Effects of cediranib, a VEGF signaling inhibitor, in combination with chemoradiation on tumor blood flow and survival in newly diagnosed glioblastoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2009-2009 ◽  
Author(s):  
Elizabeth Robins Gerstner ◽  
Kyrre E. Emblem ◽  
Andrew S. Chi ◽  
April F. Eichler ◽  
Fred Hochberg ◽  
...  
Keyword(s):  
Blood Flow ◽  
Disease Progression ◽  
Progression Free Survival ◽  
Subtotal Resection ◽  
Newly Diagnosed ◽  
Tumor Blood Flow ◽  
Phase Ib ◽  
Entire Cohort ◽  
Radiographic Response ◽  
Newly Diagnosed Glioblastoma

2009 Background: Anti-angiogenic therapy is hypothesized to synergize with radiation and chemotherapy by improving tumor blood flow. We evaluated the tolerability, efficacy and potential mechanism of action of radiation, temozolomide, and cediranib in newly diagnosed glioblastoma patients. Methods: Newly diagnosed glioblastoma patients were treated with radiation, temozolomide, and cediranib followed by monthly temozolomide for 6 cycles and daily cediranib until tumor progression or toxicity as part of an IRB-approved, Phase Ib/II clinical trial. MRI scans including measurement of cerebral blood flow were performed at baseline, weekly during the 6 weeks of chemoradiation and then monthly. Radiographic response was determined by RANO criteria. Results: Six patients were enrolled in the phase Ib part of the study with cediranib 30 mg daily in combination with temozolomide and radiation. No dose-limiting toxicities were identified. Forty patients were enrolled in the phase II part of the study. Among the entire cohort of 46 patients, median age was 57 (range 35-74), median KPS was 90% (60-100), 36 patients underwent a subtotal resection and 10 underwent biopsy. 26/30 patients taking corticosteroids were able to taper corticosteroids during chemoradiation. Off study reasons included toxicity (14), disease progression (18), and patient preference (2). Five patients remain on study without disease progression and 20 patients have died. Median duration on study was 158 days. Median progression free survival was 288 days (95%CI 240,∞) and median overall survival was 786 days (95%CI 411 ,∞). Best radiographic response in patients who completed chemoradiation was CR in 2 patients, PR in 20 patients, and SD in 15 patients. Patients with increased tumor perfusion during chemoradiation survived nearly 1 year longer (mean OS=611 days) than patients with decreased perfusion (mean OS=269 days). Conclusions: Cediranib was well tolerated and led to improved PFS and OS compared to historical controls, particularly in those with improved perfusion. This combination is being evaluated in an ongoing randomized trial (RTOG 0837).

scholarly journals CTIM-20. PHASE I STUDY OF IBRUTINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii37-ii37
Author(s):  
Yasmeen Rauf ◽  
David Peereboom ◽  
Jaleh Fallah ◽  
Cathy Schilero ◽  
Pamela Lackner ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Disease Progression ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Newly Diagnosed ◽  
Self Renewal ◽  
Nonreceptor Tyrosine Kinase ◽  
Patient Will ◽  
Newly Diagnosed Glioblastoma ◽  
Clinical Trial Results

Abstract BACKGROUND Glioblastoma is a devastating disease that is notoriously resistant to current therapies, leading to dismal patient outcomes and a median survival of just 14.6 months. A major problem in glioblastoma treatment is the inability to effectively target the cell population that gives rise to recurrence. These cells, known as glioma stem cells (GSCs) or tumor propagating cells are endowed with a large capacity for self-renewal to propagate the tumor. GSCs are resistant to radiation. Ibrutinib is a first-in-class, potent, orally administered, covalently binding Inhibitor of Bruton’s Tyrosine Kinase (BTK). Ibrutinib is a small-molecule tyrosine kinase. It also inhibits BMX. Bone marrow X-linked (BMX) nonreceptor tyrosine kinase activates STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs. Hence a combination of ibrutinib with radiation and or temozolomide in patients with newly diagnosed Glioblastoma is warranted. METHODS This is a two arm study. Arm 1 is for patients with unmethylated MGMT Glioblastoma. Every patient gets ibrutinib and 60 Gy radiation over 6 weeks. Patients will undergo a 4-week break and Ibrutinib treatment will then continue until disease progression, intolerable toxicity or death. Arm 2 is for patients with MGMT methylated glioblastoma. Every patient will receive Ibrutinib and 60 Gy radiation and daily Temozolomide at 75 mg/m2 for 6 weeks. Patients will undergo a 4-week break then receive daily ibrutinib and adjuvant Temozolomide. The temozolomide will continue until disease progression, intolerable toxicity or death or maximum of 6 cycles. Ibrutinib treatment will continue until disease progression, intolerable toxicity or death. RESULTS The maximum tolerated dose (MTD) of Ibrutinib with radiation (2 Gy x 30) in patients in each arm will be reported. The safety of Ibrutinib with radiation and with radiation and temozolomide will be reported. The Progression free survival and overall survival in each arm will be reported. CONCLUSION This is an ongoing clinical trial. Results will be reported once study is complete.

scholarly journals RADT-25. EVALUATING LYMPHOCYTE COUNTS IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii186-ii187
Author(s):  
Lubna Hammoudeh ◽  
Mary Jane Lim-Fat ◽  
Daniel Cagney ◽  
Ayal A Aizer ◽  
Shyam Tanguturi ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Subtotal Resection ◽  
Newly Diagnosed ◽  
Total Resection ◽  
Free Survival ◽  
Newly Diagnosed Glioblastoma

Abstract BACKGROUND Glioblastoma (GBM) patients are treated with chemotherapy, radiation therapy (RT) and often corticosteroids, which can all contribute to lymphopenia. We examined lymphopenia with respect to incidence, predictors, and association with progression-free survival (PFS) and overall survival (OS). METHODS We reviewed 349 newly diagnosed adult GBM patients treated at our institution in the temozolomide (TMZ) era with available lymphocyte and RT records. Data was reviewed from diagnosis through the chemoradiation (CRT) phase, defined as the period upto 6 weeks after RT. Linear regression and Cox proportional hazards modeling were used to evaluate outcomes. RESULTS Median age was 60 years (range, 19-90); 86% had KPS ≥ 70, 30% had gross total resection (GTR), and 91% received TMZ. Prior to RT, 60% (205/341) patients had a lymphocyte measurement < 1.0 x 1000 cells [K]/μL and 15% (50/341) had < 0.5 K/μL. During the CRT phase of therapy, 83% (270/324) had at least one lymphocyte measurement < 1.0 K/μL, 42% (135/324) < 0.5 K/μL, and 5% (16/324) < 0.2 K/μL. Older age was associated with lower lymphocytes pre-RT, while subtotal resection, TMZ use, and RT dose was associated with lower lymphocyte counts during CRT (p< 0.05). On multivariable analysis (MVA), age (AHR 1.03, p< 0.01), KPS > 70 (AHR 0.35, p< 0.01), MGMT status (AHR 0.47, p< 0.01), GTR (AHR 0.67, p=0.03), TMZ (AHR 0.27, p< 0.01) and lymphopenia during CRT (AHR 1.80, p< 0.01) were significantly associated with OS. Pre-RT lymphocyte level was associated with PFS on UVA (HR 0.81, p=0.03) but not on MVA (p=0.27). Lymphocyte count during CRT was not associated with PFS (p=0.24). CONCLUSION Lymphopenia is common in GBM, and chemoradiation-related lymphopenia was associated with inferior OS relative to patients without lymphopenia. Further characterization of the mechanism and optimal treatment of patients with lymphopenia are warranted to improve outcomes.

Study Protocol: Early Stereotactic Gamma Knife Radiosurgery to Residual Tumor After Surgery of Newly Diagnosed Glioblastoma (Gamma-GBM)

Neurosurgery ◽  
2018 ◽  
Vol 84 (5) ◽  
pp. 1133-1137
Author(s):  
Stefanie Brehmer ◽  
Mario Alexander Grimm ◽  
Alex Förster ◽  
Marcel Seiz-Rosenhagen ◽  
Grit Welzel ◽  
...  
Keyword(s):  
External Beam Radiotherapy ◽  
Gamma Knife Radiosurgery ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Residual Tumor ◽  
Extent Of Resection ◽  
Subtotal Resection ◽  
Newly Diagnosed ◽  
Open Label ◽  
Newly Diagnosed Glioblastoma

Abstract BACKGROUND Glioblastoma (GBM) is the most common malignant brain tumor in adult patients. Tumor recurrence commonly occurs around the resection cavity, especially after subtotal resection (STR). Consequently, the extent of resection correlates with overall survival (OS), suggesting that depletion of postoperative tumor remnants will improve outcome. OBJECTIVE To assess safety and efficacy of adding stereotactic radiosurgery (SRS) to the standard treatment of GBM in patients with postoperative residual tumor. METHODS Gamma-GBM is a single center, open-label, prospective, single arm, phase II study that includes patients with newly diagnosed GBM (intraoperative via frozen sections) who underwent STR (residual tumor will be identified by native and contrast enhanced T1-weighted magnetic resonance imaging scans). All patients will receive SRS with 15 Gy (prescribed to the 50% isodose enclosing all areas of residual tumor) early (within 24-72 h) after surgery. Thereafter, all patients undergo standard-of-care therapy for GBM (radiochemotherapy with 60 Gy external beam radiotherapy [EBRT] plus concomitant temozolomide and 6 cycles of adjuvant temozolomide chemotherapy). The primary outcome is median progression-free survival, secondary outcomes are median OS, occurrence of radiation induced acute (<3 wk), early delayed (<3 mo), and late (>3 mo post-SRS) neurotoxicity and incidence of symptomatic radionecrosis. EXPECTED OUTCOMES We expect to detect efficacy and safety signals by the immediate application of SRS to standard-of-care therapy in newly diagnosed GBM. DISCUSSION Early postoperative SRS to areas of residual tumor could bridge the therapeutic gap between surgery and adjuvant therapies.

scholarly journals Pulsed radiation therapy for the treatment of newly diagnosed glioblastoma

2020 ◽  
Author(s):  
Muayad F Almahariq ◽  
Thomas J Quinn ◽  
Jessica D Arden ◽  
P T Roskos ◽  
George D Wilson ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Verbal Learning ◽  
Prospective Trial ◽  
Progression Free Survival ◽  
Neurocognitive Function ◽  
Tumor Control ◽  
Subtotal Resection ◽  
Newly Diagnosed ◽  
Clinical Series ◽  
Newly Diagnosed Glioblastoma

Abstract Background Pulsed radiation therapy (PRT) has shown effective tumor control and superior normal-tissue sparing ability compared with standard radiotherapy (SRT) in preclinical models and retrospective clinical series. This is the first prospective trial to investigate PRT in the treatment of patients with newly diagnosed glioblastoma (GBM). Methods This is a single-arm, prospective study. Patients with newly diagnosed GBM underwent surgery, followed by 60 Gy of PRT with concurrent temozolomide (TMZ). Each day, a 2-Gy fraction was divided into ten 0.2-Gy pulses, separated by 3-minute intervals. Patients received maintenance TMZ. Neurocognitive function (NCF) and quality of life (QoL) were monitored for 2 years using the Hopkins Verbal Learning Test‒Revised and the European Organisation for Research and Treatment of Cancer QLQ-C30 QoL questionnaire. Change in NCF was evaluated based on a minimal clinically important difference (MCID) threshold of 0.5 standard deviation. Results Twenty patients were enrolled with a median follow-up of 21 months. Median age was 60 years. Forty percent underwent subtotal resection, and 60% underwent gross total resection. One patient had an isocitrate dehydrogenase (IDH)–mutated tumor. Median progression-free survival (PFS) and overall survival (OS) were 10.7 and 20.9 months, respectively. In a post-hoc comparison, median OS for the prospective cohort was longer, compared with a matched cohort receiving SRT (20.9 vs 14 mo, P = 0.042). There was no decline in QoL, and changes in NCF scores did not meet the threshold of an MCID. Conclusions Treatment of newly diagnosed GBM with PRT is feasible and produces promising effectiveness while maintaining neurocognitive function and QoL. Validation of our results in a larger prospective trial warrants consideration.

Survival and Neurodevelopmental Outcome of Young Children With Medulloblastoma at St Jude Children's Research Hospital

1999 ◽  
Vol 17 (12) ◽  
pp. 3720-3728 ◽  
Author(s):  
Andrew W. Walter ◽  
Raymond K. Mulhern ◽  
Amar Gajjar ◽  
Richard L. Heideman ◽  
David Reardon ◽  
...  
Keyword(s):  
Survival Rate ◽  
Young Children ◽  
Disease Progression ◽  
Hormone Replacement ◽  
Neurodevelopmental Outcome ◽  
Progression Free Survival ◽  
Research Hospital ◽  
Entire Cohort ◽  
Salvage Radiation Therapy ◽  
Long Term Survivors

PURPOSE: Young children treated for medulloblastoma are at especially high risk for morbidity and mortality from their disease and therapy. This study sought to assess the relationship, if any, between patient outcome and M stage. Neuropsychologic and endocrine outcomes were also assessed. PATIENTS AND METHODS: Twenty-nine consecutively diagnosed infants and young children were treated for medulloblastoma at St Jude Children's Research Hospital between November 1984 and December 1995. All patients were treated with the intent of using postoperative chemotherapy to delay planned irradiation. RESULTS: The median age at diagnosis was 2.6 years. Six patients completed planned chemotherapy without progressive disease and underwent irradiation at completion of chemotherapy. Twenty-three children experienced disease progression during chemotherapy and underwent irradiation at the time of progression. The 5-year overall survival rate for the entire cohort was 51% ± 10%. The 5-year progression-free survival rate was 21% ± 8%. M stage did not impact survival. All patients lost cognitive function during and after therapy at a rate of −3.9 intelligence quotient points per year (P = .0028). Sensory functions declined significantly after therapy (P = .007). All long-term survivors required hormone replacement therapy and had growth abnormalities. CONCLUSION: The majority of infants treated for medulloblastoma experienced disease progression during initial chemotherapy. However, more than half of these patients can be cured with salvage radiation therapy, regardless of M stage. The presence of metastatic disease did not increase the risk of dying from medulloblastoma. All patients treated in this fashion have significant neuropsychologic deficits. Our experience demonstrates that medulloblastoma in infancy is a curable disease, albeit at a significant cost.

RADT-13. SPARE TRIAL: SCALP-SPARING RADIATION WITH CONCURRENT TEMOZOLOMIDE AND TUMOR TREATING FIELDS FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi43-vi44
Author(s):  
Ryan Miller ◽  
Andrew Song ◽  
Ayesha S Ali ◽  
Voichita Bar-Ad ◽  
Nina, L Martinez ◽  
...  
Keyword(s):  
Radiation Treatment ◽  
Methylation Status ◽  
Treatment Interruption ◽  
Newly Diagnosed ◽  
Entire Cohort ◽  
Tumor Treating Fields ◽  
Newly Diagnosed Glioblastoma ◽  
Prospective Trials ◽  
Dose Constraints ◽  
Topical Medications

Abstract INTRODUCTION Current adjuvant treatment for patients with newly diagnosed glioblastoma includes concurrent chemoradiation and maintenance temozolomide with Tumor Treating Fields (TTFields). We report our clinical trial evaluating feasibility and tolerability of scalp-sparing radiation with concurrent temozolomide and TTFields. METHODS Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma with a KPS of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with temozolomide (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment. RESULTS Thirty patients were enrolled. Twenty were male and ten were female, with a median age of 58 years (range 19 to 77 years). Median follow-up was 10.8 months (range 1.6 to 21.3 months). Twenty (66.7%) patients had unmethylated MGMT promotor and ten (33.3%) patients had methylated promoter. Scalp dose constraints were achieved for all patients. Skin adverse events (erythema, dermatitis, irritation, folliculitis) were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. No patient had radiation treatment interruption due to skin AEs. Other Grade 1 events included pruritus (33.3%), fatigue (30%), nausea (13.3%), headache (10%), dizziness (6.7%), and cognitive impairment (3.3%). Other Grade 2 events included headache (3.3%). The median PFS for the entire cohort was 9.1 months (at least 8.5 months, 95% confidence). The median PFS for patients with MGMT promoter methylation status was 11.4 months (at least 9.5 months, 95% confidence). Overall survival was not reached. CONCLUSIONS Concurrent TTFields with scalp-sparing chemoradiation is feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.

scholarly journals Upfront Magnetic Resonance Imaging-Guided Stereotactic Laser-Ablation in Newly Diagnosed Glioblastoma: A Multicenter Review of Survival Outcomes Compared to a Matched Cohort of Biopsy-Only Patients

Neurosurgery ◽  
2018 ◽  
Vol 85 (6) ◽  
pp. 762-772 ◽  
Author(s):  
Alireza M Mohammadi ◽  
Mayur Sharma ◽  
Thomas L Beaumont ◽  
Kevin O Juarez ◽  
Hanna Kemeny ◽  
...  
Keyword(s):  
Laser Ablation ◽  
Tumor Volume ◽  
Cleveland Clinic ◽  
Damage Threshold ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Newly Diagnosed ◽  
Prognostic Groups ◽  
Newly Diagnosed Glioblastoma ◽  
Disease Specific

Abstract BACKGROUND Laser ablation (LA) is used as an upfront treatment in patients with deep seated newly diagnosed Glioblastoma (nGBM). OBJECTIVE To evaluate the outcomes of LA in patients with nGBM and compare them with a matched biopsy-only cohort. METHODS Twenty-four nGBM patients underwent upfront LA at Cleveland clinic, Washington University in St. Louis, and Yale University (6/2011-12/2014) followed by chemo/radiotherapy. Also, 24 out of 171 nGBM patients with biopsy followed by chemo/radiotherapy were matched based on age (&lt; 70 vs ≥ 70), gender, tumor location (deep vs lobar), and volume (&lt;11 cc vs ≥11 cc). Progression-free survival (PFS), overall survival (OS), and disease-specific PFS and OS were outcome measures. Three prognostic groups were identified based on extent of tumor ablation by thermal-damage-threshold (TDT)-lines. RESULTS The median tumor volume in LA (n = 24) and biopsy only (n = 24) groups was 9.3 cm3 and 8.2 cm3 respectively. Overall, median estimate of OS and PFS in LA cohort was 14.4 and 4.3 mo compared to 15.8 mo and 5.9 mo for biopsy only cohort. On multivariate analysis, favorable TDT-line prognostic groups were associated with lower incidence of disease specific death (P = .03) and progression (P = .05) compared to other groups including biopsy only cohort. Only age (&lt;70 yr, P = .02) and tumor volume (&lt;11 cc, P = .03) were favorable prognostic factors for OS. CONCLUSION The maximum tumor coverage by LA followed by radiation/chemotherapy is an effective treatment modality in patients with nGBM, compared to biopsy only cohort. The TDT-line prognostic groups were independent predictor of disease specific death and progression after LA.

scholarly journals Safety and tolerability of asunercept plus standard radiotherapy/temozolomide in Asian patients with newly-diagnosed glioblastoma: a phase I study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kuo-Chen Wei ◽  
Peng-Wei Hsu ◽  
Hong-Chieh Tsai ◽  
Ya-Jui Lin ◽  
Ko-Ting Chen ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Newly Diagnosed ◽  
Open Label ◽  
Free Survival ◽  
Asian Patients ◽  
Newly Diagnosed Glioblastoma ◽  
Secondary Endpoints

AbstractAsunercept (company code APG101 [Apogenix AG]; company code CAN008 [CANbridge Pharmaceuticals]) is a novel glycosylated fusion protein that has shown promising effectiveness in glioblastoma. This Phase I study was initiated to evaluate the tolerability and safety of asunercept in combination with standard radiotherapy and temozolomide (RT/TMZ) in Asian patients with newly diagnosed glioblastoma. This was the Phase I portion of a Phase I/II open label, multicenter trial of asunercept plus standard RT/TMZ. Adults with newly-diagnosed glioblastoma received surgical resection followed by standard RT/TMZ plus asunercept 200 mg/week (Cohort 1) or 400 mg/week (Cohort 2) by 30-min IV infusion. The primary endpoint was the safety and tolerability of asunercept during concurrent asunercept and RT/TMZ; dose-limiting toxicities were observed for each dose. Secondary endpoints included pharmacokinetics (PK) and 6-month progression-free survival (PFS6). All patients (Cohort 1, n = 3; Cohort 2, n = 7) completed ≥ 7 weeks of asunercept treatment. No DLTs were experienced. Only one possibly treatment-related treatment emergent adverse event (TEAE), Grade 1 gingival swelling, was observed. No Grade > 3 TEAEs were reported and no TEAE led to treatment discontinuation. Systemic asunercept exposure increased proportionally with dose and showed low inter-patient variability. The PFS6 rate was 33.3% and 57.1% for patients in Cohort 1 and 2, respectively. Patients in Cohort 2 maintained a PFS rate of 57.1% at Month 12. Adding asunercept to standard RT/TMZ was safe and well tolerated in patients with newly-diagnosed glioblastoma and 400 mg/week resulted in encouraging efficacy.Trial registration NCT02853565, August 3, 2016.

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