GammaTile® brachytherapy in the treatment of recurrent glioblastomas

Abstract Background GammaTile® (GT) is a recent U.S. Food and Drug Administration (FDA) cleared brachytherapy platform. Here, we report clinical outcomes for recurrent glioblastoma patients after GT treatment following maximal safe resection. Methods We prospectively followed twenty-two consecutive Isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients (6 O6-Methylguanine-DNA methyltransferase methylated (MGMTm); sixteen MGMT unmethylated (MGMTu)) who underwent maximal safe resection of recurrent tumor followed by GT placement. Results The cohort consisted of 14 second and eight third recurrences. In terms of procedural safety, there was one 30-day re-admission (4.5%) for an incisional cerebrospinal fluid leak, which resolved with lumbar drainage. No other wound complications were observed. Six patients (27.2%) declined in Karnofsky Performance Score (KPS) after surgery due to worsening existing deficits. One patient suffered a new-onset seizure post-surgery (4.5%). There was one (4.5%) 30-day mortality from intracranial hemorrhage secondary to heparinization for an ischemic limb. The mean follow-up was 733 days (range 279-1775) from the time of initial diagnosis. Six-month local control (LC6) and twelve-month local control (LC12) were 86 and 81%, respectively. Median progression-free survival (PFS) was comparable for MGMTu and MGMTm patients (~8.0 months). Median overall survival (OS) was 20.0 months for the MGMTu patients and 37.4 months for MGMTm patients. These outcomes compared favorably to data in the published literature and an independent glioblastoma cohort of comparable patients without GT treatment. Conclusions This clinical experience supports GT brachytherapy as a treatment option in a multi-modality treatment strategy for recurrent glioblastomas.

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RADT-15. FIRST EXPERIENCE WITH MAXIMAL SAFE RESECTION AND GAMMATILE BRACHYTHERAPY AS TREATMENT FOR RECURRENT GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.173 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi44-vi44

Author(s):

Dominic Gessler ◽

Elizabeth Neil ◽

Rena Shah ◽

Joseph Levine ◽

James Shanks ◽

...

Keyword(s):

Dna Methyltransferase ◽

Cerebrospinal Fluid Leak ◽

Extent Of Resection ◽

Recurrent Glioblastoma ◽

Wound Complications ◽

Methylguanine Dna Methyltransferase ◽

Radiation Delivery ◽

Day Range ◽

Fluid Leak

Abstract INTRODUCTION Gammatile (GT) is a recently FDA-cleared brachytherapy platform with 131Cs seeds imbedded into a resorbable collagen carrier for surgically targeted radiation delivery. We report the first experience for recurrent glioblastoma patients who underwent GT treatment following surgical resection. METHODS Twenty-two consecutive patients with 23 isocitrate dehydrogenase (IDH) wild-type glioblastomas (14 second; eight third recurrence) who underwent intra-operative MRI/5-ALA guided maximal safe resection followed by GT placement were prospectively followed. There were 6 methylguanine-DNA-methyltransferase promoter methylated (MGMTm) and 17 unmethylated (MGMTu) glioblastomas. RESULTS The median hospital stay was one day (range:1-15 days). There was one 30-day readmission (4.5%) for a cerebrospinal fluid leak from the incision site, which resolved with lumbar drainage. There were no other wound complications. One patient (4.5%) suffered new post-operative seizure. Eight patients experienced worsened neurological deficit (8/22 or 36%). While all deficits improved by the 30-day follow-up, 7 of these 8 patients suffered KPS decline due to persistent deficits. There was one 30-day mortality (4.5%) from intracranial hemorrhage secondary to heparinization for an ischemic limb. The median follow-up after GT placement for the remaining 21 patients was 296 days (range:111-931 days). Six months local control (LC) was achieved in ~75% of the patients irrespective of MGMT status. Median overall survival (OS) was 715 days for the MGMTu patients, and not reached (>1000 days) for MGMTm patients. These outcomes compared favorably to the published literature (LC: 3-49%; OS MGMTu: 135-285 days; OS MGMTm: 174-564 days) and an age, KPS, extent of resection matched glioblastoma cohort who underwent maximal safe resection without GT at our institution (LC: 52%; OS MGMTu: 462 days; OS MGMTm: 821 days; p=0.0089 and p=0.0271, respectively when compared to the GT treated patients). CONCLUSION This clinical experience supports the safety and efficacy of GT brachytherapy as a treatment option for recurrent glioblastomas.

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Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine–DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial

Journal of Clinical Oncology ◽

10.1200/jco.2015.63.4691 ◽

2016 ◽

Vol 34 (14) ◽

pp. 1611-1619 ◽

Cited By ~ 95

Author(s):

Ulrich Herrlinger ◽

Niklas Schäfer ◽

Joachim P. Steinbach ◽

Astrid Weyerbrock ◽

Peter Hau ◽

...

Keyword(s):

Quality Of Life ◽

Dna Methyltransferase ◽

Time Course ◽

Progression Free Survival ◽

Karnofsky Performance Score ◽

Life Questionnaire ◽

Newly Diagnosed ◽

Methylguanine Dna Methyltransferase ◽

Intention To Treat

Purpose In patients with newly diagnosed glioblastoma that harbors a nonmethylated O6-methylguanine–DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. Patients and Methods In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m2 every 2 weeks) or to daily TMZ (75 mg/m2) during RT followed by six courses of TMZ (150-200 mg/m2/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). Results In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) –C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. Conclusion BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

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Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Onartuzumab Plus Bevacizumab Versus Placebo Plus Bevacizumab in Patients With Recurrent Glioblastoma: Efficacy, Safety, and Hepatocyte Growth Factor and O6-Methylguanine–DNA Methyltransferase Biomarker Analyses

Journal of Clinical Oncology ◽

10.1200/jco.2015.64.7685 ◽

2017 ◽

Vol 35 (3) ◽

pp. 343-351 ◽

Cited By ~ 41

Author(s):

Timothy Cloughesy ◽

Gaetano Finocchiaro ◽

Cristóbal Belda-Iniesta ◽

Lawrence Recht ◽

Alba A. Brandes ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Phase Ii ◽

Dna Methyltransferase ◽

Phase Ii Study ◽

Progression Free Survival ◽

Recurrent Glioblastoma ◽

Free Survival ◽

Methylguanine Dna Methyltransferase ◽

Hepatocyte Growth

Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O6-methylguanine–DNA methyltransferase promoter methylation, and glioblastoma subtype. Results Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O6-methylguanine–DNA methyltransferase may benefit from Ona + Bev. Conclusion There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with recurrent glioblastoma in this phase II study; however, further investigation into biomarker subgroups is warranted.

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NIMG-37. DELAYED PSEUDOPROGRESSION IN TWO PATIENTS UNDERGOING TTFIELDS TREATMENT FOR NEWLY DIAGNOSED GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.650 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii155-ii156

Author(s):

Allison Lowman ◽

Sarah Hurrell ◽

Samuel Bobholz ◽

Jennifer Connelly ◽

Elizabeth Cochran ◽

...

Keyword(s):

Dna Methyltransferase ◽

Radiographic Progression ◽

Methylation Status ◽

Underlying Mechanism ◽

Recurrent Glioblastoma ◽

Newly Diagnosed ◽

Methylguanine Dna Methyltransferase ◽

Specific Effects ◽

Newly Diagnosed Glioblastoma ◽

Associated Risk Factors

Abstract PURPOSE Tumor treatment fields (TTFields) are approved by the FDA for newly diagnosed as well as recurrent glioblastoma (GBM). TTFields have been shown to extend survival by 4.9 months in newly diagnosed GBM, and a landmark overall survival rate of 13% at 5 years. However, the specific effects remain widely unknown, which has prevented widespread clinical use of this treatment. METHODS This case study examines two glioblastoma patients, IDH-1 wildtype, MGMT unmethylated, that received TTFields (Optune) in addition to maintenance temozolomide (TMZ) following radiation (RT). Both cases were followed using standard MR imaging. Second resections were performed due to radiographic progression of contrast enhancement. RESULTS Although imaging was concerning for tumor progression, pathology showed only treatment effect, ultimately leading to the diagnosis of pseudoprogression. Both patients fell outside the normal expected timeline for chemo-radiation induced pseudoprogression. Based on the pathology, both patients resumed treatment with TMZ/TTFields. One patient expired at 25 months and one is still alive. CONCLUSIONS Pathologic confirmation was essential for guiding further treatment and allowed patients to continue treatment that was effective despite contrary indications on imaging. These findings suggest that pathological confirmation should be strongly considered in patients receiving TMZ/TTFields who develop radiographic progression, potentially with a less invasive biopsy procedure. Future studies should look to characterize the underlying mechanism of interaction between TTFields/TMZ and quantify the prevalence, associated risk factors and whether there is a genotype more susceptible. Both patients reported here had O(6)-methylguanine-DNA methyltransferase (MGMT) unmethylated GBM, and while about 60% of glioblastomas are diagnosed likewise, it is possible that MGMT methylation status plays a role in TTFields response. Better characterization of this phenomenon will improve treatment guidance, potentially reducing unnecessary surgeries and the discontinuance of successful therapies.

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Acquired temozolomide resistance in MGMT-deficient glioblastoma cells is associated with regulation of DNA repair by DHC2

Brain ◽

10.1093/brain/awz202 ◽

2019 ◽

Vol 142 (8) ◽

pp. 2352-2366 ◽

Cited By ~ 15

Author(s):

Guo-zhong Yi ◽

Guanglong Huang ◽

Manlan Guo ◽

Xi’an Zhang ◽

Hai Wang ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Methyltransferase ◽

Molecular Mechanisms ◽

Progression Free Survival ◽

Recurrent Glioblastoma ◽

Dna Lesions ◽

Dna Repair Proteins

Abstract The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by O6-methylguanine-DNA methyltransferase (MGMT). However, some MGMT-deficient glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DYNC2H1 (DHC2) was expressed more in MGMT-deficient recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT promotor methylated glioblastoma patients. Furthermore, silencing DHC2, both in vitro and in vivo, enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-deficient glioblastoma. Using a combination of subcellular proteomics and in vitro analyses, we showed that DHC2 was involved in nuclear localization of the DNA repair proteins, namely XPC and CBX5, and knockdown of either XPC or CBX5 resulted in increased temozolomide-induced DNA damage. In summary, we identified the nuclear transportation of DNA repair proteins by DHC2 as a critical regulator of acquired temozolomide resistance in MGMT-deficient glioblastoma. Our study offers novel insights for improving therapeutic management of MGMT-deficient glioblastoma.

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Survival benefits of hypofractionated radiotherapy combined with temozolomide or temozolomide plus bevacizumab in elderly patients with glioblastoma aged ≥ 75 years

Radiation Oncology ◽

10.1186/s13014-019-1389-7 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 6

Author(s):

Makoto Ohno ◽

Yasuji Miyakita ◽

Masamichi Takahashi ◽

Hiroshi Igaki ◽

Yuko Matsushita ◽

...

Keyword(s):

Elderly Patients ◽

Dna Methyltransferase ◽

Karnofsky Performance Status ◽

Performance Status ◽

Methylation Status ◽

Progression Free Survival ◽

Promoter Hypermethylation ◽

Hypofractionated Radiotherapy ◽

Methylguanine Dna Methyltransferase ◽

Grade 3

Abstract Background and purpose The purpose of this study was to evaluate the outcomes of elderly patients (aged ≥75 years) with newly diagnosed glioblastoma (GBM), who were treated with hypofractionated radiotherapy comprising 45 Gy in 15 fractions combined with temozolomide (TMZ) or TMZ and bevacizumab (TMZ/Bev). Materials and methods Between October 2007 and August 2018, 30 patients with GBM aged ≥75 years were treated with hypofractionated radiotherapy consisting of 45 Gy in 15 fractions. Twenty patients received TMZ and 10 received TMZ/Bev as upfront chemotherapy. O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed by pyrosequencing. The cutoff value of the mean level of methylation at the 16 CpG sites was 16%. Results Median overall survival (OS) and progression-free survival (PFS) were 12.9 months and 9.9 months, respectively. The 1-year OS and PFS rates were 64.7 and 34.7%, respectively. Median OS and PFS did not differ significantly between patients with MGMT promoter hypermethylation (N = 11) and those with hypomethylation (N = 16) (17.4 vs. 11.8 months, p = 0.32; and 13.1 vs. 7.3 months, p = 0.11, respectively). The median OS and PFS were not significantly different between TMZ (N = 20) and TMZ/Bev (N = 10) chemotherapy (median OS: TMZ 12.9 months vs. TMZ/Bev 14.6 months, p = 0.93, median PFS: TMZ 8.5 months vs TMZ/Bev 10.0 months, p = 0.64, respectively). The median time until Karnofsky performance status (KPS) score decreasing below 60 points was 7.9 months. The best radiological responses included 11 patients with a partial response (36.7%). Grade 3/4 toxicities included leukopenia in 15 patients (50%), anorexia in 4 (13.3%), and hyponatremia during concomitant chemotherapy in 3 (10%). Conclusion Our hypofractionated radiotherapy regimen combined with TMZ or TMZ/Bev showed benefits in terms of OS, PFS, and KPS maintenance with acceptable toxicities in elderly patients with GBM aged ≥75 years.

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A randomized phase II trial of concurrent temozolomide (TMZ) and radiotherapy (RT) followed by dose dense compared to metronomic TMZ and maintenance cis-retinoic acid for patients with newly diagnosed glioblastoma multiforme (GBM)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.2031 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 2031-2031 ◽

Cited By ~ 3

Author(s):

J. Sul ◽

K. S. Panageas ◽

A. B. Lassman ◽

A. Hormigo ◽

C. Nolan ◽

...

Keyword(s):

Retinoic Acid ◽

Dna Methyltransferase ◽

Progression Free Survival ◽

Phase Iii ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Methylguanine Dna Methyltransferase ◽

Angiogenic Therapy ◽

Progression Of Disease ◽

Dose Dense

2031 Background: Metronomic and dose dense scheduling are alternatives to conventional TMZ regimens to overcome drug resistance in part by depleting O-6 methylguanine-DNA methyltransferase (MGMT). Furthermore, metronomic TMZ may inhibit endothelial recovery and act as an anti-angiogenic therapy; dose dense TMZ increases the intensity of drug delivery. Objective: To determine the overall (OS) and progression free survival (PFS) of patients with newly diagnosed GBM treated with concurrent TMZ and RT followed by dose dense or metronomic TMZ and maintenance cis-retinoic acid. Methods: Patients with newly diagnosed, histologically confirmed GBM underwent standard RT with TMZ. Upon completion of this treatment, patients were randomized to receive dose-dense TMZ (150mg/m2, days 1–7 and 15–21 of a 28 day cycle) or metronomic TMZ (50mg/m2 daily in 28 day cycles), for 6 cycles. Maintenance cis-retinoic acid was prescribed following the 6 cycles of adjuvant TMZ. OS and PFS were calculated from date of diagnosis. Prospective correlative tissue analysis of MGMT status is planned. A Simon minimax 2-stage design was used for each cohort. If either group has 70% survival probability at 1 year, further evaluation in a phase III trial will be recommended. Results: 51 patients were randomized: 24 to metronomic, and 27 to dose dense. Median age is 57, and median KPS 90. 26 patients have progression of disease (POD), with a median follow up of 5 months. Grade 3/4 hematologic toxicity occurred in 7 patients (14%), 3 in the metronomic and 4 in the dose dense arm. Conclusions: Our patient population is comparable to that of other upfront GBM treatment trials. Metronomic and dose dense TMZ appear to be well tolerated with equivalent toxicities. Early analysis suggests that patients on the dose dense regimen may have better PFS than those on the metronomic arm. [Table: see text] No significant financial relationships to disclose.

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Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.6650 ◽

2010 ◽

Vol 28 (16) ◽

pp. 2712-2718 ◽

Cited By ~ 286

Author(s):

Roger Stupp ◽

Monika E. Hegi ◽

Bart Neyns ◽

Roland Goldbrunner ◽

Uwe Schlegel ◽

...

Keyword(s):

Phase I ◽

Promoter Methylation ◽

Dna Methyltransferase ◽

Progression Free Survival ◽

Recurrent Glioblastoma ◽

Mgmt Promoter Methylation ◽

Newly Diagnosed ◽

Mgmt Promoter ◽

Newly Diagnosed Glioblastoma

Purpose Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma. Patients and Methods Patients (age ≥ 18 to ≤ 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months. Results Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified. Conclusion Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.

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Is the absolute value of O6-methylguanine-DNA methyltransferase gene messenger RNA a prognostic factor, and does it predict the results of treatment of glioblastoma with temozolomide?

Journal of Neurosurgery ◽

10.3171/2014.6.jns132535 ◽

2014 ◽

Vol 121 (4) ◽

pp. 818-826 ◽

Cited By ~ 7

Author(s):

Satoshi Tanaka ◽

Jiro Akimoto ◽

Yoshitaka Narita ◽

Hidehiro Oka ◽

Takashi Tashiro

Keyword(s):

Prognostic Factor ◽

Real Time ◽

Messenger Rna ◽

Dna Methyltransferase ◽

Progression Free Survival ◽

Rt Pcr ◽

Free Survival ◽

Absolute Value ◽

Methylguanine Dna Methyltransferase ◽

The Absolute

Object Methylation of O6-methylguanine-DNA methyltransferase (MGMT) has been reported to be a good prognostic factor for patients with glioblastoma multiforme (GBM). To determine whether the absolute value of MGMT messenger RNA (mRNA) might be a prognostic factor and useful for predicting the therapeutic effectiveness of temozolomide, especially with regard to GBMs, the authors measured the absolute value of MGMT mRNA in gliomas by using real-time reverse-transcription polymerase chain reaction (RT-PCR). Methods MGMT mRNA was measured in 140 newly diagnosed gliomas by real-time RT-PCR using the Taq-Man probe. Among 73 GBMs, 45 had been initially treated with temozolomide and radiation. Results The mean MGMT mRNA value was significantly lower in oligodendroglial tumors than in other tumors. In the 73 GBMs, a significant prognostic factor for progression-free survival was fewer than 1000 copies/ μgRNA of MGMT mRNA (p = 0.0150). Of 45 patients with GBMs that had been treated with temozolomide and radiation, progression-free survival was significantly longer for those whose GMB had fewer than 1000 copies/μgRNA of MGMT mRNA than for those whose GBM had more than 1000 copies/μgRNA (p = 0.0090). In 32 patients with GBMs treated by temozolomide and radiation whose age was younger than 75 years and whose Karnofsky Performance Scale score was more than 70, progression-free and overall survival times were longer for those with GBMs of fewer than 5000 copies/μgRNA of MGMT mRNA than for those with GBMs of more than 5000 copies/μgRNA (p = 0.0365 and p = 0.0312). Conclusions MGMT mRNA might be useful as a prognostic factor and for predicting the results of therapy for GBMs treated by temozolomide. New individual adjuvant therapy based on the results of MGMT mRNA quantitation has been proposed.

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Differential Predictors and Clinical Implications Associated With Long-Term Survivors in IDH Wildtype and Mutant Glioblastoma

Frontiers in Oncology ◽

10.3389/fonc.2021.632663 ◽

2021 ◽

Vol 11 ◽

Author(s):

Haihui Jiang ◽

Kefu Yu ◽

Yong Cui ◽

Xiaohui Ren ◽

Mingxiao Li ◽

...

Keyword(s):

Dna Methyltransferase ◽

Progression Free Survival ◽

Clinical Implications ◽

Therapeutic Implications ◽

Methylguanine Dna Methyltransferase ◽

Molecular Features ◽

Younger Age ◽

One Year ◽

Long Term Survivors

BackgroundGlioblastoma (GBM) is the most aggressive intracranial tumor which can be divided into two subtypes based on status of isocitrate dehydrogenase (IDH). A small fraction of patients after receiving standard treatment can be long-term survivors (LTS). This study was designed to disclose the predictors and clinical implications associated with LTS in IDH wildtype and mutant GBM.MethodsPatients who survived beyond five years after diagnosis of GBM were defined as LTS, while those with a survival less than one year were defined as short-term survivors (STS). A total of 211 patients with diagnosis of GBM in Beijing Tiantan Hospital from January 2007 to January 2015 were enrolled, including 44 (20.9%) LTS and 167 (79.1%) STS. The clinical, radiological and molecular features between groups were systematically compared.ResultsCompared with STS, LTS were a subgroup of patients with a younger age at diagnosis (P=0.006), a higher KPS score (P=0.011), higher rates of cystic change (P=0.037), O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (P=0.007), and IDH mutation (P=0.049), and more likely to have undergone gross total resection (P<0.001). Survival analysis demonstrated that LTS with wildtype IDH conferred a longer progression-free survival (66.0 vs. 27.0 months, P=0.04), but a shorter post-progression survival (46.5 months vs. not reached, P=0.0001) than those of LTS with mutant IDH. LTS with mutant IDH showed a trend towards increased survival after receiving re-operation (P=0.155) and reirradiation (P=0.127), while this clinical benefit disappeared in the subset of LTS with wildtype IDH (P>0.05).ConclusionThe prognostic value and therapeutic implications associated with LTS in GBM population significantly differed on the basis of IDH status. Our findings provide a new approach for physicians to better understand the two subtypes of GBM, which may assist in making more tailored treatment decisions for patients.

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