Intraoperative MRI-Guided Resection in Cerebral Glioma Surgery
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Clinical Question
In patients with KPS >=70, between the age 18-70 with newly diagnosed (radiographically or by needle biopsy) supratentorial malignant glioma who have undergone gross total resection (GTR), does intraoperative MRI-guided GTR versus standard neuronavigation/neurophysiological monitoring lead to superior gross total resection by percentage as the primary endpoint, and secondary end points are decreased morbidity, better overall survival and progression-free survival of cerebral gliomas (WHO Grade II-IV)?
Bottom Line
The preliminary findings show that use of 3T iMRI is associated with superior gross total resection in low grade glioma patients, and does not demonstrate improved survival or reduced postoperative complications. Results from the final, completed study, which will be more adequately powered, may be able to address this point.
Major Points
iMRI has been an important advance in neurosurgical oncology since the first iMRI at Brigham and Women's Hospital was introduced in 1993. As of 2015, most studies on iMRI are retrospective cohort or case-control studies to test the effect of iMRI. Although most studies agree that iMRI-guided resection is more extensive than standard navigation resections, they have not conclusively demonstrated overall survival benefit for the use of iMRI. The first and only randomized, controlled trial reported by Senft et al in 2011 shows some valuable evidence for the use of iMRI guidance in glioma surgery because it shows a significant increase in gross total resection from 68% to 96% in the iMRI group vs control group. Yet, this study is specific for malignant gliomas away from eloquent structures and under ultra-low field (0.15 T) MRI system. It also did not allow for subgroup analysis of tumors by WHO classification.
This study aims to conduct a well-designed, single center, prospective, randomized, triple-blind, parallel- controlled trial to assess the effect of 3.0-T iMRI-guided glioma resection on surgical efficiency, morbidity, OS, and progression-free survival (PFS) of cerebral gliomas (WHO grade II-IV).
Guidelines
As of September 2015, no guidelines have been published that reflect the results of this trial.
Design
- Single center, triple-blind, parallel-group, randomized, controlled trial
- N=114
- iMRI group (n=58)
- Conventional navigation (n=56)
- Setting: Single Center - Huashan Hospital, Shanghai, China
- Enrollment: February 2012 and August 2013
- Mean follow-up: 6-16 months for HGG, all patient >6 months follow-up
- Analysis: Intention-to-treat
- Primary outcome: Gross Total Resection
Population
Inclusion Criteria
- 18 to 70 years of age with newly diagnosed (diagnosed presurgically by board-certified radiologists and neurosurgeons)
- untreated malignant cerebral glioma (WHO grade II-IV)
- with supratentorial lesion involving the frontal, temporal, parietal, occipital, and/or insular lobe
- with or without the lesion in an eloquent area
- with preoperative assessment of attainable radiologically gross total tumor resection (by board-certified anesthesiologists and neurosurgeons)
- presurgical KPS score greater or equal to 70.
Exclusion Criteria
- Individuals with recurrent glioma after initial surgical intervention (except needle biopsy);
- Primary glioma with prior radiotherapy or chemotherapy
- Lesions of the midline, basal ganglia, cerebellum, or brainstem
- Renal insufficiency or hepatic insufficiency
- History of malignancy at the body site
- Other critical tumor location or physical status that did not enable complete resection of the tumor or restricted life expectancy
- Contraindications precluding iMRI acquisition.
- Neuropathologically confirmed nonglioma lesions or benign histologies, including pilocytic astrocytoma, subependymal giant-cell astrocytoma, pleomorphic xanthroastrocytoma, ganglioglioma, and dysembryoplasric neuroepithelial tumor (DNET), were excluded from the secondary endpoint follow-up
Baseline Characteristics
| Variable | iMRI (n = 44) | Control (n = 43) | P-value |
| Female sex, n (%) | 15 (34.09) | 19 (44.19) | 0.38 |
| Mean (SD) age, y | 43.93 | 42.52 | 0.59 |
| KPS (100), n (%) | 40 (90.91) | 38 (88.37) | 0.74 |
| Site, n (%) | |||
| Frontal lobe | 28 (63.64) | 30 (69.77) | |
| Parietal lobe | 3 (6.82) | 3 (6.98) | |
| Temporal lobe | 7 (15.91) | 6 (13.95) | |
| Insular lobe | 3 (6.82) | 4 (9.30) | |
| Occipital lobe | 3 (6.82) | 0 (0.0) | |
| Tumor location, n (%) | 0.83 | ||
| Noneloquent | 17 (38.64) | 18 (41.86) | |
| Eloquent | 27 (61.36) | 25 (58.14) | |
| Hemisphere, n (%) | 0.83 | ||
| Dominant | 20 (45.45) | 21 (48.84) | |
| Nondominant | 24 (54.55) | 22 (51.16) | |
| Grade, n (%) | 0.34 | ||
| II | 22 (50.00) | 28 (65.12) | |
| Astrocytoma | 17 | 19 | |
| Oligodendroglioma | 3 | 7 | |
| Oligoastrocytoma | 2 | 2 | |
| III | 12 (27.27) | 7 (16.28) | |
| Anaplastic astrocytoma | 7 | 5 | |
| Anaplastic oligodendroglioma | 5 | 1 | |
| Anaplastic oligoastrocytoma | 0 | 1 | |
| IV | 10 (22.73) | 8 (18.60) | |
| Glioblastoma multiforme | 10 | 8 | |
| IONM | 0.81 | ||
| Yes | 36 | 36 | |
| No | 8 | 7 | |
| Genotype | iMRI n, % (n = 44) | Control n, % (n = 43) | P-value |
| IDH1 | |||
| Mutation | 26 (59.09) | 28 (65.12) | 0.66 |
| Wild type | 18 (40.91) | 15 (34.88) | |
| MGMT | |||
| Methylation | 36 (81.82) | 32 (74.42) | 0.44 |
| Unmethylation | 8 (18.18) | 11 (25.58) | |
Interventions
- Performed conventional NAV surgery (n=114)
- Randomized to iMRI resection (n=58) or standard neuronavigation/neurophysiological monitoring-based resection (n=56)
- If allocated to iMRI, iMRI evaluation, if 100% resection, closure. If not 100% resection, determine if more safe resection possible, if so, another resection is initiated, followed by iMRI evaluation.
- If allocated to conventional NAV group, closure after resection.
Outcomes
Comparisons are intensive therapy vs. standard therapy.
Primary Outcomes
| Rate of Gross Total Resection Stratified by High-Grade | iMRI (n = 44) | Control (n = 43) | P-value |
| High-grade glioma (n = 37) | 22 | 15 | 0.2 |
| GTR (100%), n (%) | First iMRI: 12 (54.55) | 11 (73.33) | |
| Final: 20 (90.91) | |||
| Low-grade glioma (n = 50) | 22 | 28 | 0.01 |
| GTR (100%), n (%) | First iMRI: 9 (40.91) | 12 (42.86) | |
| Final: 18 (81.82) | |||
While not explicitly stated in the paper, the absolute risk of failed GTR was 16.6% in the iMRI group and 46.5% in the control group, with a resultant NNT of 3.3.
Secondary Outcomes
| Extent of Resection: Volumetric Cutoff Value for Survival | iMRI (n = 44) | Control (n = 43) | P Value |
| Benefit | |||
| HGG (n = 37) | 22 | 15 | 0.37 |
| greater than or equal to 98% resection - n (%) | First iMRI: 13 (59.09) | 12 (80.00) | |
| Final: 20 (90.91) | |||
| LGG (n = 50) | 22 | 28 | 0.01 |
| greater than or equal to 90% resection - n (%) | |||
Progression free survival and postoperative morbidity did not differ between groups.
Subgroup Analysis
Awaiting final results for subgroup analysis by genotype.
Adverse Events
| Postoperative Neurological Deficits | iMRI (n = 44) | Control (n = 43) | P Value |
| Language deficits | |||
| After surgery | 6 (13.64) | 13 (30.23) | 0.06 |
| At 6 mo | 1 (2.27) | 1 (2.33) | 0.99 |
| Motor deficits | |||
| After surgery | 11 (25.0) | 11 (25.58) | 0.95 |
| At 6 mo | 3 (6.82) | 2 (4.65) | 0.99 |
Criticisms
Although an interim analysis, it is an attempt at Level 1b evidence (Oxford Centre for Evidence-Based Medicine) evidence for the use of iMRI in this patient population. The re-estimated sample size is adjusted to 75 for LGG and 228 for HGG for 90% power, respectively as reported by the authors.
Rates of chemo/radiation did not differ between group, though there is a subset of “Radiotherapy + other” adjuvant treatment which is not explored.
Results are presented with p values only; no confidence intervals are presented. Interquartile ranges are presented for preoperative tumor volumes.
Funding
National Key Technology R&D Program of China (No. 2014BAI04B05) and the Shanghai Municipal Health Bureau (XBR2011022)
Further Reading
1) Senft C, Bink A, Franz K, Vatter H, Gasser T, Seifert V. Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol. 2011;12(11):997-1003.