MGMT status through the ages, literally.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13550-e13550
Author(s):  
Assad Ali ◽  
Anas Saeed Bamashmos ◽  
Addisson Barnett ◽  
Hong Li ◽  
Soumya Sagar ◽  
...  
Keyword(s):  
Reference Group ◽  
Cox Model ◽  
Tertiary Care ◽  
Gene Promoter ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Newly Diagnosed ◽  
Tertiary Care Institution ◽  
Methylguanine Methyltransferase ◽  
And Gender

e13550 Background: It is known that in the setting of glioblastoma (GBM) having a methylated O6-Methylguanine Methyltransferase (MGMT) gene promoter confers a greater response to Temozolomide (TMZ) and an increased progression free survival (PFS) and overall survival (OS). Recent literature has uncovered interesting results when dichotomizing patients by demographics (i.e. age and gender) and analyzing response to the various available GBM therapies. Our primary objective is to analyze the effect of both age and MGMT status on OS and PFS in patients with newly diagnosed GBM. Understanding the role of MGMT on age in the setting of GBM can allow for a better understanding of disease course and treatment. Methods: 464 adult patients with newly diagnosed GBM and documented MGMT status were analyzed from a single major tertiary care institution between 2012 and 2018. Patients were stratified into four groups based on age (above or below 65 years) and MGMT status. A univariate Cox model was used to analyze the effect of age and MGMT status on PFS and OS, where our reference group was the group with the highest OS ( < 65/methylated). Results: The median age of the whole dataset was 63.4 years, and 65.2 years for patients who were MGMT methylated. Patients less than 65 years and were MGMT methylated had the best prognosis with a PFS and an OS of 10.9 months and 18.9 (Table), respectively. Patients above the age of 65 were more likely to be MGMT methylated (p = 0.002). There was an association between IDH1-mutant status and MGMT methylation (p = 0.006). Conclusions: Using MGMT status and age of the patient, our model predicts outcomes that can vary from 7.4 months to 18.9 months (HR = 3.41 p < 0.001).[Table: see text]

scholarly journals PATH-13. SEX-LINKED TUMORAL MGMT STATUS AND OUTCOMES IN NEWLY DIAGNOSED GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi145-vi145
Author(s):  
Addison Barnett ◽  
Anas Saeed Bamashmos ◽  
Assad Ali ◽  
Hong Li ◽  
David Bosler ◽  
...  
Keyword(s):  
Tertiary Care ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Newly Diagnosed ◽  
Cox Proportional Hazard ◽  
Kaplan Meier ◽  
Newly Diagnosed Glioblastoma ◽  
Cox Proportional Hazard Models ◽  
Tertiary Care Institution ◽  
The Impact

Abstract INTRO/OBJECTIVE Glioblastoma (GBM) and MGMT have been reported to have sexual dimorphism. The primary objective of this study was to analyze the impact and association between sex and MGMT status on progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed GBM. METHODS 582 patients with newly diagnosed GBM who underwent first surgical intervention at a single tertiary care institution between 2012 and 2018 were reviewed. Adults with documented methylated (≥ 12) and un-methylated (≤ 7) MGMT status were included. A Kaplan-Meier and Cox proportional hazard models were used to analyze the association between sex and MGMT status on PFS and OS. RESULTS 464 adult patients (median age 63.4, 36.6% female) had documented MGMT status. Overall rate of MGMT methylated patients was 42.5%, while females were more often methylated than males (52.1% vs 37.4%, p=0.004). MGMT methylated compared to un-methylated females (median: 12.8 vs 7.4 months; 1-yr: 53% vs 27%) had a greater PFS benefit than males (median: 9.6 vs 6.8 months; 1-yr: 44% vs 23%). OS was significantly improved in MGMT methylated compared to un-methylated patients among females (p=0.001) but not among males (p=0.22). Among MGMT methylated patients, females had significantly better OS compared to males (median: 18.7 vs 12.4 months; 2-yr OS: 36.8% vs 24.3%, p=0.03). Although statistically not significant, a similar pattern was observed on PFS (median: 12.8 vs 9.6 months; 1-yr PFS: 52.6% vs 44.4%). Compared to MGMT methylated females, MGMT methylated males had a PFS HR=1.22 (95% CI=0.80 – 1.85, p=0.36), and an OS HR=1.45 (95% CI=1.03 – 2.04, p=0.032). CONCLUSION MGMT methylation is more common in females and methylation had a larger impact on both PFS and OS in females compared to males. These analyses highlight the need to further investigate sex differences that can inform clinical management of GBM.

Impact of EGFR amplification status in newly diagnosed glioblastoma treated with Stupp protocol.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13569-e13569
Author(s):  
Addison Barnett ◽  
Anas Saeed Bamashmos ◽  
Assad Ali ◽  
Xuefei Jia ◽  
Wei (Auston) Wei ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Tertiary Care ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Egfr Amplification ◽  
Newly Diagnosed Glioblastoma ◽  
Cox Proportional Hazard Models ◽  
Tertiary Care Institution ◽  
Stupp Protocol

e13569 Background: Standard post-surgical glioblastoma (GBM) treatment, per Stupp protocol, includes six-weeks of concurrent Temozolomide chemoradiation followed by at least six cycles of adjuvant-Temozolomide. Previous investigations into epidermal growth factor receptor (EGFR) amplification as a prognostic factor in GBM have yielded contradicting results, requiring further investigation. The primary aim of this study was to determine the degree to which EGFR amplification, in newly diagnosed GBM, impacted progression free survival (PFS) and overall survival (OS). Methods: Data from 582 patients who underwent surgical intervention for GBM at a tertiary care institution between 2012 and 2018 were analyzed. Only adult patients who underwent treatment per Stupp protocol and had pathological analysis on EGFR and CEP7 were included. Amplification and non-amplification status was calculated by a ratio of EGFR/CEP7 > 2 and < 2, respectively. PFS and OS outcomes were compared using Cox proportional hazard models stratified by surgery type and sex. Results: Of the original 582 patients, 122 were treated per Stupp protocol and had documented EGFR analysis. Of patients who were EGFR amplified, 41 (58.5%) were male and 25 (48.1%) were female (p = 0.38) and median amplification was 1.07 and 1.16 (p < 0.001), respectively. EGFR non-amplified patients had a PFS hazard ratio, HR = 0.70 (95% CI = 0.44 – 1.12, p = 0.14); and an OS HR = 0.60 (95% CI = 0.35 – 1.03, p = 0.065). When the EGFR/CEP7 ratio was stratified by quartile, it was found that Q4 compared to Q1 (Q4 > 6.50 vs 0 < Q1 ≤ 1.06) had a PFS HR = 2.1 (95% CI = 1.11 – 4.07, p = 0.024); and an OS HR = 2.48 (95% CI = 1.10 – 5.60, p = 0.028). Conclusions: There was no statistical difference in prevalence of EGFR amplification by sex. However, despite statistical significance, there was minimal difference in median degree of amplification by sex (0.09). Trends begin to show that patients who were EGFR non-amplified had better PFS and OS outcomes than patients who were EGFR amplified, although this was not statistically significant. Patients with very high EGFR amplification (Q4) had significantly poorer PFS and OS outcomes than patients with very low EGFR amplification (Q1).

CTNI-21. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi63-vi64
Author(s):  
Zhong-ping Chen ◽  
Cheng-Cheng Guo ◽  
Yang Qun-ying ◽  
Jia-Wei Li ◽  
Shao-xiong Wu ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Radiation Treatment ◽  
Gene Promoter ◽  
Progression Free Survival ◽  
Common Adverse Event ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study

Abstract Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) gene promoter, which confers a limited clinical response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with a methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces interstrand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated TMZ resistance in vitro and in vivo. A Phase 2 study has been conducted to evaluate efficacy and safety of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. The study was conducted in 2 stages: Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). At the end of this stage, 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. All patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. All 29 patients have completed treatment and patients are in the follow-up phase of the study. Consistent with our prior experience, myelosuppression was the most common adverse event. As of March 2021, 22/29 (75.9%) subjects had disease progression. The median progression free survival for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Sixteen (16/29; 55.2%) patients had died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.

Reintroduction of Oxaliplatin Is Associated With Improved Survival in Advanced Colorectal Cancer

2007 ◽  
Vol 25 (22) ◽  
pp. 3224-3229 ◽  
Author(s):  
Aimery de Gramont ◽  
Marc Buyse ◽  
Jose Cortinas Abrahantes ◽  
Tomasz Burzykowski ◽  
Emmanuel Quinaux ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Reference Group ◽  
Cox Model ◽  
Progression Free Survival ◽  
Second Line ◽  
Treatment Groups ◽  
Number Of Patients ◽  
Baseline Factors ◽  
The Impact

Purpose In the OPTIMOX1 trial, previously untreated patients with advanced colorectal cancer were randomly assigned to two different schedules of leucovorin, fluorouracil, and oxaliplatin that were administered until progression in the control arm or in a stop-and-go fashion in the experimental arm. The randomly assigned treatment groups did not differ significantly in terms of response rate, progression-free survival, and overall survival (OS). However, the impact of oxaliplatin reintroduction on OS was potentially masked by the fact that a large number of patients did not receive the planned oxaliplatin reintroduction or received oxaliplatin after second-line therapy in both treatment groups. Patients and Methods A Cox model was fitted with all significant baseline factors plus time-dependent variables reflecting tumor progression, reintroduction of oxaliplatin, and use of second-line irinotecan. A shared frailty model was fitted with all significant baseline factors plus the number of lines of chemotherapy received by the patient and the percentage of patients with oxaliplatin reintroduction in the center. An adjusted hazard ratio (HR) was calculated for three reintroduction classes (1% to 20%, 21% to 40%, and > 40%), using centers with no reintroduction (0%) as the reference group. Results Oxaliplatin reintroduction had an independent and significant impact on OS (HR = 0.56, P = .009). The percentage of patients with oxaliplatin reintroductions also had a significant impact on OS. Centers in which more than 40% of the patients were reintroduced had an adjusted HR for OS of 0.59 compared with centers in which no patient was reintroduced. Conclusion Oxaliplatin reintroduction is associated with improved survival in patients with advanced colorectal cancer.

Allergic Mucin With and Without Fungus

2001 ◽  
Vol 125 (11) ◽  
pp. 1442-1447
Author(s):  
Jonathan F. Lara ◽  
J. Daniel Gomez
Keyword(s):  
Tertiary Care ◽  
Fungal Sinusitis ◽  
Allergic Fungal Sinusitis ◽  
Radiographic Findings ◽  
Care Institution ◽  
Tertiary Care Institution ◽  
Allergic Mucin ◽  
And Gender

Abstract Context.—Allergic mucin, a lamellated collection of inspissated inflammatory debris, has been a hallmark of allergic fungal sinusitis. While its identification is a clue for pathologists to search for fungi, and directs clinicians toward specific therapy and follow-up, recent reports describe cases with allergic mucin but without concomitant fungus. The absence of such organisms in otherwise typical allergic mucin brings into question the role of fungi in allergic fungal sinusitis. Objectives.—To study clinical and pathologic differences between patients with allergic mucin in surgical nasal resection specimens and to elucidate the role of fungus in allergic sinusitis. Design.—Patients with histologic evidence of allergic mucin, with and without fungus, were identified and retrieved from the surgical pathology files of a tertiary-care institution. The patients were separated into 2 groups for analysis, and their clinical and pathologic findings were reviewed and compared. Setting.—Tertiary-care institution. Patients.—All patients who underwent sinus mucosal resection between 1992 and 1998. Results.—Clinical presentation and radiographic findings were similar in both groups. Incidence, age, and gender distribution were similar to data reported previously. However, the amount of allergic mucin was much greater in the group with fungus than in the group without fungus, which to our knowledge is an unreported observation to date. Conclusion.—The presence of allergic mucin is not unique to allergic fungal sinusitis, but rather is the result of a process that could have other etiologies. While perhaps not always causative to the disease, the fungus continues to fuel the process and is likely an entrapped bystander. Allergic fungal sinusitis is more appropriately termed allergic mucinous sinusitis or eosinophilic mucinous rhinosinusitis.

scholarly journals Comparison of bortezomib-cyclophosphamide-dexamethasone versus bortezomib-dexamethasone based regimens in newly diagnosed multiple myeloma patients

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Rafiye Ciftciler ◽  
Hakan Goker ◽  
Yahya Buyukasik ◽  
Nilgun Sayınalp ◽  
Ibrahim C. Haznedaroglu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Mortality Rate ◽  
Care Center ◽  
Tertiary Care ◽  
Progression Free Survival ◽  
Tertiary Care Center ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Significant Difference

The treatment landscape and clinical outcome of multiple myeloma (MM) patients have changed in the last decades, with an improved median survival of 8-10 years. This study aimed to evaluate the bortezomib, cyclophosphamide and dexamethasone (VCD) regimen versus bortezomib and dexamethasone (VD) regimen in patients with newly diagnosed MM. This study has been performed in a retrospective manner. One hundred and three patients with newly diagnosed MM who received chemotherapy at our tertiary care center between the years of 2009 and 2018 were evaluated. A total of 103 patients were included. The 5-year overall survival (OS) for patients who received VD regimen and patients who received VCD regimen were 75% and 83%, respectively. The OS for VD patients was 113.1±12.5 versus 122.2±9.5 months for VCD patients with no statistically significant difference (P=0.47). The 5- year PFS (progression free survival) for patients who received VD regimen and patients who received VCD regimen were 66% and 75%, respectively. The PFS for VCD patients was higher than the PFS for VD patients (67.1±7.4 versus 97.7±13.4 months), but no statistically significant difference was observed (P=0.59). Relapse rate (P=0.002) and mortality rate (P=0.01) were higher in VD group than VCD group and they were statistically significant. The OS and PFS were clinically longer in patients receiving VCD regimen than in patients receiving VD regimen, although not statistically significant. Cyclophosphamide should be given to patients at physician discretion and depending on patient’s frailty function.

scholarly journals PATH-62. QUANTITATIVE ANALYSIS OF SEX-ASSOCIATED MGMT METHYLATION IN NEWLY DIAGNOSED GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi157-vi157
Author(s):  
Addison Barnett ◽  
Anas Saeed Bamashmos ◽  
Hong Li ◽  
David Bosler ◽  
Justin Lathia ◽  
...  
Keyword(s):  
Cpg Island ◽  
Cohort Analysis ◽  
Tertiary Care ◽  
Population Based ◽  
Primary Objective ◽  
Cpg Methylation ◽  
Rank Test ◽  
Newly Diagnosed ◽  
Mgmt Methylation ◽  
The Mean

Abstract INTRO/OBJECTIVE Glioblastoma (GBM) and MGMT have been reported to have sexual dimorphism. In multiple studies, including our own population-based cohort analysis, females had higher rates of MGMT methylation and improved methylation-associated progression-free and overall survival outcomes compared to males. MGMT methylation is assessed as a mean of five cysteine-phosphate-guanine (CpG1-5) islands (CpG methylation is highly inversely correlated with MGMT RNA expression). The primary objective of this study was to investigate differences in mean and individual CpG methylation by sex. METHODS 155 patients who underwent first surgical intervention for newly diagnosed GBM at a single tertiary care institution between 2016 and 2018 were reviewed. Of these, 135 patients had available CpG methylation data determined by a clinically validated test using bisulfate conversion followed by PCR and pyrosequencing. MGMT was defined as methylated if the mean of CpG1-5 ≥ 12. The mean of CpG1-5 and each CpG parameter were compared by sex using the Wilcoxon signed-rank test. RESULTS Overall (mean age 62, 34% female, 42% MGMT methylated), the median (IQR) of mean degree of methylation was 4.0% (2–33) and median CpG1-5 ranged from 3.0 to 4.5%. More females (53.3%) were MGMT methylated than males (37.1%). Females had significantly higher rates of mean methylation compared to males (14.0 vs 3.0%, p=0.046). Females also had higher rates of methylation at each CpG island compared to males CpG1(7.0 vs 3.0%, p=0.15), CpG2(8.0 vs 4.0%, p=0.10), CpG3(9.0 vs 4.0%, p=0.23), CpG4(7.0 vs 3.0%, p=0.047), and CpG5(6.0 vs 4.0%, p=0.097). CONCLUSION Females had higher rates of mean methylation and methylation of each CpG island compared to males, although only mean and CpG4 methylation values were statistically significant given the limited sample size. Further investigation with a larger cohort is ongoing to elucidate this dimorphism and establish whether sex-specific methylation cut-offs need to be implemented into clinical practice.

scholarly journals Comparison of clinical characteristics, efficacy and survival of newly diagnosed extramedullary multiple myeloma patients between single and multiple sites invasion

2021 ◽  
Author(s):  
Yongfeng Zhao ◽  
Fuling Zhou
Keyword(s):  
Multiple Myeloma ◽  
Lactate Dehydrogenase ◽  
Clinical Characteristics ◽  
Cox Model ◽  
Progression Free Survival ◽  
Single Site ◽  
New Drugs ◽  
Newly Diagnosed ◽  
Hematopoietic Stem ◽  
Blood Calcium

Abstract PurposeWe aimed to compare the clinical characteristics, efficacy and survival of newly diagnosed extramedullary multiple myeloma patients (EMM) between single and multiple sites invasion.MethodsA total of 90 EMM patients were included. The characteristics including gender, age, Durie-Salmon stage, ISS stage, hemoglobin, blood calcium, creatinine, M-protein types, β2-microglobulin, lactate dehydrogenase and so on were analyzed. We compared the overall remission rates (ORR) in patients with single site invasion and multiple sites invasion. Progression free survival (PFS) and overall survival (OS) were also compared.ResultsPatients with multiple sites invasion had higher lactate dehydrogenase than single site invasion (179.0U/L vs. 154.7U/L, P=0.016). The ORR in patients with single site invasion (72.1%) was not significantly higher than multiple sites invasion (68.2%) (P=0.690). In patients with multiple sites invasion, PI-based regimen (78.9% vs. 33.3%, P=0.035) or PI combined with IMiD regimen (84.6% vs. 33.3%, P=0.026) could achieve superior efficacy than routine chemotherapy. Among patients with single site invasion, the COX model analysis showed that proteasome inhibitors combined with immunomodulators could significantly improve the PFS (HR=0.080, 95%CI: 0.007-0.855, P=0.037). Among patients with multiple sites invasion, the associations of RISS 3 with poor PFS (HR=4.081, 95%CI: 1.533-10.865, P=0.005) and OS (HR=13.295, 95%CI: 3.219-54.907, P=0.000) were showed.ConclusionRISS stage 3 was possibly associated with poor survival of extramedullary multiple myeloma patients with multiple sites invasion. We propose a prospective and large-sample study to explore the effects of new drugs and autologous hematopoietic stem cell transplantation on survival of patients at RISS stage 3.

scholarly journals Avelumab in newly diagnosed glioblastoma

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Francois H Jacques ◽  
Garth Nicholas ◽  
Ian A J Lorimer ◽  
Victorine Sikati Foko ◽  
Jasmine Prevost ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Open Label

Abstract Background Glioblastoma (GBM) is known to use both local and systemic immunosuppressive strategies. One such strategy is the expression of the immune checkpoint protein programmed cell death ligand-1 (PD-L1) by both tumor cells and tumor-associated immune cells. Recent phase III trials using IgG4 antibodies targeting PD-1, the ligand for PD-L1, failed to show any benefit. Avelumab is an IgG1 monoclonal antibody targeting PD-L1. In contrast to the previously tested immune checkpoint inhibitors, it can directly bind tumor cells and immune cells expressing PD-L1 and can induce antibody-dependent cellular cytotoxicity. Methods We conducted a single center, open label, phase II study where avelumab 10 mg/kg IV Q2W was added concurrently to the first monthly temozolomide cycle in patients with newly diagnosed GBM. Immunohistochemical analyses were performed on surgery samples. The primary objective was safety. Secondary objectives were efficacy outcomes according to the immunotherapy Response Assessment in Neuro Oncology criteria, progression free survival (PFS), and overall survival (OS). Exploratory objectives aimed at determining prognostic biomarkers. Results Thirty patients were started on therapy and two were lost to follow-up. Median follow-up time (reverse Kaplan-Meier) was 41.7 months (IQR: 28.3–43.4). Three (10.0%) patients had a related or possibly related treatment emergent adverse event that lead to transient or permanent discontinuation of avelumab. Eight (26.7%) patients had one or more immune-related adverse events, and 8 (26.7%) patients had an infusion-related reaction. The overall response rate was 23.3%, median PFS was 9.7 months, and the median OS was 15.3 months. No pretreatment biomarkers showed any predictive value. Conclusions The addition of avelumab to standard therapy in patients with GBM was not associated with any new safety signal. There was no apparent improvement in OS. Trial Registration NCT03047473 Registered February 9, 2017.

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter: Key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study.

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. LBA2009-LBA2009 ◽  
Author(s):  
Roger Stupp ◽  
Monika E. Hegi ◽  
Thierry Gorlia ◽  
Sara Erridge ◽  
Danica Grujicic ◽  
...  
Keyword(s):  
Safety Profile ◽  
Dna Methyltransferase ◽  
Gene Promoter ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Open Label ◽  
Who Grade ◽  
Mgmt Gene ◽  
Newly Diagnosed Glioblastoma

LBA2009 Background: Cilengitide (CIL) is a selective αvβ3 and αvβ5 integrin inhibitor. In a phase II study in patients with newly diagnosed glioblastoma, CIL added to standard temozolomide (TMZ) and radiotherapy (RT) was well tolerated and appeared to confer improved survival in patients with glioblastoma and methylated MGMT gene promoter (Stupp et al. J Clin Oncol. 2010;28:2712-8). Methods: This multicenter, randomized, controlled, open-label, phase III study randomized (1:1) patients (≥ 18 years) with newly diagnosed, histologically proven supratentorial glioblastoma (WHO Grade IV) and centrally determined MGMT gene promoter methylation. Treatment consisted of CIL 2000 mg twice weekly i.v. plus standard TMZ/RT→TMZ (concomitant and adjuvant temozolomide and radiotherapy; Stupp et al. N Engl J Med. 2005;352:987-96) or standard TMZ/RT→TMZ alone. CIL was to be administered for ≥ 18 months, or until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) per investigator read and safety. Results: 272 patients received CIL plus TMZ/RT→TMZ, and 273 were treated with TMZ/RT→TMZ alone (intention-to-treat population). 54% and 52% of patients were male, and 42% and 44% had ECOG-PS ≥ 1, respectively. 75% of patients of both arms were ≥ 50 years old. Overall, baseline characteristics were well balanced across treatment arms. Median OS was 26.3 months in both arms (Hazard Ratio [HR] = 1.02 [95%CI: 0.81-1.29], p = 0.86). Median PFS per investigator read was 13.5 months in the CIL arm and 10.7 months in the control arm (HR = 0.93 [95%CI: 0.76-1.14], p = 0.48). Treatment was generally well tolerated and the known safety profile of CIL was confirmed. Conclusions: CIL failed to prolong PFS or OS in patients with newly diagnosed glioblastoma and methylated MGMT gene promoter. The previously reported safety profile of CIL in addition to standard therapy was confirmed. Clinical trial information: NCT00689221.

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