Dose-intensified chemoradiation is associated with altered patterns of failure and favorable survival in patients with newly diagnosed glioblastoma

Kim, Michelle M.; Speers, Corey; Li, Pin; Schipper, Matthew J.; Junck, Larry; Leung, Denise; Orringer, Daniel A.; Heth, Jason; Umemura, Yoshie; Spratt, Daniel E.; Wahl, Daniel R.; Cao, Yue; Lawrence, Theodore S.; Tsien, Christina

doi:10.1007/s11060-019-03166-3

Cited by 15 publications

(7 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Taken together, these results suggest that successful identification of these treatment-resistant subregions before CRT may enable a dose-intensified approach that could alter patterns of failure and prolong time to progression. 44 Although the number of patients with persistent MTV was small, persistent MTV was more likely to be encompassed in the TV POF than any other imaging subvolume. Additionally, MTV at baseline and at 3 months was more likely to be encompassed by TV POF than the GTV-Gd, suggesting MTV can help identify the volumes of tumor most likely progress.…”

Section: Discussionmentioning

confidence: 95%

Metabolic Tumor Volume Response Assessment Using (11)C-Methionine Positron Emission Tomography Identifies Glioblastoma Tumor Subregions That Predict Progression Better Than Baseline or Anatomic Magnetic Resonance Imaging Alone

Miller

Schipper

et al. 2020

Advances in Radiation Oncology

Self Cite

View full text Add to dashboard Cite

To evaluate whether response assessment of newly diagnosed glioblastoma at 3 months using 11 C-methionine-positron emission tomography (MET-PET) is better associated with patient outcome compared with baseline MET-PET or anatomic magnetic resonance imaging alone. Methods and Materials: Patients included were participants in a phase I/II trial of dose-escalated chemoradiation based on anatomic magnetic resonance imaging. Automated segmentation of metabolic tumor volume (MTV) was performed at a threshold of 1.5 times mean cerebellar uptake. Progression-free (PFS) and overall survival were estimated with the Kaplan-Meier method and compared with log-rank tests. Multivariate analysis for PFS and overall survival was performed using Cox proportional hazards, and spatial overlap between imaging and recurrence volumes were analyzed. Results: Among 37 patients, 15 had gross total resection, of whom 10 (67%) had residual MTV, 16 subtotal resection, and 6 biopsy alone. Median radiation therapy dose was 75 Gy (range, 66-81). Median baseline T1 Gd-enhanced tumor volume (GTV-Gd) was 38.0 cm 3 (range, 8.0-81.5). Median pre-CRT MTV was 4.9 cm 3 (range, 0-43.8). Among 25 patients with 3-month MET-PET, MTV was only 2.4 cm 3 (range, 0.004-18.0) in patients with uptake. Patients with MTV Z 0 cm 3 at 3 months had superior PFS (18.2 vs 10.1 months,

show abstract

Section: Discussionmentioning

confidence: 95%

Metabolic Tumor Volume Response Assessment Using (11)C-Methionine Positron Emission Tomography Identifies Glioblastoma Tumor Subregions That Predict Progression Better Than Baseline or Anatomic Magnetic Resonance Imaging Alone

Miller

Schipper

et al. 2020

Advances in Radiation Oncology

Self Cite

View full text Add to dashboard Cite

show abstract

“…This result confirms the widespread skepticism about the potential role of dose escalation in GBM. Only a few studies suggested an improvement in the outcome with higher than standard doses ( 28 , 29 ), while most evidence showed lack of improved outcomes ( 30 – 33 ). This would explain the trend toward a progressive reduction of higher than the standard dose RT recorded in the USA ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

Post-Operative Accelerated-Hypofractionated Chemoradiation With Volumetric Modulated Arc Therapy and Simultaneous Integrated Boost in Glioblastoma: A Phase I Study (ISIDE-BT-2)

et al. 2021

View full text Add to dashboard Cite

BackgroundGlioblastoma Multiforme (GBM) is the most common primary brain cancer and one of the most lethal tumors. Theoretically, modern radiotherapy (RT) techniques allow dose-escalation due to the reduced irradiation of healthy tissues. This study aimed to define the adjuvant maximum tolerated dose (MTD) using volumetric modulated arc RT with simultaneous integrated boost (VMAT-SIB) plus standard dose temozolomide (TMZ) in GBM.MethodsA Phase I clinical trial was performed in operated GBM patients using VMAT-SIB technique with progressively increased total dose. RT was delivered in 25 fractions (5 weeks) to two planning target volumes (PTVs) defined by adding a 5-mm margin to the clinical target volumes (CTVs). The CTV1 was the tumor bed plus the MRI enhancing residual lesion with 10-mm margin. The CTV2 was the CTV1 plus 20-mm margin. Only PTV1 dose was escalated (planned dose levels: 72.5, 75, 77.5, 80, 82.5, 85 Gy), while PTV2 dose remained unchanged (45 Gy/1.8 Gy). Concurrent and sequential TMZ was prescribed according to the EORTC/NCIC protocol. Dose-limiting toxicities (DLTs) were defined as any G ≥ 3 non-hematological acute toxicity or any G ≥ 4 acute hematological toxicities (RTOG scale) or any G ≥ 2 late toxicities (RTOG-EORTC scale).ResultsThirty-seven patients (M/F: 21/16; median age: 59 years; median follow-up: 12 months) were enrolled and treated as follows: 6 patients (72.5 Gy), 10 patients (75 Gy), 10 patients (77.5 Gy), 9 patients (80 Gy), 2 patients (82.5 Gy), and 0 patients (85 Gy). Eleven patients (29.7%) had G1-2 acute neurological toxicity, while 3 patients (8.1%) showed G ≥ 3 acute neurological toxicities at 77.5 Gy, 80 Gy, and 82.5 Gy levels, respectively. Since two DLTs (G3 neurological: 1 patient and G5 hematological toxicity: 1 patient) were observed at 82.5 Gy level, the trial was closed and the 80 Gy dose-level was defined as the MTD. Two asymptomatic histologically proven radionecrosis were recorded.ConclusionsAccording to the results of this Phase I trial, 80 Gy in 25 fractions accelerated hypofractionated RT is the MTD using VMAT-SIB plus standard dose TMZ in resected GBM.

show abstract

“…Furthermore, the findings reported here also have therapeutic implications; if the prognostic role of RAD51 is confirmed by a prospective study, adaptive management strategies could be designed based on the level of RAD51 expression, such as clinical trials of different radiation regimens and/or intensity; for example, patients with high repair capacity could be assigned to receive hypo-fractionated radiation therapy to compensate for the increased cellular capacity to repair DNA double-strand breaks [ 36 , 37 ]. Indeed, hypo-fractionated radiation could theoretically be more effective in patients with increased DNA damage repair mechanisms, a hypothesis currently under investigation [ 38 , 39 ]. Finally, and more importantly, the results reported here point the way toward a potential therapeutic target that could be exploited to increase the sensitivity of GBM to radiation, a concept that already has support in in vitro studies of inhibition of the c-MET receptor tyrosine kinase, which in turn leads to a decrease in Rad51 expression levels, thereby increasing the radio-sensitivity of GBM cell lines [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Expression Levels of RAD51 Inversely Correlate with Survival of Glioblastoma Patients

Morrison

Weterings

Mahadevan

et al. 2021

Cancers

View full text Add to dashboard Cite

Treatment failures of glioblastoma (GBM) occur within high-dose radiation fields. We hypothesized that this is due to increased capacity for DNA damage repair in GBM. We identified 24 adult GBM patients treated with maximal safe resection followed by radiation with concurrent and adjuvant temozolomide. The mRNA from patients was quantified using NanoString Technologies’ nCounter platform and compared with 12 non-neoplastic temporal lobe tissue samples as a control. Differential expression analysis identified seven DNA repair genes significantly upregulated in GBM tissues relative to controls (>4-fold difference, adjusted p values < 0.001). Among these seven genes, Cox proportional hazards models identified RAD51 to be associated with an increased risk of death (HR = 3.49; p = 0.03). Kaplan–Meier (KM) analysis showed that patients with high RAD51 expression had significantly shorter OS compared to low levels (median OS of 10.6 mo. vs 20.1 mo.; log-rank p = 0.03). Our findings were validated in a larger external dataset of 162 patients using publicly available gene expression data quantified by the same NanoString technology (median OS of 13.8 mo. vs. 17.4 mo; log-rank p = 0.006). Within this uniformly treated GBM population, RAD51, in the homologous recombination pathway, was overexpressed (vs. normal brain) and inversely correlated with OS. High RAD51 expression may be a prognostic biomarker and a therapeutic target in GBM.

show abstract

Dose-intensified chemoradiation is associated with altered patterns of failure and favorable survival in patients with newly diagnosed glioblastoma

Cited by 15 publications

References 31 publications

Metabolic Tumor Volume Response Assessment Using (11)C-Methionine Positron Emission Tomography Identifies Glioblastoma Tumor Subregions That Predict Progression Better Than Baseline or Anatomic Magnetic Resonance Imaging Alone

Metabolic Tumor Volume Response Assessment Using (11)C-Methionine Positron Emission Tomography Identifies Glioblastoma Tumor Subregions That Predict Progression Better Than Baseline or Anatomic Magnetic Resonance Imaging Alone

Post-Operative Accelerated-Hypofractionated Chemoradiation With Volumetric Modulated Arc Therapy and Simultaneous Integrated Boost in Glioblastoma: A Phase I Study (ISIDE-BT-2)

Expression Levels of RAD51 Inversely Correlate with Survival of Glioblastoma Patients

Contact Info

Product

Resources

About