Highlights
– The RANO four‑tier classification of residual T2‑FLAIR tumour volume (class 1: supramaximal beyond FLAIR; class 2: 0–5 cm3 remnant; class 3: 5–25 cm3; class 4: >25 cm3) stratifies long‑term outcomes in IDH‑mutant grade 2 glioma.
– Supramaximal resection (class 1) yielded the best outcomes (10‑year overall survival 98%; 5‑year PFS 83%), with graded decrement in outcomes across classes 2–4.
– Survival benefits of more extensive resection appear earlier in astrocytomas (separation by ~3 years) than in oligodendrogliomas (separation at 6–8 years), but benefit is present across molecular subtypes.
– The classification was robust in multivariable models, in patients receiving first‑line adjuvant therapy, and in an independent UCSF validation cohort.
Background
Diffuse, IDH‑mutant grade 2 gliomas (encompassing molecularly defined astrocytomas and oligodendrogliomas) are infiltrative primary brain tumours with prolonged natural histories. Over decades, surgical strategy has trended toward maximal safe resection, but terminology and quantitative thresholds for ‘‘extent of resection’’ have varied across studies, complicating prognostication and trial design. A reproducible classification linked to clinically meaningful outcomes would help surgeons, oncologists, and trialists balance oncological benefit against functional risk and standardize reporting.
Study design
Karschnia and colleagues report an international, multicentre, retrospective cohort study spanning 16 centres in North America, Europe and Asia, identifying adults (≥18 years) with newly diagnosed IDH‑mutant WHO grade 2 glioma diagnosed between Sept 1, 1993 and May 10, 2024. The analysis included 1,391 patients with a median follow‑up of 81 months (95% CI 78–85).
Key features:
- Primary exposure: residual T2‑FLAIR tumour volume after initial surgery, categorised according to a four‑tier RANO classification: class 1 (supramaximal — resection extending beyond FLAIR abnormality), class 2 (maximal T2‑FLAIR resection with 0–5 cm3 remnant), class 3 (submaximal 5–25 cm3 remnant), class 4 (minimal >25 cm3 remnant).
- Coprimary endpoints: progression‑free survival (PFS) and overall survival (OS).
- Analytic methods: Cox proportional hazards models, multivariable adjustment for clinical and tumour variables, and subgroup analyses by molecular subtype (astrocytoma vs oligodendroglioma). An independent external validation cohort from UCSF (n=381; diagnoses 1998–2017) tested reproducibility.
- A subgroup of 728 patients who received no first‑line therapy beyond surgery allowed analysis of isolated surgical effects; an additional 625 patients received first‑line radiotherapy and/or chemotherapy to test the classification’s prognostic relevance in patients given adjuvant treatment.
Key findings
Primary cohort (n=1,391): the RANO classification separated outcomes in a graded fashion.
Overall survival (10‑year rates):
- Class 1 (supramaximal): 98% (95% CI 92–99)
- Class 2 (0–5 cm3 remnant): 82% (95% CI 76–87)
- Class 3 (5–25 cm3 remnant): 75% (95% CI 62–84)
- Class 4 (>25 cm3 remnant): 48% (95% CI 29–65)
Progression‑free survival (5‑year rates):
- Class 1: 83% (95% CI 76–88)
- Class 2: 44% (95% CI 38–50)
- Class 3: 25% (95% CI 16–34)
- Class 4: 12% (95% CI 4–24)
Statistical comparison across classes was highly significant (p < 0.0001 for both OS and PFS). Multivariable Cox models that adjusted for age, performance status, histological subtype, tumour size and adjuvant treatment confirmed that greater residual volume independently predicted worse PFS and OS.
Isolated effect of surgery
In the subgroup of 728 patients who received no adjuvant therapy after resection, class‑specific survival differences persisted, strengthening the argument that surgical extent itself is an important determinant of long‑term outcome rather than merely a correlate of later therapy selection.
Subtype‑specific timing of benefit
When stratified by molecular subtype, survival curves separated earlier for astrocytomas (around 3 years post‑surgery), whereas in oligodendrogliomas the divergence between resection classes emerged at approximately 6–8 years. This suggests differing natural histories and latency to clinically relevant progression between subtypes—important for patient counselling and follow‑up planning.
External validation and adjuvant therapy subgroup
The prognostic value of the RANO classification was reproduced in an independent UCSF cohort (n=381). The classification retained its prognostic relevance in patients receiving first‑line chemotherapy or radiotherapy (n=625), indicating applicability irrespective of early adjuvant therapy use.
Safety and functional outcomes
The primary report emphasises survival differences but provides limited, harmonised data on postoperative neurological deficits and functional outcomes across centres. Because the balance of oncological benefit versus preservation of neurologic function is central to surgical decision‑making, this remains an important caveat.
Expert commentary and interpretation
This study addresses a longstanding problem: heterogeneity in how extent of resection is reported. By anchoring the classification to quantifiable residual T2‑FLAIR volumes and validating it across centres, the RANO scheme provides an objective tool for prognostic stratification and uniform reporting.
Strengths:
- Large, molecularly defined cohort with long median follow‑up (81 months), enhancing the ability to observe late events, especially in slower‑growing oligodendrogliomas.
- Objective, volumetric categorisation of residual disease that is reproducible and clinically interpretable.
- External validation in an independent institution and retention of effects in multivariable models and treated subgroups.
Limitations and cautions:
- Retrospective design and potential selection bias: patients selected for more extensive resections may have more favourable tumour locations, younger age, or better baseline function.
- Heterogeneity in surgical approaches (awake mapping, intraoperative MRI, resection philosophy), imaging protocols and volumetric measurement across 16 centres over three decades could introduce measurement variability despite standardised thresholds.
- Limited harmonised data on functional outcomes or quality of life, which are critical when recommending supramaximal resections in or near eloquent cortex.
- Temporal changes in adjuvant therapy paradigms over the long recruitment window may confound some associations although multivariable adjustment was applied.
Clinical implications: The data provide strong, pragmatic evidence that more extensive resection — and in particular supramaximal resection where safely achievable — is associated with substantial, durable survival benefits in patients with IDH‑mutant grade 2 gliomas. However, decisions should remain individualized, integrating tumour location, mapping findings, patient priorities and risk tolerance. The RANO classification can standardise communication and stratification in clinical practice and trials, but it should be paired with routine assessment of functional outcomes in future work.
Practical recommendations and future directions
For clinicians:
- Adopt the RANO residual volume classification in operative reports and multidisciplinary tumour board discussions to improve prognostic clarity and cross‑institutional comparability.
- When feasible, plan for maximal safe resection with advanced techniques (awake mapping, intraoperative functional monitoring, tractography) prioritising preservation of neurologic function.
- Counsel patients that survival benefits accrue with decreasing residual FLAIR volume, but the magnitude and timing of benefit differ between astrocytoma and oligodendroglioma.
For researchers and guideline developers:
- Incorporate the RANO classification into prospective registries and clinical trials as a stratification factor to reduce confounding by surgical variability.
- Pursue prospective studies that systematically capture patient‑reported outcomes and objective functional measures alongside volumetric resection data.
- Investigate biological correlates of invasive margins and why oligodendrogliomas demonstrate later separation of survival curves, which might inform tailored surveillance intervals and adjuvant strategies.
Conclusion
This large, international, retrospective study and its external validation support a reproducible, volumetric RANO classification for residual T2‑FLAIR tumour after surgery in IDH‑mutant grade 2 glioma. Supramaximal resection provides the greatest survival advantage and maximal resection with minimal remnant (0–5 cm3) confers substantially better outcomes than larger residual volumes. The data strengthen the evidence base for striving toward maximal safe resection when functionally feasible but underscore the need to balance oncologic gain with preservation of neurologic function. The RANO classification offers a pragmatic framework for reporting, prognostication and trial stratification; prospective efforts should integrate functional outcomes and standardised imaging protocols.
Funding and clinicaltrials.gov
The published study reports no funding. There is no clinicaltrials.gov registration number associated with this retrospective cohort analysis.
References
1. Karschnia P, Young JS, Wijnenga MMJ, et al. A prognostic classification system for extent of resection in IDH‑mutant grade 2 glioma: an international, multicentre, retrospective cohort study with external validation by the RANO resect group. Lancet Oncol. 2025 Dec;26(12):1638‑1650. doi:10.1016/S1470-2045(25)00534-0.
2. Jakola AS, Myrmel KS, Kloster R, et al. Comparison of a strategy favouring early surgical resection vs watchful waiting in low‑grade gliomas. JAMA. 2012;308(18):1881‑1888.
3. Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the long‑term outcome of low‑grade gliomas. J Clin Oncol. 2008;26(8):1338‑1345.
4. RANO resect working group consensus publications and contemporary reviews on surgical strategies for diffuse low‑grade gliomas (see Karschnia et al., Lancet Oncol. 2025 for consolidated discussion and references).
Thumbnail prompt (AI image generation)
Axial T2‑FLAIR brain MRI split into pre‑ and post‑operative panels showing a diffuse IDH‑mutant grade 2 glioma with a clear reduction in FLAIR abnormality after surgery; overlaid translucent colour‑coded residual volumes (green/yellow/red), with an inset silhouette of a neurosurgeon reviewing scans at a workstation. Clean clinical aesthetic, cool color palette, high medical realism.
