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INTRAMET

Intraoperative radiotherapy after resection of newly diagnosed brain metastases in adult patients - results of a prospective phase II trial (INTRAMET)

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Year of Publication: 2026

Authors: Brehmer S, Sarria GR, Würfel S, ..., Giordano FA

Journal: Journal of Neuro-Oncology

Citation: Journal of Neuro-Oncology (2026) 178:28

Link: https://doi.org/10.1007/s11060-026-05649-6

Clinical Question

Does intraoperative radiotherapy delivered to the resection cavity provide effective local control and acceptable safety in patients with newly diagnosed brain metastases?

Bottom Line

Low-energy X-ray IORT (30 Gy at the applicator surface) delivered to the resection cavity at the time of brain metastasis resection achieved a 94.3% local control rate at 1 and 2 years with no grade 4/5 IORT-related toxicities, suggesting it may be a feasible alternative to postoperative stereotactic radiosurgery in selected patients.

        Major Points
        Local control rate was 94.3% (95% CI 82.9–98.8%) at both 1 and 2 years — only 2 local recurrences observed
Distant brain control rate was 57.1% (95% CI 40.7–72.4%); 1-year distant brain control 62.9%
Median overall survival was 43.6 months (95% CI 8.8–78.4)
Radionecrosis occurred in 20% of patients (5 grade 1, 1 grade 2, 1 grade 3); no grade 4 or 5 IORT-related adverse events
Leptomeningeal dissemination outside the irradiated field occurred in 8.6% (3 patients)
Median time to initiation of subsequent systemic therapy was 45 days, numerically shorter than retrospective conventional radiotherapy cohort (56.6 days)
Patients who did not require salvage WBRT had significantly longer median OS (42.4 vs 17.5 months, p=0.027)
Enrollment was discontinued early after pre-specified A'Hern statistical success criterion was met

      

Design

Study Type: Prospective, single-arm, open-label phase II trial

Randomization:

Blinding: Open-label

Allocation: Single-arm

Enrollment Period: 2017 to 2022

Follow-up Duration: Median 25.7 months (range 0.8–64.5)

Centers: 1

Countries: Germany

Sample Size: 35

Analyzed: 35

Analysis: Kaplan–Meier method with log-rank test; t-tests, Fisher's exact, and Fisher–Freeman–Halton tests for group comparisons; SPSS v28

Power Calculation: A'Hern single-stage design: null hypothesis LCR <60%, alternative >80%, one-sided alpha 5%, 90% power, requiring 45 patients with 50 planned to account for 10% dropout; enrollment stopped early upon meeting success criterion

Inclusion Criteria

Age ≥18 years
KPS ≥50
Suspected brain metastases with anticipated gross total resection on contrast-enhanced T1-weighted MRI
Histopathological confirmation of metastasis by intraoperative frozen section
Technical feasibility of IORT as determined intraoperatively

Exclusion Criteria

Contraindications to surgery or MRI
Meningeal involvement
Pregnancy or breastfeeding
Psychiatric or social conditions impairing protocol compliance
Predicted maximum IORT dose exceeding 8 Gy to critical organs at risk
Prior whole-brain radiotherapy or stereotactic radiosurgery to the target lesion (lesion had to be treatment-naïve)

Baseline Characteristics

IORT:

N: 35
Female: 16 (45.7%)
Male: 19 (54.3%)
Median Age: 64 (range 45–85)
Median KPS: 80 (range 50–100)
KPS ≥80: 74.3%
Median GPA: 2.5 (range 0.5–3.5)
Single BM at diagnosis: 27 (77.1%)
2 BM: 5 (14.3%)
3 BM: 3 (8.4%)
Previously known primary: 18 (51.4%)
Indication for systemic therapy after surgery: 24 (68.6%)
Primary site - Lung: 24 (68.6%)
Primary site - CUP: 3 (8.6%)
Primary site - GI: 3 (8.6%)
Primary site - Kidney: 3 (8.6%)
Primary site - Breast: 1 (2.9%)
Primary site - Ovary: 1 (2.9%)
Histology - Adeno: 20 (57.1%)
Histology - Squamous: 5 (14.3%)
Histology - Undifferentiated: 4 (11.4%)
Histology - Clear cell: 3 (8.6%)
Deep lesion: 15 (42.9%)
Eloquent lesion: 15 (42.9%)
Median metastasis volume (cm³): 5.9 (1.2–43.1)
Median FLAIR volume (cm³): 110.3 (14.4–192.6)
Median applicator size: 2.0 cm (range 1.5–3.0)
Mean radiation time (mm:ss): 16:55 (08:24–40:57)
Total resection: 34 (97.1%)
Seizures at diagnosis: 13 (37.1%)
Median follow-up (months): 25.7 (0.8–64.5)
Patients alive: 18 (51.4%)

Arms

Field	IORT after resection
N	35
Intervention	Surgical resection of brain metastasis followed by intraoperative kilovoltage radiotherapy using the INTRABEAM system (Carl Zeiss Meditec AG), 50 kV nominal output, with applicator size selected based on cavity geometry; 30 Gy prescribed to the applicator surface (0 mm)
Duration	Single intraoperative session (mean radiation time 16:55, range 08:24–40:57)

Outcomes

Outcome	Type	Control	Intervention	P-value
Local control rate (LCR) — absence of in-cavity or marginal contrast-enhancing lesions suggestive of recurrence on serial contrast-enhanced T1-weighted MRI per RANO-BM criteria	Primary		94.3% at 1 and 2 years (2 local recurrences at 1 and 2 months post-treatment)
	Secondary	57.1% (95% CI 40.7–72.4%); 1-year 62.9% (95% CI 46.3–77.3%); 2-year 57.1%
	Secondary	Median 43.6 months (95% CI 8.8–78.4); 51.4% alive at analysis
	Secondary	42.4 months (95% CI 31.9–52.9) vs 17.5 months (95% CI 3.8–31.1), p=0.027
	Secondary	Median 45.0 days (95% CI 35.1–54.8); retrospective conventional radiotherapy cohort 56.6 days (95% CI 49.0–64.2)
	Secondary	8.6% (3 patients at 3, 38, and 44 months)
	Secondary	20% (n=7); median time from IORT to WBRT 147 days (range 20–601)
	Secondary	Cerebral progression 11.8%; combined cerebral and systemic 23.5%; systemic alone 23.5%; unrelated causes 41.2%
	Safety	20% (5 grade 1, 1 grade 2, 1 grade 3); 5 asymptomatic, 2 symptomatic (managed with corticosteroids n=1, bevacizumab n=1; 1 surgical resection in asymptomatic patient for suspected progression)
	Safety	12 events total, all classified as at least possibly related
	Safety	None observed
	Safety	None
7/35 (20%)				Adverse
5				Adverse
1				Adverse
1				Adverse
12				Adverse
0				Adverse
0				Adverse

Subgroup Analysis

No significant survival differences by primary tumor histology (p=0.618), immunotherapy receipt (p=0.928), preoperative seizures (p=0.169), or radionecrosis (p=0.214). Baseline KPS effect did not reach significance (p=0.056). Non-significant trend toward improved survival without intracranial failure (p=0.250). No associations between radionecrosis and metastasis volume, applicator size, number of BM, resection status, immunotherapy, WBRT, BM location, or histology.

Criticisms

Small single-arm, single-center study (n=35) with no concurrent randomized comparator to SRS or FSRT
Enrollment stopped early after meeting A'Hern success criterion, potentially limiting precision
Retrospective comparison of time to systemic therapy was not prespecified and used unmatched institutional cohort — descriptive only, prone to selection bias
Median follow-up of 25.7 months may underestimate late radionecrosis and recurrence events
Highly selected population requiring intraoperative technical feasibility of IORT
Most metastases were from lung cancer (68.6%) — generalizability to other primaries less certain
Patients receiving salvage WBRT were censored at WBRT initiation for local control, potentially biasing LCR estimate upward

Based on: INTRAMET (Journal of Neuro-Oncology, 2026)

Authors: Brehmer S, Sarria GR, Würfel S, ..., Giordano FA

Citation: Journal of Neuro-Oncology (2026) 178:28

Content summarized and formatted by NeuroTrials.ai.

INTRAMET

(2026)

Objective

To evaluate the efficacy and safety of low-energy X-ray intraoperative radiotherapy (IORT) following resection of newly diagnosed brain metastases.

Study Summary

• Local control rate was 94.3% (95% CI 82.9–98.8%) at both 1 and 2 years
• Distant brain control was 57.1% (95% CI 40.7–72.4%); median OS was 43.6 months (95% CI 8.8–78.4)
• Radionecrosis occurred in 20% (predominantly low grade); no grade 4/5 IORT-related toxicities
• Median time to initiation of subsequent systemic therapy was 45 days (vs 56.6 days in retrospective conventional radiotherapy cohort)
• Leptomeningeal dissemination outside irradiated field in 8.6%

Intervention

Intraoperative radiotherapy (IORT) delivered with the INTRABEAM mobile low-energy (50 kV) X-ray device to the resection cavity, 30 Gy prescribed to the applicator surface, immediately following surgical resection and frozen-section confirmation.

Inclusion Criteria

Age ≥18, KPS ≥50, suspected brain metastases with anticipated gross total resection on contrast-enhanced T1 MRI, histopathological confirmation by intraoperative frozen section, technical feasibility of IORT.

Study Design

Arms: IORT after resection of brain metastases (n=35, single arm)

Patients per Arm: 35

Outcome

• Local control 94.3% (95% CI 82.9–98.8%) at 1 and 2 years; only 2 local recurrences
• Distant brain control 57.1% (95% CI 40.7–72.4%); 1-year 62.9%
• Median overall survival 43.6 months (95% CI 8.8–78.4)
• Radionecrosis 20% (5 grade 1, 1 grade 2, 1 grade 3); no grade 4/5 events
• Median time to subsequent systemic therapy 45 days (95% CI 35.1–54.8)
• Patients without WBRT had longer OS (42.4 vs 17.5 months, p=0.027)

Bottom Line

Major Points

Local control rate was 94.3% (95% CI 82.9–98.8%) at both 1 and 2 years — only 2 local recurrences observed
Distant brain control rate was 57.1% (95% CI 40.7–72.4%); 1-year distant brain control 62.9%
Median overall survival was 43.6 months (95% CI 8.8–78.4)
Radionecrosis occurred in 20% of patients (5 grade 1, 1 grade 2, 1 grade 3); no grade 4 or 5 IORT-related adverse events
Leptomeningeal dissemination outside the irradiated field occurred in 8.6% (3 patients)
Median time to initiation of subsequent systemic therapy was 45 days, numerically shorter than retrospective conventional radiotherapy cohort (56.6 days)
Patients who did not require salvage WBRT had significantly longer median OS (42.4 vs 17.5 months, p=0.027)
Enrollment was discontinued early after pre-specified A'Hern statistical success criterion was met

Study Design

Study Type: Prospective, single-arm, open-label phase II trial
Randomization: No
Blinding: Open-label
Sample Size: 35
Follow-up: Median 25.7 months (range 0.8–64.5)
Centers: 1
Countries: Germany

Primary Outcome

Definition: Local control rate (LCR) — absence of in-cavity or marginal contrast-enhancing lesions suggestive of recurrence on serial contrast-enhanced T1-weighted MRI per RANO-BM criteria

Control	Intervention	HR/OR	P-value
	94.3% at 1 and 2 years (2 local recurrences at 1 and 2 months post-treatment)	- (82.9–98.8%)

Limitations & Criticisms

Small single-arm, single-center study (n=35) with no concurrent randomized comparator to SRS or FSRT
Enrollment stopped early after meeting A'Hern success criterion, potentially limiting precision
Retrospective comparison of time to systemic therapy was not prespecified and used unmatched institutional cohort — descriptive only, prone to selection bias
Median follow-up of 25.7 months may underestimate late radionecrosis and recurrence events
Highly selected population requiring intraoperative technical feasibility of IORT
Most metastases were from lung cancer (68.6%) — generalizability to other primaries less certain
Patients receiving salvage WBRT were censored at WBRT initiation for local control, potentially biasing LCR estimate upward

Citation

Journal of Neuro-Oncology (2026) 178:28

View Original Publication →

INTRAMET

Intraoperative radiotherapy after resection of newly diagnosed brain metastases in adult patients - results of a prospective phase II trial (INTRAMET)

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

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