Phase 2 Study of a Temozolomide-Based Chemoradiation Therapy Regimen for High-Risk, Low-Grade Gliomas: Long-Term Results of Radiation Therapy Oncology Group 0424

Fisher, Barbara; Pugh, Stephanie L.; Macdonald, David R.; Chakravatri, Arnab; Lesser, Glenn J.; Fox, Sherry; Rogers, C. Leland; Werner‐Wasik, Maria; Doyle, Thomas J.; Bahary, Jean Paul; Fiveash, John B.; Bovi, Joseph; Howard, Steven; Yu, Hsiang-Hsuan Michael; D’Souza, David; Laack, Nadia N.; Barani, Igor J.; Kwok, Young; Wahl, Daniel R.; Strasser, Jon; Won, Minhee; Mehta, Minesh P.

doi:10.1016/j.ijrobp.2020.03.027

Cited by 39 publications

(33 citation statements)

References 17 publications

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“…Several studies carried out in high-grade gliomas analyzed temozolomide to be delivered in association with radiotherapy [ 21 , 110 , 111 ]. The phase 2 study RTOG 0424 combined radiotherapy (54 Gy) with concomitant and sequential temozolomide [ 112 ]. Between 2005 and 2009, that study enrolled 129 high-risk diffuse low-grade glioma patients (oligodendroglioma, oligoastrocytoma and astrocytoma).…”

Section: Role Of Radiotherapymentioning

confidence: 99%

“…Finally, the RTOG 0424 phase II trial [ 112 ] evaluated the combination of radiotherapy and concomitant and adjuvant temozolomide for newly diagnosed high-risk LGG defined by the presence of at least three poor prognostic factors. In this trial, authors compared their results with those of an historical control cohort, suggesting that the combination could be beneficial for a subgroup of LGG displaying a particularly high risk of recurrence.…”

Section: Role Of Chemotherapy and New Systemic Treatmentsmentioning

confidence: 99%

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Clinical Management of Diffuse Low-Grade Gliomas

Lombardi

Barresi

Castellano

et al. 2020

Cancers

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Diffuse low-grade gliomas (LGG) represent a heterogeneous group of primary brain tumors arising from supporting glial cells and usually affecting young adults. Advances in the knowledge of molecular profile of these tumors, including mutations in the isocitrate dehydrogenase genes, or 1p/19q codeletion, and in neuroradiological techniques have contributed to the diagnosis, prognostic stratification, and follow-up of these tumors. Optimal post-operative management of LGG is still controversial, though radiation therapy and chemotherapy remain the optimal treatments after surgical resection in selected patients. In this review, we report the most important and recent research on clinical and molecular features, new neuroradiological techniques, the different therapeutic modalities, and new opportunities for personalized targeted therapy and supportive care.

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Section: Role Of Radiotherapymentioning

confidence: 99%

Section: Role Of Chemotherapy and New Systemic Treatmentsmentioning

confidence: 99%

Clinical Management of Diffuse Low-Grade Gliomas

Lombardi

Barresi

Castellano

et al. 2020

Cancers

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“…However, RT combined with TMZ or PCV resulted in an overall survival benefit in patients [ 43 ]. IDH-mutant oligodendrogliomas benefit from the addition of PCV to RT (RTOG 9802 [ 44 , 45 ], RTOG 9402 [ 46 ], EORTC 26951 [ 47 ], and NOA-04 [ 48 ]), while RT plus TMZ treatment shows more benefit in astrocytomas in clinical (EORTC 26053-22054 (CATNON) [ 49 ], RTOG 0424 [ 50 ]), and retrospective [ 51 ] studies. The interim analysis of the CATNON trial indicate a trend toward benefit with concurrent TMZ in IDH-mutant tumors, but not in IDH-wt gliomas.…”

Section: Temozolomide Treatment In Idh-mutant Gliomasmentioning

confidence: 99%

From Laboratory Studies to Clinical Trials: Temozolomide Use in IDH-Mutant Gliomas

Sun

Turcan

2021

Cells

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In this review, we discuss the use of the alkylating agent temozolomide (TMZ) in the treatment of IDH-mutant gliomas. We describe the challenges associated with TMZ in clinical (drug resistance and tumor recurrence) and preclinical settings (variabilities associated with in vitro models) in treating IDH-mutant glioma. Lastly, we summarize the emerging therapeutic targets that can potentially be used in combination with TMZ.

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“…Long-term results from this study demonstrated that survival for patients treated with RT and TMZ was significantly longer compared with a prespecified historical RT-only control group. 1 Molecular analyses for patients on NRG/RTOG 0424 revealed MGMT promoter methylation to be a strong prognostic biomarker, independent of other clinical variables as well as IDH1/2 mutation status. 2 It is clear from numerous clinical trials of lower-grade gliomas (LGGs, grade II-III) that the addition of alkylating chemotherapy to RT extends survival for these patients.…”

Section: Introductionmentioning

confidence: 96%

“…2 It is clear from numerous clinical trials of lower-grade gliomas (LGGs, grade II-III) that the addition of alkylating chemotherapy to RT extends survival for these patients. 1,[3][4][5] What remains unclear is whether this is true for all molecular subgroups. We recently reported that only the IDHmutant (IDHmut) WHO subgroups (IDHmutant/codeleted [IDHmut/co-del] and IDHmutant/non-co-deleted [IDHmut/non-co-del]) received therapeutic benefit from the addition of PCV (procarbazine, lomustine (CCNU), and vincristine) chemotherapy to RT in the NRG/RTOG 9802 trial, but whether the same observation could be extended to TMZ-based regimens remained unclear.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Report of a Comprehensive Molecular and Genomic Analysis in NRG Oncology/RTOG 0424: A Phase II Study of Radiation and Temozolomide in High-Risk Grade II Glioma

Fleming

Pugh

Fisher

et al. 2021

JCO Precision Oncology

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PURPOSE This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX, CIC, FUBP1, TERT, and TP53, in NRG/RTOG 0424 using long-term follow-up data. METHODS Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. RESULTS We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDHmutant/co-deleted, 28 (35%) were IDHmutant/non-co-deleted, and 26 (32.5%) were IDHwild-type. Upon single-marker MVA, both IDHmutant subgroups were associated with significantly better OS and PFS ( P values < .001), compared with the IDHwild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS ( P value < .001) and PFS ( P value = .003). In a multimarker MVA, one WHO subgroup comparison ( IDHmutant/co-deleted v IDHwild-type) was significant for OS ( P value = .045), whereas MGMT methylation did not retain significance. CONCLUSION This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status.

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Phase 2 Study of a Temozolomide-Based Chemoradiation Therapy Regimen for High-Risk, Low-Grade Gliomas: Long-Term Results of Radiation Therapy Oncology Group 0424

Cited by 39 publications

References 17 publications

Clinical Management of Diffuse Low-Grade Gliomas

Clinical Management of Diffuse Low-Grade Gliomas

From Laboratory Studies to Clinical Trials: Temozolomide Use in IDH-Mutant Gliomas

Long-Term Report of a Comprehensive Molecular and Genomic Analysis in NRG Oncology/RTOG 0424: A Phase II Study of Radiation and Temozolomide in High-Risk Grade II Glioma

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