bluuebunny/crossref_metadata_2025_split huggingface dataset:
EORTC Study 26041–22041: Phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with or without PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma—Results of a phase I trial
Authors: Brandes A. A. , Stupp R. , Hau P. , Sleijfer S. , Lacombe D. , Gorlia T. , Yun H. , Tosoni A. , Mirimanoff R. , van den Bent M. J. 
Published: March 2020

2026 Background: VEGF is an essential mediator of angiogenesis. PTK/ZK is an orally available tyrosine kinase inhibitor of all known VEGF receptors. The EORTC has initiated a randomized phase I/II study in which PTK/ZK is being investigated in combination with standard RT and concomitant TMZ. The results of the safety and dose-finding run-in of the triple combination are reported here. Methods: Escalating doses of PTK/ZK QD continuously (using classical 3+3 design) and concomitant RT (60 Gy) and TMZ (75 mg/m2/day) during 6–7 weeks were to be administered. During the adjuvant/maintenance part, PTK/ZK was prescribed at a fixed standard dose of 750mg bid until progression. Dose limiting toxicities (DLT) were defined as >G3 toxicity occurring during RT + 2 weeks. Results: 18 GBM pts (M/F: 11/7, median age: 53 years, PS 0/1) have been enrolled and complete data for 15 pts are currently available. DL1 (500 mg): 4 pts; no DLT; DL2 (1000 mg): 6 pts: 1 DLT: G3, liver enzyme (ALAT) elevation and hyponatremia DL3 (1250 mg); 8 pts: 3 DLTs: G3 hepatic toxicity (2 pts) and G3 platelets and G4 neutrophil (1 pt). In a 4th patient a G3 diarrhea and hepatic DLT leading to PTK/ZK interruption was doubtful therefore it was decided to extend DL3. Frequently observed possibly related non-dose limiting drug adverse events of all grades included: abdominal pain/cramping (2 pts), ALAT/ASAT elevation (10 pts), creatinine elevation (2 pts), allergic reaction (2 pts), constipation (4 pts), diarrhea (5 pts), fatigue (11 pts), hypertension (6 pts), nausea (8 pts), vomiting (3 pts), and weight loss (4 pts). All toxicities were reversible. Conclusions: MTD has been reached at 1250 mg and the recommended dose of PTK/ZK in combination with RT and TMZ is 1000 mg/day. A randomized 3-arm phase II will start accrual in January 2007. Patients will receive standard TMZ/RT alone or with PTK/ZK starting at the beginning of radiotherapy or at the beginning of adjuvant therapy 4 weeks after the end of radiotherapy. [Table: see text]
One week on/one week off regimen of temozolomide: Phase II trial in recurrent glioma
Authors: Wick W. , Wick A. , Schuth J. , Platten M. , Reifenberger G. , Weller M. 
Published: March 2020

2032 Background: Evaluation of toxicity and efficacy of a one week on/one week off temozolomide regimen in patients with recurrent gliomas. Methods: Ninety adult patients (median Karnofsky performance score 90; median age 51 years) with recurrent gliomas (9 patients with low-grade gliomas, 11 with anaplastic gliomas, 64 with GBM, and 6 with other brain tumors) accrued in one center received chemotherapy with temozolomide at 150 mg/m2/d (days 1–7 and 15–21 every four weeks) with individual dose adjustments according to hematological toxicity. Results: A total of 906 treatment weeks was delivered. Grade 4 hematotoxicity according to the common terminology criteria for adverse events (CTCEA v 3.0) was observed in 24 treatment weeks (2.6%). CTCEA grade 4 lymphopenia eventually developed in 11 patients (12%). There were no cumulative lymphopenia or opportunistic infections. The progression-free survival (PFS) rate at 6 months for the patients with GBM was 43.8%. The median PFS was 24 weeks (95% CI, 17 to 26 weeks), the median survival time (MST) from diagnosis of progression was 38 weeks (95% CI, 30 to 46 weeks), the 1-year survival rate from progression was 23%. O6-methylguanine DNA methyltransferase (MGMT) gene promoter methylation in the tumor tissue was not associated with longer PFS (p=0.37, log-rank test). Conclusions: This data imply that the one week on/one week off schedule is feasible, safe and effective and clearly warrant investigation in randomized studies. In contrast, protracted low-dose temozolomide at 75 mg/m2 has been shown to be toxic, resulting in cumulative lymphopenia and opportunistic infections. Compared with protracted low-dose temozolomide 1 the one week on/one week off schedule was far less toxic. In addition this dosing schedule may circumvent the disadvantage of an unmethylated MGMT gene promoter by depleting MGMT. [Table: see text]
Re-challenge with temozolomide (TMZ) at recurrence in high-grade gliomas (HGG)
Authors: Jauch T. , Hau P. , Bogdahn U. 
Published: March 2020

2034 Background: TMZ is standard therapy for patients (pts) with HGG. Recent data suggest potentially enhanced efficacy of alternative schedules of TMZ administration based on optimizing depletion of MGMT. However, no prospective data have been published on the efficacy of TMZ regimens after failure of first-line TMZ (FL-TMZ). We therefore assessed the outcome of rechallenge with TMZ in pts with HGG. Methods: A retrospective review of pt with recurrent HGG who were rechallenged with TMZ between Jan 2000 and Oct 2006 was conducted. Standard criteria for rechallenge were as follows: if pts relapsed=8 wks after discontinuation of FL-TMZ, they were treated with the same or an alternative regimen of TMZ; however, if they progressed while still receiving TMZ, they were treated with an alternative regimen. Results: Of a total 81 pts identified, 54 intra-institutional pts were evaluable, 23 glioblastoma (GBM), 22 anaplastic glioma (AG). Median age was 44 yr with median KPS of 80. The response rate (RR) to FL-TMZ was 65% in GBM and 95% in AG using Macdonald criteria. At rechallenge, pts received one of four TMZ regimens: 150–200 mg/m2/d for 5/28 days (n=35), 150 mg/m2/d for 7/14 days (n=7), 75 mg/m2/d for 21/28 days (n=4), or continuous 50 mg/m2/d (n=7). All pts had progressed during FL-TMZ or after initial discontinuation of TMZ. Discontinuation during rechallenge TMZ was due to progressive disease in 36 pts and patient request in 6 pts. None of the pts discontinued due to toxicity. The response rates were 66% and 70% in GBM and AG, respectively. 8/12 non-responders to FL-TMZ responded to alternate regimens of TMZ. Median time to progression (TTP) was 20 weeks and 22 weeks, respectively. Six-month progression-free survival was 41% in GBM and 43% in AG. Conclusions: TMZ was well tolerated without major toxicities and had a good RR in pts who had previously failed TMZ. Durable responses were observed in patients who had not initially responded to front-line TMZ. These data suggest that rechallenge with TMZ in previous responders and non-responders warrants further investigation in a prospective study. No significant financial relationships to disclose.
Phase I study of vorinostat (suberoylanilide hydroxamic acid) in combination with temozolomide (TMZ) in patients with malignant gliomas (NABTC 04–03)
Authors: Wen P. Y. , Puduvalli V. , Kuhn J. , Reid J. , Cloughesy T. , Yung W. A. , Chang S. M. , Robbins H. I. , McGovern R. , Ames M. , Prados M. D. 
Published: March 2020

2039 Background: Vorinostat (V) is an oral inhibitor of histone deacetylase. In preclinical studies it inhibits growth of glioblastoma (GBM) cell lines and has supra-additive activity when combined with TMZ. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I study of V in combination with TMZ in patients with malignant gliomas (MG). Eligibility criteria are histologically proven GBM and anaplastic gliomas (AG) who have received radiotherapy and have not progressed on temozolomide, > 18 yrs old, life expectancy > 8 weeks, KPS > 60, adequate bone marrow reserve and organ function. There was no limitation to the type of antiepileptic drugs that could be used. All patients received TMZ at a dose of 150 mg/m2/day on days 1–5 days every 28 days. Variable doses of V were administered with food on days 1–14 every 28 days. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade 4 hematologic toxicity except for grade 3 thrombocytopenia, and any grade 3 non-hematologic toxicities. Escalation was performed in standard groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 patients. PKs were determined on cycle 1 for TMZ, V and its metabolites. Results: To date, 19 eligible patients have been enrolled (15 GBM; 4 AG). Patients’ characteristics are 11 male, 8 female; median age 54 yrs (36–78); median KPS 90 (70–100). DLTs were encountered at 300 mg bid of vorinostat (1 grade 3 thrombocytopenia; 1 grade 3 fatigue in 3 patients), 200 mg tid (1 grade 3 nausea, 1 grade 4 thrombocytopenia in 3 patients) and 200 mg twice daily (grade 3 fatigue in 2/6 patients). No DLTs were encountered in 6 patients receiving 300 mg daily. TMZ PKs included [n=16: Cmax 5.2 (± 1.55) μg/ml; AUC 20.1 (±4.66) μg x hr/ml; t1/2 1.9 (±0.32)/hr]. Vorinostat PKs (300mg dose level) were [n=4; Cmax 267 (±174) ng/ml; AUC0–8 603 (±197) ng x hr/ml]. The t1/2 for V and its glucuronide metabolite were identical (1.6 hrs) vs. 5.6 hrs for the acid metabolite. Conclusions: The MTD of vorinostat in combination with TMZ is 300 mg daily on days 1–14 every 28 days. Final PK results, and toxicities from an additional 10 patients enrolled at the MTD will be presented. [Table: see text]
Clinical results of continuous intrathecal or intracavitary administration of sodium butyrate for patients with recurrent and progressive malignant glioma: Experience with 23 cases
Authors: Nakagawa H. , Yoshida M. , Motozaki T. , Yoshioka K. , Itoh K. 
Published: March 2020

2040 Background: We evaluated the clinical potential of intrathecal use of sodium butyrate (NaB) for malignant glioma in experimental research. Based on the results of experimental research, continuous intrathecal or intracavitary administration of NaB for recurrent and progressive malignant glioma was clinically attempted. We evaluated the efficacy and therapeutic safety of this treatment. Methods: A total of 23 patients (pts)(glioblastoma:GB,19; anaplastic astrocytoma: AN, 4) were enrolled in this study between Oct. 2001 and Feb. 2006 and followed until Oct. 2006. Five patients showed CSF dissemination of tumor cells. Sixty milimolar NaB was administered to all pts after dose-escalation study using a simple balloon pump system and continued as long as possible by changing the pump containing NaB weekly. The primary end point was radiographic response, and the secondary end points were progression-free survival (PFS), overall survival, and therapeutic safety. Results: Nineteen of 23 pts (GB, 16; AN,3) were evaluable. Nine pts showed regression of the tumor, 5 showed stable disease, and 5 showed growth of the tumor. The overall median PFS of the pts was 6.0 months (mos) and that of pts with GB was 5.5 mos, while the 6-month PFS was 53.3.% and that of GB was 50%. The overall median survival time was 11.0 mos and that of GB was also 11.0 mos. The overall 1-year survival rate was 42 % and that of GB was 29.4%. Four of 5 pts with CSF tumor cell dissemination showed therapeutic response, including temporary negative cytological conversion. Various adverse effects and complications have been encountered to date, including bacterial meningitis, temporary bradycardia and convulsions. Conclusions: The present therapy was well tolerated and resulted in long-term inhibition of the growth of the tumor in some pts, and showed therapeutic safety. No significant financial relationships to disclose.
Intra-arterial chemotherapy and osmotic blood-brain barrier disruption for primitive neuroectodermal tumors
Authors: Jahnke K. , Kraemer D. F. , Fortin D. , Bell S. , Doolittle N. D. , Knight K. R. , Muldoon L. L. , Neuwelt E. A. 
Published: March 2020

2046 Background: The blood-brain barrier (BBB) may, in part, contribute to the poor outcome in primitive neuroectodermal tumors (PNETs) treated with chemotherapy. Intra-arterial chemotherapy and osmotic BBB disruption (IA/BBBD) increases drug delivery to the central nervous system while preserving neurocognitive functioning and minimizing systemic toxicity. Methods: The study aims were evaluation of efficacy and toxicity in patients with PNETs other than medulloblastoma treated with IA/BBBD. A chart review of patients from 3 centers treated on various protocols was conducted. Study outcomes included overall survival (OS) and time to progression (TTP, from date of first study treatment). Times to events were estimated using Kaplan-Meier product limit method. Results: Twenty-nine patients (median age 20.5 years, median Karnofsky performance status 90%) were identified. Pathologic diagnoses included pineoblastoma (n = 13 patients), atypical pineocytoma (n = 2), neuroblastoma (n = 3), and other supratentorial or disseminated PNETs (n = 11). Thirteen patients were pretreated before IA/BBBD: 5 with only chemotherapy, 4 with radiotherapy alone, and 4 with both. Intraarterial chemotherapy included carboplatin (n = 24), methotrexate (n = 3), or a combination of both (n = 2). Six patients had a complete and 11 a partial response to IA/BBBD (response rate 58.6%). Ten patients received adjuvant radiotherapy. Twenty (69%) patients relapsed. Median TTP was 1.1 (95% confidence interval 0.8 to 8.4) years, and 9/28 (32.1%) evaluable patients have not yet progressed. Median OS was 2.5 (1.2–11.7) years, 40% survived 4.0 years, and 30% survived 8.7 years. Nine out of 29 (31%) patients are alive, and 6/29 (20.7%) are alive 11+ years after first treatment. Twenty patients have died: 16 due to disease progression, 3 due to toxicity, and 1 due to other reasons. No deaths or permanent neurologic or vascular sequelae related to the IA/BBBD procedure were observed. Conclusions: Survival in PNETs treated with IA/BBBD appears favorable as compared to the literature, especially when considering that 11 patients received IA/BBBD as salvage treatment. A plateau in survival suggests that select patients may be cured. No significant financial relationships to disclose.
A phase II study of radiosurgery and temozolomide for patients with one to four brain metastases
Authors: Fiveash J. B. , Sawrie S. M. , Guthrie B. L. , Spencer S. A. , Meredith R. F. , Markert J. M. , Nordal R. A. , Conry R. M. , Nabors L. B. 
Published: March 2020

2048 Background: To determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1–4 brain metastases treated with radiosurgery without whole brain radiation therapy. Methods: Twenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase II trial of radiosurgery (15–24 Gy) and adjuvant temozolomide. Temozolomide was started within 14 days of radiosurgery and was administered 150–200 mg/m2 p.o. q day x 5 days in 28 day cycles. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy. If more than 4 metastases were identified on the MRI performed on the day of radiosurgery, then the patient could still be treated on the clinical trial if all tumors could be treated with radiosurgery. In addition to clinical and radiographic follow-up, QOL was assessed utilizing the FACT-Br questionnaire. Results: Twenty-five patients were enrolled 2002–2005; three were not evaluable for determining DBF. Of the remaining twenty-two patients, tumor types included NSCLC (n=8), melanoma (n=7), other (n=7). Extracranial disease was present in ten (45%) patients. The median number of tumors was 3 (range 1–6). The median overall survival was 31 weeks. The median radiographic follow-up for patients that did not develop DBF was 33 weeks. Six patients developed DBF. The one year actuarial risk of DBF was 37%. Patients with melanoma had a higher risk of DBF than other patients (p<0.001, log-rank). Only 1/15 patients without melanoma vs. 5/7 patients with melanoma developed DBF. 15 serious adverse events (SAEs) occurred in 10 of the patients, but none of the SAEs were judged to be likely related to temozolomide. Among patients that experienced DBF, no significant differences were seen in QOL when pretreatment FACT-Br and time of distant brain failure FACT-Br scores were compared. Conclusions: Adjuvant temolozomide after radiosurgery is associated with a low risk of distant brain failure in non-melanoma patients. Larger clinical trials should examine the relative efficacy and QOL of WBRT and temozolomide in non-melanoma brain metastases patients. No significant financial relationships to disclose.
CD8 count measurement has independent prognostic significance in individuals with AIDS-Kaposi sarcoma
Authors: Stebbing J. , Sanitt A. , Teague A. , Powles T. , Nelson M. , Gazzard B. , Bower M. 
Published: March 2020

20500 Background: We recently published a prognostic index for Acquired Immunodeficiency Syndrome (AIDS)-associated Kaposi sarcoma (KS) diagnosed in the era of highly active antiretroviral therapy (HAART) based on clinical and routine laboratory characteristics. Because immune subset measurement is often performed in human immunodeficiency virus (HIV) positive individuals, we examined whether these were predictive of mortality independently of the prognostic index, or could predict time to progression of KS. Methods: We performed univariate and multivariate Cox regression analyses on a dataset of 326 individuals with AIDS-KS to identify immune subset covariates predictive of overall survival and time to progression. Adaptive (CD8 T cell and CD19 B cell) and innate (CD16/56 natural killer cell) immune parameters were studied by flow cytometry. Results: In univariate analyses all 3 immune subsets had significant effects on overall survival (p < 0.025). In multivariate analyses including the prognostic index, only CD8 counts remained significant (p = 0.026) although its effect on the overall prognostic index is small. An increase of 100 cells/mm3 in the CD8 count confers a 5% improvement in overall survival. Individuals with a higher CD8 count did not have an increased time to progression. Patients who were already on HAART at the time of KS diagnosis did not have a shorter time to progression than those who were antiretroviral naïve at KS diagnosis. Conclusions: The CD8 count appears to provide independent prognostic information in individuals with AIDS-KS. Measurement of the CD8 count is clinically useful in patients with KS. No significant financial relationships to disclose.
International collaboration is feasible in trials for rare conditions: The EURAMOS experience
Authors: Marina N. , Bielack S. , Sydes M. , Bernstein M. , Butterfass-Bahloul T. , Smeland S. , Holiday A. , Whelan J. 
Published: March 2020

20501 Background: Osteosarcoma is rare and the outcome for patients has plateaued following the introduction of multi-agent chemotherapy. To demonstrate further improvements would likely require large numbers of patients, only achievable in this setting via International collaboration. Therefore, in October 2001, 4 multinational groups - Children's Oncology Group (COG), Cooperative Osteosarcoma Study Group (COSS), European Osteosarcoma Intergroup (EOI) and Scandinavian Sarcoma Group (SSG) - agreed on the merits of collaboration to determine whether altering post-operative therapy based on histological response improved outcome. Following a number of practical and regulatory hurdles the trial opened to accrual in April 2005. Methods: Eligibility criteria include: new diagnosis with resectable osteosarcoma; age <40 years; normal organ function. Standard therapy includes 29 weeks of cisplatin, doxorubicin and high-dose methotrexate (MAP). Following two cycles of cisplatin/doxorubicin and 2–6 cycles of high-dose methotrexate, patients undergo resection. Post-operative therapy is dependent on histological response. Good histological responders (>90% necrosis) are randomized to continuing MAP or MAP with maintenance pegylated interferon. Poor histological responders are randomized to MAP or MAP plus ifosfamide and etoposide. Results: All groups are recruiting and accrual is ahead of schedule: 373 patients have been enrolled (159 COG, 108 COSS, 83 EOI, 23 SSG) and 160 patients randomized: 87 (54%) good responders (46 MAP), 73 (46%) poor responders (39 MAP). Conclusions: International collaboration is feasible and results in rapid accrual of large number of patients. The implementation of such trials is difficult and time consuming due to the complexity of multinational regulatory issues. However, the effort is worthwhile to potentially improve outcomes for patients with rare diseases. No significant financial relationships to disclose.
Clinical, pathological and immunistochemistry characterization of primary breast cancer metastasizing to the central nervous system (CNS): Analysis of time to development of CNS metastasis
Authors: Filho A. F. Ferreira , Saueressig S. , da Silva D. L. , dos Santos M. P. , Wunder A. P. , Santana R. , Zetler C. 
Published: March 2020

2051 Background: The characterization of breast cancer patients (BCP) with high risk of developing CNS metastases still remains a challenge. The identification of these patients could enable new strategies of prevention, early detection and innovative treatments. Methods: We analyzed the records of 950 BCP treated at our institutions during 1997 to 2003 and found that 38 (4%) of these patients developed CNS metastases. In these 38 patients, we reviewed the clinical course, initial pathology and the primary tumor immunohistochemistry profile of hormone receptors, HER-2, p53, as well as microvessel density by the Chalkey count technique by the anti-CD105 antibody E-9. Results: Median age was 54 years (30–75), 11% < 40 years, median tumor size was 3.5 cm (1.2–17). Median number of positive axillary nodes was 6 (0–27) and axillary lymph nodes were negative in 10 patients (29%). Only two patients (5%) had grade 1 tumors. The median survival after the development of CNS metastases was of 4.5 months (0.5 - 27 months), with 8% of patients living longer than one year. Treatment consisted of whole brain radiotherapy in 79% of the patients. Hormone negative receptor status was found in 24 patients (63%), HER-2 was overexpressed in 26 patients (68%) and p53 was positive in 16 patients (46%). Mean Microvessel density was > 7 in 23 patients (59%). For the whole group of patients, the median time to the development of CNS metastases was 22 months (5–96). Patients with p53 positive tumors had a lower time to development of CNS metastasis (19.3 versus 34.6 months, p = 0.005), as compared to p53 negative tumors. No differences were found between subgroups of patients, as defined by tumor grade, microvessel density, hormone receptors and HER-2 status, or positivity of axyllary lymph nodes. Conclusions: The primary tumors of BCP who developed CNS metastases showed a high percentage of hormonoreceptor negativity (63%), overexpression of HER-2 (68%), and high counts of microvessel density . While the role of CD 105 expression and the development of CNS metastases in BC patients deserve further research, p53 positivity may be a marker of risk of early development of CNS metastases in BCP. No significant financial relationships to disclose.