Dose escalation with intraoperative radiotherapy in newly diagnosed glioblastoma (INTRAGO-II): an open-label, multicentre, randomised, controlled, phase 3 trial.
In this multicentre phase 3 trial in adults with newly diagnosed resectable glioblastoma, adding 30 Gy intraoperative radiotherapy to standard chemoradiotherapy did not improve progression-free survival or reduce local recurrence and was associated with more serious adverse events.
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In this multicentre phase 3 trial in adults with newly diagnosed resectable glioblastoma, adding 30 Gy intraoperative radiotherapy to standard chemoradiotherapy did not improve progression-free survival or reduce local recurrence and was associated with more serious adverse events.
Research significance
The trial directly refutes the tested hypothesis that spatially precise intraoperative dose escalation improves progression-free survival in resectable adult glioblastoma; it supports the inference that avoiding this additional local therapy could reduce treatment burden and toxicity, although pediatric applicability was not evaluated.
Source abstract
BACKGROUND: Despite maximal safe resection and chemoradiotherapy, most glioblastomas recur locally. We aimed to evaluate whether additional intraoperative radiotherapy compared with standard of care improves outcomes in patients with newly diagnosed glioblastoma. METHODS: INTRAGO-II was an open-label, multicentre, randomised, controlled, phase 3 trial enrolling patients aged 18-80 years with supratentorial glioblastoma amenable to resection of the contrast enhancing tumour with Karnofsky performance score (KPS) of ≥60%. Patients from 18 centres in Brazil, Canada, China, Germany, Spain, South Korea, and the USA were randomly assigned (1:1) intraoperatively to receive additional kilovoltage intraoperative radiotherapy with 30 Gy (intraoperative radiotherapy group) or surgery alone (standard-of-care group), stratified by age, KPS, and residual tumour. Postoperative treatment consisted of external-beam radiotherapy to 60 Gy with concurrent temozolomide (75 mg/m2), followed by six adjuvant cycles of temozolomide (150-200 mg/m2, days 1-5 every 28 days). The primary endpoint was median progression-free survival in the full-analysis set, confirmed by masked, centralised review. This ongoing study is closed to recruitment and is registered with ClinicalTrials.gov, NCT02685605. FINDINGS: Between Dec 9, 2016, and June 17, 2024, of 411 patients assessed for eligibility, 314 were randomly assigned. The full-analysis set comprised 298 patients (intraoperative radiotherapy, n=161; standard-of-care, n=137), of whom 127 (43%) patients were female and 171 (57%) were male. Data on race and ethnicity were not collected. At a median follow-up of 17·2 months (IQR 10·5-27·1), median progression-free survival was 11·0 months (95% CI 9·2-12·6) in the intraoperative radiotherapy group versus 11·4 months (9·7-13·9) in the standard-of-care group (hazard ratio [HR] 1·1, 95% CI 0·85-1·44; p=0·47). Local recurrence was the predominant pattern of failure in both groups (76 [72%] in the intraoperative radiotherapy group vs 60 [71%] in the standard-of-care group, p=0·87). The most common grade 3-4 adverse events were seizure (21 [13%] in the intraoperative radiotherapy group vs nine [7%] in the standard-of-care group), radiation necrosis (11 [7%] vs three [2%]; p=0·06), thrombocytopenia (seven [4%] vs 11 [8%]), and muscle weakness (12 [7%] vs 19 [14%]). In total, 252 serious adverse events occurred in 105 (65%) patients in the intraoperative radiotherapy group and 142 serious adverse events in 72 (53%) patients in the standard-of-care group. Of these, 65 (26%) events in 40 (38%) patients in the intraoperative radiotherapy group and 27 (19%) events in 19 (26%) patients in the standard-of-care group were considered possibly related to the treatment. Of all grade five adverse events reported, 14 in the intraoperative radiotherapy group (CNS toxicity [n=2], myocardial infarction [n=2], sepsis [n=2], and one each cardiac arrest, fever, lung infection, fracture, postoperative haemorrhage, neoplasm, haematoma, and not otherwise specified death) and six in the standard-of-care group (lung infection [n=2], and one each multiorgan failure, encephalitis, neoplasm, and cystitis) were attributable to specific CTCAE terms. INTERPRETATION: Instant, spatially precise dose escalation with intraoperative radiotherapy added to standard of care did not improve outcomes, questioning the value of further local dose intensification in resectable glioblastoma. FUNDING: Universities of Heidelberg and Bonn, Carl Zeiss Meditec, Deutsche Forschungsgemeinschaft.