scholarly journals SYST-08. A phase II trial of concurrent Sunitinib, Temozolomide and Radiation Therapy followed by adjuvant Temozolomide for newly diagnosed Glioblastoma patients with an unmethylated MGMT gene promoter (A01-M121-11A, McG1132)

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv10-iv10
Author(s):  
Mame Daro Faye ◽  
Siham Sabri ◽  
Paula De Robles ◽  
Raman Agnihotram ◽  
Alexander Torres-Vasquez ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Standard Of Care ◽  
Treatment Modalities ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Who Grade ◽  
Adjuvant Temozolomide ◽  
Mgmt Promoter ◽  
Grade 3

Abstract INTRODUCTION Despite advances in treatment modalities, the overall prognosis of GBM remains dismal, particularly for patients with unmethylated MGMT promoter. Thus, alternative treatment strategies are warranted. Our group has previously shown that addition of Sunitinib (SU11248) to standard therapy significantly improved the response of unmethylated MGMT cells through decreased angiogenicity and tumorigenicity. In this phase II trial, we tested for the first time the combination of Sunitinib with RT and Temozolomide in newly diagnosed MGMT unmethylated GBM patients. METHODS Patients with histologically confirmed WHO Grade IV GBM and MS-PCR confirmed unmethylated MGMT promoter, age 18-70, KPS ≥70, life expectancy ≥6 months were eligible. 41 patients treated between 2012 and 2017 were screened, 37 of which were eligible. Patients received 12.5 mg of daily Sunitinib for 7 days, followed by concurrent RT, Temozolomide and 12.5 mg Sunitinib for 6 weeks, then adjuvant Temozolomide x6 cycles. RT and Temozolomide doses were as per standard of care. Primary objective was PFS as assessed by RANO criteria, secondary objectives were OS and safety. RESULTS Median follow-up time was 15 months. Median PFS was 7 months (95%CI, 6.7-7.2) and 6-month PFS was 59.3%. Median OS was 13 months (95%CI, 12.62-13.37) and 2-year OS was 17.8%. Two patients had OS >50 months, with one surviving 71 months. Having received >3 cycles of adjuvant Temozolomide, surgery at progression or age ≤65 significantly predicted for better OS, with hazard ratios of 0.184 (p=0.001), 0.402 (p=0.026) and 10.017 (for age >65, p=0.002) respectively. Grade ≥3 thrombocytopenia occurred in 18.9% of patients, grade ≥3 neutropenia in 10.8% and grade ≥3 thromboembolic events in 13.5%. There were no grade 5 evens. CONCLUSION Addition of Sunitinib to RT and Temozolomide was well tolerated and survival outcomes compared favorably to the current standard of care for GBM patients with unmethylated MGMT promoter status.

Promising Survival for Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Concomitant Radiation Plus Temozolomide Followed by Adjuvant Temozolomide

2002 ◽  
Vol 20 (5) ◽  
pp. 1375-1382 ◽  
Author(s):  
Roger Stupp ◽  
Pierre-Yves Dietrich ◽  
Sandrine Ostermann Kraljevic ◽  
Alessia Pica ◽  
Ivan Maillard ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Phase Ii ◽  
Pneumocystis Carinii ◽  
Survival Rates ◽  
Concomitant Treatment ◽  
Newly Diagnosed ◽  
Open Label ◽  
Fractionated Radiotherapy ◽  
Adjuvant Temozolomide ◽  
Grade 3

PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM. PATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m2/d × 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy × 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m2/d × 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival. RESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome. CONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.

Phase II trial of carboplatin in the management of malignant mesothelioma.

1990 ◽  
Vol 8 (1) ◽  
pp. 151-154 ◽  
Author(s):  
D Raghavan ◽  
P Gianoutsos ◽  
J Bishop ◽  
J Lee ◽  
I Young ◽  
...  
Keyword(s):  
Phase Ii ◽  
Malignant Mesothelioma ◽  
Phase Ii Trial ◽  
Objective Response ◽  
World Health ◽  
Hematological Toxicity ◽  
Who Grade ◽  
Life Threatening ◽  
Grade 3 ◽  
Health Organization

Thirty-one patients with advanced malignant mesothelioma, previously untreated or having received only one prior cytotoxic regimen, were treated in a prospective, single-arm phase II trial with carboplatin (NSC 241240) at a dose of 150 mg/m2 per day intravenously (IV) for 3 days (450 mg/m2/course). One complete remission and four partial remissions were achieved, yielding an overall objective response rate of 16% (95% confidence interval [CI], 5.4% to 34%). The median duration of remission was 8 months (range, 5 to 17). Nonhematological toxicity was mild (only 12% with World Health Organization [WHO] grade 3 vomiting); 16% suffered WHO grade 3 to 4 hematological toxicity, but there were no life-threatening episodes and no treatment-related deaths. Carboplatin has modest activity against malignant mesothelioma and, because of its low toxicity, has a role in the management of this disease.

Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 445-445 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Craig B. Reeder ◽  
Edward N. Libby ◽  
Luciano J. Costa ◽  
P. Leif Bergsagel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Initial Phase ◽  
Stem Cell Transplant ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

scholarly journals Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline

2021 ◽  
Author(s):  
Nimish A. Mohile ◽  
Hans Messersmith ◽  
Na Tosha Gatson ◽  
Andreas F. Hottinger ◽  
Andrew Lassman ◽  
...  
Keyword(s):  
Performance Status ◽  
Treatment Options ◽  
Poor Performance ◽  
Best Supportive Care ◽  
Poor Performance Status ◽  
Newly Diagnosed ◽  
Who Grade ◽  
Oligodendroglial Tumors ◽  
Mgmt Promoter ◽  
Grade 3

PURPOSE To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults. METHODS ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature. RESULTS Fifty-nine randomized trials focusing on therapeutic management were identified. RECOMMENDATIONS Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)–mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMT promoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines .

First toxicity and efficacy analysis of a phase II trial of a novel 5-FU-oxaliplatin based chemoradiation schema for stage II and III rectal carcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14591-14591 ◽  
Author(s):  
E. M. Rishe ◽  
S. Malamud ◽  
K. Hu ◽  
W. Enker ◽  
P. Kozuch ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Neoadjuvant Treatment ◽  
Standard Of Care ◽  
Neoadjuvant Chemoradiation ◽  
Stage Ii ◽  
Efficacy Analysis ◽  
Significant Toxicity ◽  
Grade 3

14591 Background: 5-FU based neoadjuvant chemoradiation (CRT) has become the standard of care for stage 2 and 3 rectal cancer (ca). Pathologic complete responses (pCR) and downstaging have been associated with improved survival outcomes. The addition of oxaliplatin or irinotecan to neoadjuvant treatment has led to improved pCR and downstaging. The feasibility and efficacy of “total” oxaliplatin therapy (pre and postoperative oxaliplatin) for stage 2 and 3 rectal ca patients has yet to be defined. Objective: To determine the feasibility, toxicity and efficacy of neoadjuvant oxaliplatin, 5-FU and RT followed by surgery, with postop adjuvant modified FOLFOX6. Methods: Single institution, single arm phase II trial of oxaliplatin 60mg/m2 weekly for 6 weeks with continuous infusion 5- FU 225 mg/m2/excision. Postoperative therapy consisted of mFOLFOX6 every 2 weeks for 6 cycles. Eligibility included previously untreated, histologically proven rectal cancer, T3–4N0M0 or TanyN+M0 (stage II-III). Results: 15 pts have been enrolled in this study. One died of disease prior to CRT. Eight pts have completed total oxaliplatin therapy. One pt had 1 cycle deleted due to grade 2 neuropathy. Prior to adjuvant therapy 2 pts dropped out: 1 from pulmonary symptoms and one asthenia. Two pts attained a pCR and 6 attained downstaging. Significant toxicity has been limited to grade 3 neuropathy in one pt (completely resolved) and one grade 3 GI toxicity (self limited). Conclusions: Early analysis shows the feasibility of pre and post operative oxaliplatin based therapy. The limited data permit only observation of pCR and tumor downstaging rates but toxicity outcomes are encouraging. Further accrual and follow-up will better define efficacy and toxicity of this regimen. [Table: see text]

Randomized phase II 8-arm factorial study of adjuvant dose-dense (dd) temozolomide (TMZ) with permutations of thalidomide (Thal), isotretinoin (CRA), and/or celecoxib (Cel) for newly diagnosed glioblastoma (GBM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2003-2003
Author(s):  
Mark R. Gilbert ◽  
Kenneth R. Hess ◽  
Lore Lagrone ◽  
Morris D. Groves ◽  
Victor A. Levin ◽  
...  
Keyword(s):  
Factorial Design ◽  
Phase Ii ◽  
Standard Of Care ◽  
Hepatic Function ◽  
Newly Diagnosed ◽  
Cytostatic Agents ◽  
Current Standard ◽  
Eligibility Criteria ◽  
Randomized Phase Ii ◽  
The Impact

2003 Background: Concurrent radiation and TMZ followed by 6-12 months of adjuvant TMZ (d 1-5 of a 28d cycle) is the current standard of care for patients with newly diagnosed GBM. The addition of cytostatic or signal transduction agents may enhance efficacy without a significant increase in toxicity. A phase I trial (Neuro-oncology 2009) established the safety of ddTMZ with 2 or 3 of the cytostatic agents. Methods: This randomized phase II study was conducted by the Brain Tumor Trials Collaborative (BTTC) and the MDACC CCOP. The primary objectives: determine if specific cytostatic agents added to ddTMZ alters outcomes (PFS, OS) and compare triplet with doublet therapy. Eligibility criteria: centrally confirmed newly diagnosed GBM, age ≥18, KPS≥60, stable or improved after chemoradiation (pseudoprogression allowed), adequate hematologic, renal and hepatic function. Pts were randomly assigned to 12 treatment cycles (28 d/cycle) in 8 arms: ddTMZ alone (150 mg/m2/day, 7-d on, 7-d off) or TMZ-containing doublet, triplet and quadruplet combinations with Thal, CRA, or Cel. Results: The study enrolled 155 eligible patients from 11/2005 to 9/2010 to the 8 arms of the factorial design. Median age was 53 (18-84) and median KPS, 90 (60-100). Compared with TMZ alone, the TMZ+CRA doublet had worse PFS (10.5, 6.5 mo; p=0.043) and OS (21.2, 11.7 mo; p=0.037). Trends were also seen for worse outcome (PFS, OS) for CRA-containing regimens, improved OS for Cel containing arms and no impact of Thal. A strong trend for OS improvement was seen for triplet compared with doublet regimens (20.1, 17.0 mo; p=0.15), but no difference for PFS. Treatment was well tolerated with expected high rates of grade 3/4 lymphopenia, and overall a modest toxicity rate. Conclusions: The results indicate that the addition of CRA to ddTMZ may be detrimental in patients with newly diagnosed GBM. This study demonstrated the utility of the factorial design in efficiently testing drug combinations, the impact of individual agents in these combinations as well as doublet vs. triplet regimens and supports its utility in testing combinations of targeted agents.

Phase I/randomized phase II trial of either dasatinib or placebo combined with standard chemoradiotherapy for newly diagnosed glioblastoma multiforme (GBM): Final results of phase I study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2032-2032 ◽  
Author(s):  
Nadia N. Laack ◽  
Evanthia Galanis ◽  
Clinton Leinweber ◽  
Jan C. Buckner ◽  
Caterina Giannini ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Progressive Disease ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Entire Study ◽  
Randomized Phase Ii ◽  
Level 1 ◽  
Grade 3

2032 Background: Dasatinib is a potent oral ATP competitive multi-targeted kinase inhibitor of multiple members of the Src kinase family, known to be involved in gliomagenesis and invasion. N0877 is a phase I/randomized phase II trial evaluating the combination of dasatinib, radiation (RT) and temozolomide (TMZ) in newly diagnosed GBM. The phase I portion has been completed and is the focus of this report. Methods: A cohorts-of-3 design was used to assess the safety of dasatinib in combination with RT and concomitant TMZ, and establish the phase II dose of the combination. Dasatinib was given orally for 42 days, beginning with the first day of RT (total dose 60 Gy) and first dose of TMZ (75 mg/m2/d). A 24 - 42 day rest (cycle 2) followed the RT/TMZ/dasatinib. Patients (pts) were observed for DLT to the end of cycle 2. Patients then received 6 cycles (28 day cycles) of dasatinib (once daily) and TMZ (days 1-5). At the completion of 6 cycles of TMZ + dasatinib, pts stay on dasatinib only (28 day cycles) until progressive disease. Results: Phase I component is complete with 13 patients (3 at dose level 0, 3 at dose level 0-A, 7 at dose level 1). One patient in dose level 1 had to be replaced due to the development of unrelated medical issues. One DLT (grade 4 pancytopenia) was observed in 1 patient at dose level 0 (50mg bid) and one DLT (grade 3 rash) was observed in 1 patient at dose level 1 (150mg qd). MTD of dasatinib was determined to be 150mg daily. Most common adverse events throughout the entire study period were hematologic with the most common toxicity being lymphopenia (grade 3 in 69% of patients, grade 4 in 8%). Other toxicities attributed to treatment and occurring in > 10% of patients included anemia (31%), neutropenia (15%), and fatigue(15%). Best response was stable disease in 10 patients, progressive disease in 1 patient, and not evaluable in 2. Conclusions: MTD for dasatinib in combination with TMZ and RT in newly diagnosed GBM patients is 150mg daily. Toxicity was primarily hematologic with minimal non-hematologic events. This dose is currently being used in the ongoing placebo-controlled, randomized phase II trial.

scholarly journals ACTR-03. FINAL RESULTS OF A PHASE II STUDY OF HYPOFRACTIONATED RADIOTHERAPY WITH CONCURRENT AND ADJUVANT TEMOZOLOMIDE IN PATIENTS OVER 70 YEARS OLD WITH NEWLY DIAGNOSED GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi12-vi12
Author(s):  
Mehran Yusuf ◽  
Jeremy Gaskins ◽  
Shiao Woo ◽  
Eric Burton
Keyword(s):  
Phase Ii ◽  
Methylation Status ◽  
Progression Free Survival ◽  
Hypofractionated Radiotherapy ◽  
Newly Diagnosed ◽  
Linear Effect ◽  
Adjuvant Temozolomide ◽  
Kaplan Meier ◽  
Newly Diagnosed Glioblastoma ◽  
Grade 3

Abstract BACKGROUND We sought to determine the efficacy and tolerability of hypofractionated radiotherapy (HFRT), 34Gy given over two weeks with concurrent and adjuvant temozolomide, in patients over 70 years old with newly diagnosed GBM. METHODS Patients ≥ 70 years of age with newly diagnosed GBM received HFRT to a dose of 34 Gy in 10 fractions over 2 weeks, delivered with concurrent and adjuvant TMZ. Quality of life (QOL) data using the validated functional assessment of cancer therapy-brain (FACT-BR) questionnaire was collected. Kaplan-Meier methods and log-rank tests were used for survival analyses. A random intercepts growth model with baseline and linear effect in time terms was used to assess QOL with relation to protocol treatment. RESULTS Eleven patients were enrolled from 12/1/2015 to 2/5/2018. Median age and KPS of the cohort was 74 years (range 70 -81) and 80 (range 60–100). Eight patients have died. Median follow-up of the cohort was 13.8 months (range 3 – 26 months). The median progression free survival (PFS) was 6.0 months (CI 4.7 months -not achieved (NA) and the median overall survival (OS) was 24.5 months (CI 10.2 months –NA). MGMT methylation status was significantly associated with both PFS (p =0.02) and OS (p =0.02). All patients completed HFRT with no patients developing ≥ grade 3 adverse treatment events. QOL did not significantly worsen over time with therapy (p =0.75). CONCLUSIONS This completed phase II trial suggest a HFRT schedule of 34Gy delivered over 2 weeks with concomitant and adjuvant TMZ is well tolerated in elderly GBM patients without compromising clinical outcomes. This result compares favorably to the longer HFRT regimen of 40Gy over 3 weeks. ClinicalTrials.gov identifier: NCT01985087

scholarly journals SS-1 Therapeutic challenges for glioblastoma: Temozolomide and its issues?

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii1-ii1
Author(s):  
Motoo Nagane
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Standard Of Care ◽  
Phase Iii ◽  
Lower Grade ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Who Grade ◽  
Phase Iii Trial ◽  
Mgmt Gene

Abstract Glioblastoma (GBM), the most malignant form (WHO grade IV) of gliomas, remains incurable despite recent advances in medical technologies and molecular knowledge, with 5-year survival rate being just beyond 10%, thus undoubtedly leaving unmet needs to develop effective therapeutics to improve outcome. Current standard of care for patients with newly diagnosed GBM is maximum safe resection of the enhancing tumor bulk, followed by involved-field radiotherapy with temozolomide (TMZ) given concomitantly and as an adjuvant therapy thereof with or without Tumor-Treating Fields (TTF). The efficacy of TMZ for GBM was proved in 2005 by a randomized phase III trial (EORTC25981) for the first time ever in history, since then, however, any other agents have failed to show benefit to improve survival until now. O6-methylguanine-DNA methyltransferase (MGMT), a specific DNA repair enzyme, has been shown to restore the cytotoxic O6-methylguanine lesion induced by TMZ to normal, responsible for a major reason of TMZ resistance. Expression of MGMT is tightly regulated by methylation of the promoter region of the MGMT gene, where promoter methylation results in suppression of its expression. Accordingly, the promoter methylation of the MGMT gene (meth-MGMT) has been consistently associated with a better response to and outcome by TMZ treatment, and furthermore a favorable prognostic factor for patients with newly diagnosed GBM in a number of prospective clinical trials. In this line, efforts have been made to overcome TMZ resistance including intensifying dose schedulings of TMZ, one of which has been currently tested in a multi-institutional prospective phase III trial in Japan (JCOG1308C). TMZ has also been investigated in lower grade gliomas. A major issue in treating lower grade glioma with TMZ is potential development of the hypermutated tumors by virtue of O6-methylguanine-induced mutagenesis. The clinical and molecular consideration related to TMZ in glioma treatment will be presented.

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