scholarly journals Prospective Biomarker Study in Newly Diagnosed Glioblastoma: Cyto-C Clinical Trial

2021 ◽  
Author(s):  
Corinne E Griguer ◽  
Claudia R Oliva ◽  
Christopher S Coffey ◽  
Merit E Cudkowicz ◽  
Robin A Conwit ◽  
...  
Keyword(s):  
Survival Time ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Term Survival ◽  
Mgmt Promoter ◽  
Mgmt Promoter Methylation Status

Abstract Background Glioblastoma (GBM) has a 5-year survival rate of 3–5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome c oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. Methods This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival time (OS), and the secondary end point was progression-free survival time (PFS). Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. Results OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Conclusions Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a sub-group of GBM patients with improved long term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.

Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles

2014 ◽  
Vol 37 (6) ◽  
pp. E4 ◽  
Author(s):  
Giuseppe M. V. Barbagallo ◽  
Sabrina Paratore ◽  
Rosario Caltabiano ◽  
Stefano Palmucci ◽  
Hector Soto Parra ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma ◽  
Group A ◽  
Group B ◽  
Mgmt Promoter Methylation Status

Object The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol. Methods A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m2 starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30–72 years (mean 56.1 years), received 150 mg/m2 for 5 days every 28 days for more than 6 cycles (range 7–101 cycles). The 18 patients in Group B, aged 46–82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered. Results All patients but 1 in Group A survived at least 18 months (range 18–101 months), and patients in Group B survived no more than 17 months (range 2–17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long-term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group. Conclusions This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe.

scholarly journals RARE-39. COMBINATION OF TUMOR TREATING FIELDS (TTFIELDS) WITH LOMUSTINE (CCNU) AND TEMOZOLOMIDE (TMZ) IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS - A BI-CENTRIC ANALYSIS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi229-vi230
Author(s):  
Lazaros Lazaridis ◽  
Niklas Schäfer ◽  
Teresa Schmidt ◽  
Johannes Weller ◽  
Theophilos-Dimitrios Tzaridis ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Case Series ◽  
Mgmt Promoter Methylation ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Skin Reactions ◽  
Term Survival ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma

Abstract BACKGROUND TTFields combined with TMZ chemotherapy demonstrated significantly improved PFS, OS and long-term survival in newly diagnosed glioblastoma (ndGBM) patients in the EF-14 trial; independent of MGMT-promoter methylation-status, age, grade of resection, and performance status. Recently, improved efficacy of lomustine/TMZ compared to TMZ monotherapy in ndGBM patients with MGMT-promotor methylation was reported in the CeTeG trial. As TTFields demonstrated a favorable safety profile as well as a high potential for being combined with other modalities and the encouraging results for methylated MGMT-promoter GBM patients in the CeTeG trial, there is a strong rationale for combining these treatment regimens. Here, we present a case series of patients receiving a combination of TTFields and lomustine/TMZ. METHODS Patients with ndGBM and MGMT-promoter methylation underwent combined therapy of TTFields plus lomustine/TMZ after surgery and radiochemotherapy. MGMT-promoter status was measured by pyrosequencing. Safety, feasibility, and first efficacy results are reported at data cut-off (April 26, 2019). RESULTS Sixteen patients with MGMT-promoter methylated ndGBM (median, range: age 50, 27–70; KPS 90, 60–100) have been treated with a combination of TTFields plus lomustine/TMZ. The analysis included patients with complete resection (n=7), partial resection (n=8), as well as biopsy (n=1). CTCAE grade 3 hematotoxicity was observed in seven patients (44%) but was unlikely related to the addition of TTFields to lomustine/TMZ. Medical device site reactions (low-grade skin reactions) were detected in six patients (38%). At data cut-off, the analyzed patient population demonstrated a median PFS of 20 months; the median OS was not yet reached. CONCLUSION The results of this analysis indicate that the combination of TTFields/lomustine/TMZ is safe and feasible. Moreover, the observed survival outcomes point to preliminary beneficial effects of the triple combination. Additional follow-up and increased sample size are required and planned for further safety and efficacy assessment of this treatment regimen.

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