Background
Consensus guidelines paper by the Response Assessment in Neuro-Oncology (RANO) Working Group — an international multidisciplinary effort to develop updated, standardized response criteria for high-grade glioma trials. Prior Macdonald Criteria (1990) used two-dimensional contrast-enhancing measurements with recognized limitations in the era of temozolomide chemoradiotherapy and antiangiogenic agents.
Interventions and follow up
Type: Consensus response-criteria framework (not a treatment trial)
Problems addressed: Pseudoprogression (transient enhancement increase post-chemoRT, seen in 20–30%); antiangiogenic pseudoresponse (reduced contrast permeability without true tumor reduction); non-enhancing T2/FLAIR tumor not captured by enhancement-based criteria
Core changes: require ≥4 weeks on stable/decreasing steroids for response; progression defined as ≥25% increase in enhancing tumor OR new lesion OR clinical deterioration; new pseudoprogression category (enhancement increase within 12 weeks of chemoRT attributed to treatment effect unless histologically confirmed); incorporation of T2/FLAIR; standardized MRI (T1 pre/post Gd, T2/FLAIR)
Problems addressed: Pseudoprogression (transient enhancement increase post-chemoRT, seen in 20–30%); antiangiogenic pseudoresponse (reduced contrast permeability without true tumor reduction); non-enhancing T2/FLAIR tumor not captured by enhancement-based criteria
Core changes: require ≥4 weeks on stable/decreasing steroids for response; progression defined as ≥25% increase in enhancing tumor OR new lesion OR clinical deterioration; new pseudoprogression category (enhancement increase within 12 weeks of chemoRT attributed to treatment effect unless histologically confirmed); incorporation of T2/FLAIR; standardized MRI (T1 pre/post Gd, T2/FLAIR)
Results
Output: Updated standardized response criteria for high-grade glioma
Progression threshold: ≥25% increase in enhancing tumor (consensus-based)
Pseudoprogression window: within 12 weeks of chemoRT completion
Adoption: Standard response framework for neuro-oncology trials since 2010
Progression threshold: ≥25% increase in enhancing tumor (consensus-based)
Pseudoprogression window: within 12 weeks of chemoRT completion
Adoption: Standard response framework for neuro-oncology trials since 2010
Adverse events
Toxicity endpoints: None — methodological/criteria paper, no treatment delivered
Note: Not applicable to early-phase trials without imaging endpoints
Note: Not applicable to early-phase trials without imaging endpoints
Conclusions
RANO updated the Macdonald framework to account for pseudoprogression, antiangiogenic radiographic effects, and non-enhancing tumor, becoming the standard response assessment framework for neuro-oncology trials since 2010.
Key Limitations
Pseudoprogression vs true progression remains difficult to distinguish even with RANO — perfusion MRI, MR spectroscopy, and PET are not standardized within the criteria. The 25% threshold is consensus-based, not biostatistically validated. Non-enhancing (FLAIR) assessment remains subjective. Superseded by RANO 2.0 (2023).
Clinical Context
Required for interpreting endpoints in nearly all neuro-oncology RCTs from 2010 onward. Pseudoprogression is most common 4–12 weeks after chemoRT completion in MGMT-methylated GBM. Used in RTOG, EORTC, and cooperative-group trials worldwide.