalation than ‘classical 3+3’ (RR=4.9 [1.6–14.2]) and almost the absence of clear definition of the MTD (RR=10.7 [3.6–32.2]). Indeed, in 9% of these studies (26/288), the definition of the MTD was not clearly established. Moreover, in 17% of all studies (38/288), the authors had proposed alternative but not standardised definitions of the P2RD (13 different definitions). These alternative definitions of P2DR were used in 18% of studies investigating cytotoxic agents, in 19% of studies investigating immunostimulant agents and in 24% of studies investigating molecular targeted therapies. Conclusions: In studies investigating cytotoxic agents, the definition of the MTD needs to be clarified in its 3 dimensions: severity of toxicity, duration of toxicity and proportion of patients experiencing this toxicity. Nevertheless, this appears less relevant for studies investigating immunostimulant agents and molecular targeted therapies. We have to explore and standardise alternative definitions of the P2DR in the era of modern agents. [Table: see text]
Comparison between RECIST evaluations and variations in tumor growth dynamics in patients included in phase I trials
Authors: Gomez-Roca C. A. , Koscielny S. , Dromain C. , Marzouk I. , Bidault F. , Bahleda R. , Ferte C. , Massard C. , Soria J. 
Published: August 2020

2515 Background: Monitoring of treatment efficacy is mainly based on RECIST post-treatment evaluations. We investigated the impact of pre-treatment tumor growth dynamics on the evaluation of response to treatment in phase I trials. Methods: Response at 12 weeks was evaluated using RECIST criteria in 76 patients treated in phase I trials. All patients had a scannographic evaluation at the start of the experimental treatment (D0), at least 2 evaluations before D0 and one evaluation after D0. The mean time between evaluations was 6 weeks. Tumor growth rate (GR=% change in tumor volume per month) was calculated for the pre-treatment period (from the 1st available evaluation to D0), and the experimental period (after D0). GR was compared to RECIST and to time to progression. Disease control (DC) was defined as stable disease, partial response or complete response. We also classified patients according to the variation in GR. Results: A total of 550 evaluations were performed: 256 before D0, 76 at D0 and 218 after. Tumor GR differed according to the time period: 26.6% per month during pre-treatment period vs. 6.6% in experimental period (P<0.01). The GR was significantly higher in patients without DC during pre-treatment (30% vs. 19%; P=0.003) and experimental time periods (+13% vs. -9%; P=0.0005). There was a significant association between a time to progression > 12 weeks and a decrease in GR during the experimental period (P=0.01). Several discordances however were noted. Eight patients with a time to progression >12 weeks (8/46=17%) had an increased GR with the experimental treatment. Thirteen patients who progressed <12 weeks (13/22=59%) had a decreased GR with the experimental treatment. Conclusions: Pre-treatment growth dynamic may directly impact RECIST evaluation of tumor response and thus should be carefully documented. Patients with slow growing tumors tend to experience DC, even if treatment has little effect. The evaluation of response to treatment should take into account pre-treatment tumor GR. No significant financial relationships to disclose.