Article
INTRAGO: Intraoperative radiotherapy in newly diagnosed glioblastoma multiforme results of an open-label dose-escalation phase 1/2 trial
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Authors
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Stefanie Brehmer
- Neurochirurgische Klinik, Universitätsmedizin Mannheim, Medizinischen Fakultät Mannheim der Universität Heidelberg, Mannheim, Deutschland
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Frank Anton Giordano
- Klinik für Strahlentherapie und Radioonkologie, Universitätsmedizn Mannheim, Medizinischen Fakultät Mannheim der Universität Heidelberg, Deutschland
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Bettina Mürle
- Abteilung für Neuroradiologie, Universitätsmedizin Mannheim, Medizinischen Fakultät Mannheim der Universität Heidelberg, Mannheim, Deutschland
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Marcel Seiz-Rosenhagen
- Neurochirurgische Klinik, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Deutschland
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Daniel Hänggi
- Universitätsklinikum Mannheim, Neurochirurgische Klinik, Universitätsmedizin Mannheim, Medizinischen Fakultät Mannheim der Universität Heidelberg, Mannheim, Deutschland
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Peter Schmiedek
- Neurochirurgische Klinik, Universitätsmedizin Mannheim, Medizinischen Fakultät Mannheim der Universität Heidelberg, Mannheim, Deutschland
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Frederik Wenz
- Universitätsmedizin Mannheim, Institut f. Klinische Radiologie, Strahlentherapie, Mannheim, Deutschland
| Published: | June 9, 2017 |
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Outline
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Objective: Patients diagnosed with glioblastoma (GBM) have despite aggressive treatment with surgery and adjuvant radiochemotherapy a poor prognosis with a progression-free survival (PFS) of about 7 month. As almost every progress is seen at the resection cavity an augmentation of local treatments may improve outcome. We here present the results of a dose finding trial testing intraoperative radiotherapy (IORT) with low-energy x-rays to the resection cavity.
Methods: In a single-center, open-label, phase 1/2 dose-escalation trial for adult patients with newly diagnosed GBM (INTRAGO) patients received (IORT) at three dose levels starting at 20Gy prescribed to the surface of the resection cavity and escalated in 10Gy steps up to 40Gy. Afterwards patients received standard adjuvant therapy consisting of classic radiotherapy (60Gy) in combination with temozolomide followed by maintenance temozolomide. The primary endpoint was safety respectively the occurrence of dose-limiting toxicities within the first 3 months following IORT defined as wound healing disorders, cerebral hemorrhage/ischemia, radionecrosis and early termination of radiochemotherapy). Secondary endpoints were PFS and overall survival (OS). Additional the local PFS, defined as tumor recurrence within 1 cm of the treated resection cavity was analyzed. The trial is registered at ClinicalTrials.gov (NCT02104882).
Results: Between 8/2013 and 8/2015 15 patients with GBM were treated at three dose levels (7 at 20Gy, 4 at 30Gy, 4 at 40Gy). Of these 13 underwent incomplete resection; 6 had unresected multifocal tumors; and 3 did not receive per-protocol treatment (PPT). The MGMT promoter was not methylated in 10 patients. The median follow-up was 13.8 months. The majority of grade 3-5 adverse events (25 of 30) were deemed related to external-beam radiotherapy, chemotherapy, or tumor progression. 5 patients developed suspected or confirmed radionecrosis. No IORT-related deaths occurred. The median PFS was 11.2 months (95%CI 5.4-17.0) for all patients and 11.3 months (95%CI 10.9-11.6) for those receiving PPT. The median local PFS was 14.3 month (95%CI 8.4-20.2) for all patients and 17.8 month (95%CI: 9.7-25.9) for those receiving PPT. The median OS was 16.2 month (95%CI 11.1-21.4) for all patients and 17.8 month (95%CI 13.9-21.7) for those receiving PPT.
Conclusion: IORT caused a highly relevant increase of local progression-free survival with manageable side effects in a cohort with predominantly incompletely resected GBM and unfavorable prognostic factors.
