Thema: Temozolomid und unmethylierter MGMTp sowie IDH Wildtyp
Temozolomid und unmethylierter MGMTp sowie IDH Wildtyp
Lichtgeist2
07.02.2021 08:51:37
Temozolomid verlängert nicht das Leben bei Biomarkern wie unmethylierter MGMTp und IDH Wildtyp
Eine neue Studie zeigt auf, dass die berichteten Wirkungen von TZM bei einem unmethylierten MGMTp nur Zustande gekommen sei, durch den IDH 1/2 Typ (bei 5-10%) bzw. durch eine ungenaue Einteilung in unmethyliert und methyliert. Es gibt auch partiell methylierte und diese wurden, laut der Studie, zu unmethyliert zugeordnet und hätten dadurch von TZM profitiert. Wenn es sich um ein „echten“ unmethylierten MGMTp, sowie IDH Wildtyp handelt, zeigt TZM keine lebensverlängernde Wirkung.
https://jamanetwork.com/journals/jamaoncology/fullarticle/2775176
The routine use of temozolomide in patients with MGMTp unmethylated glioblastoma has been justified by a modest tail on the survival curves from randomized studies that demonstrate that a few patients with MGMTp unmethylated tumors have prolonged survival if they receive temozolomide.1,5 As clinicians have been unable to identify which of these patients might do unexpectedly well, temozolomide is prescribed to most of those with unmethylated MGMTp tumors in the US.2
However, new evidence has emerged since 2005 that illuminates the unusually long survival of the few patients with MGMTp unmethylated glioblastoma who receive temozolomide. First, large-scale validation studies of quantitative methylation-specific polymerase chain reaction suggest that the prior method of classifying tumors in a binary fashion as either methylated or unmethylated is overly simplistic.6 An alternate approach identifies 3 clinically distinct groups of MGMTp methylation scores that are strongly associated with survival outcomes in patients who receive temozolomide. Patients with methylation scores in the highest range (highly methylated) experienced the maximum clinical benefit from the addition of temozolomide. Those in the intermediate range (partially methylated or gray zone) had partial benefit, while those in the low (truly unmethylated) range derived no survival benefit from the addition of temozolomide.3 Because many glioblastomas with partially methylated MGMTp were classified as unmethylated using the binary classification system, their response to temozolomide likely contributed to the tail of the survival curve in the previously mentioned trials.
Furthermore, the crucial role of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations in predicting responses to temozolomide has been elucidated over the past decade, and testing for mutant IDH has become routine after its inclusion in the 2016 World Health Organization classification of central nervous system tumors. It is now known that (1) IDH1/2 mutations are present in 5% to 10% of all adult World Health Organization grade IV astrocytomas, (2) patients with IDH-mutant tumors benefit from temozolomide added to their treatment regimen, and (3) a smaller, yet substantial proportion of patients with these sequence variants may be MGMTp unmethylated. Consequently, this IDH-mutant subpopulation is also likely to contribute to a set of long-term survivors in IDH agnostic trials, such as the EORTC-NCIC that established the role of temozolomide in adults with glioblastoma.1 These observations are supported by recent results from the CATNON trial, which failed to demonstrate a survival advantage in IDH–wild-type anaplastic astrocytoma (grade III) when concurrent or adjuvant temozolomide was used with radiation, which was similar to observations with glioblastoma (grade IV astrocytoma).7 In summary, it appears that survival in patients with IDH–wild-type and truly MGMTp unmethylated high-grade astrocytomas, including glioblastoma, is not enhanced by the addition of temozolomide administered concurrently with radiation or in the adjuvant setting.
Eine neue Studie zeigt auf, dass die berichteten Wirkungen von TZM bei einem unmethylierten MGMTp nur Zustande gekommen sei, durch den IDH 1/2 Typ (bei 5-10%) bzw. durch eine ungenaue Einteilung in unmethyliert und methyliert. Es gibt auch partiell methylierte und diese wurden, laut der Studie, zu unmethyliert zugeordnet und hätten dadurch von TZM profitiert. Wenn es sich um ein „echten“ unmethylierten MGMTp, sowie IDH Wildtyp handelt, zeigt TZM keine lebensverlängernde Wirkung.
https://jamanetwork.com/journals/jamaoncology/fullarticle/2775176
The routine use of temozolomide in patients with MGMTp unmethylated glioblastoma has been justified by a modest tail on the survival curves from randomized studies that demonstrate that a few patients with MGMTp unmethylated tumors have prolonged survival if they receive temozolomide.1,5 As clinicians have been unable to identify which of these patients might do unexpectedly well, temozolomide is prescribed to most of those with unmethylated MGMTp tumors in the US.2
However, new evidence has emerged since 2005 that illuminates the unusually long survival of the few patients with MGMTp unmethylated glioblastoma who receive temozolomide. First, large-scale validation studies of quantitative methylation-specific polymerase chain reaction suggest that the prior method of classifying tumors in a binary fashion as either methylated or unmethylated is overly simplistic.6 An alternate approach identifies 3 clinically distinct groups of MGMTp methylation scores that are strongly associated with survival outcomes in patients who receive temozolomide. Patients with methylation scores in the highest range (highly methylated) experienced the maximum clinical benefit from the addition of temozolomide. Those in the intermediate range (partially methylated or gray zone) had partial benefit, while those in the low (truly unmethylated) range derived no survival benefit from the addition of temozolomide.3 Because many glioblastomas with partially methylated MGMTp were classified as unmethylated using the binary classification system, their response to temozolomide likely contributed to the tail of the survival curve in the previously mentioned trials.
Furthermore, the crucial role of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations in predicting responses to temozolomide has been elucidated over the past decade, and testing for mutant IDH has become routine after its inclusion in the 2016 World Health Organization classification of central nervous system tumors. It is now known that (1) IDH1/2 mutations are present in 5% to 10% of all adult World Health Organization grade IV astrocytomas, (2) patients with IDH-mutant tumors benefit from temozolomide added to their treatment regimen, and (3) a smaller, yet substantial proportion of patients with these sequence variants may be MGMTp unmethylated. Consequently, this IDH-mutant subpopulation is also likely to contribute to a set of long-term survivors in IDH agnostic trials, such as the EORTC-NCIC that established the role of temozolomide in adults with glioblastoma.1 These observations are supported by recent results from the CATNON trial, which failed to demonstrate a survival advantage in IDH–wild-type anaplastic astrocytoma (grade III) when concurrent or adjuvant temozolomide was used with radiation, which was similar to observations with glioblastoma (grade IV astrocytoma).7 In summary, it appears that survival in patients with IDH–wild-type and truly MGMTp unmethylated high-grade astrocytomas, including glioblastoma, is not enhanced by the addition of temozolomide administered concurrently with radiation or in the adjuvant setting.
Lichtgeist2
Prof. Mursch
07.02.2021 09:19:08
Ja, aber.
Im Prinzip handelt es sich bei dem Artikel nicht um eine Studie, sondern um einen Kommentar, eine Meinung. Sie wird vor allem damit begründet, dass die Einteilung „methyliert oder nicht“ so nicht mehr haltbar ist.
Man ist der Meinung, dass TMZ bei eindeutig nicht methylierten, IDH 1/2 wild type GBM keinen Sinn macht.
Prof. Dr. med. Kay Mursch
Neurochirurg
Zentralklinik Bad Berka
Im Prinzip handelt es sich bei dem Artikel nicht um eine Studie, sondern um einen Kommentar, eine Meinung. Sie wird vor allem damit begründet, dass die Einteilung „methyliert oder nicht“ so nicht mehr haltbar ist.
Man ist der Meinung, dass TMZ bei eindeutig nicht methylierten, IDH 1/2 wild type GBM keinen Sinn macht.
Prof. Dr. med. Kay Mursch
Neurochirurg
Zentralklinik Bad Berka
Prof. Mursch
