RANO 2.0 response criteria for adult gliomas

{
  "categories": [
    {
      "outcome_code": "CR",
      "label": "complete_response",
      "applicability": "enhancing_nonenhancing_or_mixed_adult_glioma_with_measurable_disease_at_baseline"
    },
    {
      "outcome_code": "PR",
      "label": "partial_response",
      "applicability": "enhancing_nonenhancing_or_mixed_adult_glioma_with_measurable_disease_at_baseline"
    },
    {
      "outcome_code": "MR",
      "label": "minor_response",
      "applicability": "nonenhancing_component_only_with_enhancing_component_at_least_stable"
    },
    {
      "outcome_code": "SD",
      "label": "stable_disease",
      "applicability": "assessable_disease_not_meeting_CR_PR_MR_or_PD"
    },
    {
      "outcome_code": "PD",
      "label": "progressive_disease",
      "applicability": "any_qualifying_radiologic_or_clinical_progression_trigger"
    }
  ],
  "applicability": {
    "use_for": "RANO 2.0 response assessment in clinical trials of adult high- and low-grade gliomas across enhancing, nonenhancing and mixed phenotypes.",
    "classification_unit": "one_patient_at_one_MRI_timepoint_with_declared_baseline_nadir_phenotype_measurement_method_steroid_dose_and_clinical_state",
    "required_inputs": [
      "adult_glioma_diagnosis_and_IDH_context",
      "newly_diagnosed_or_recurrent_setting",
      "radiotherapy_completion_date",
      "treatment_and_start_date",
      "baseline_MRI",
      "current_and_nadir_MRI_measurements",
      "enhancing_nonenhancing_or_mixed_phenotype",
      "corticosteroid_dose_and_change",
      "neurologic_or_performance_status",
      "new_lesion_and_leptomeningeal_status"
    ],
    "outside_scope": [
      "pediatric_glioma_without_protocol_validation",
      "brain_metastasis_RANO_BM",
      "immunotherapy_iRANO_confirmation_without_naming_it",
      "pathologic_response",
      "treatment_selection_from_response_code_alone"
    ]
  },
  "version_boundary": {
    "current_rule": "This record implements RANO 2.0 from 2023. It updates and unifies RANO-HGG 2010 and RANO-LGG 2011 for adult glioma trials.",
    "legacy_RANO_HGG_2010": "The 2010 system used the immediate postoperative scan and qualitative T2/FLAIR progression more broadly. If a protocol still mandates RANO-HGG 2010, identify it and do not silently substitute the 2.0 result.",
    "modified_and_immune_variants": "mRANO and iRANO have different confirmation constructs. Preserve the trial-specified variant instead of combining rules from multiple frameworks."
  },
  "baseline_MRI_rules": {
    "newly_diagnosed_with_radiotherapy": "Use the first post-radiotherapy MRI obtained around 4 weeks, operationalized as 21 to 35 days after radiotherapy, as the response baseline when the patient is clinically stable.",
    "newly_diagnosed_without_radiotherapy": "Use the postsurgical pretreatment MRI as baseline.",
    "recurrent_glioma": "Use a pretreatment MRI obtained as close as possible to treatment start and ideally no more than 14 days before it.",
    "postoperative_scan_role": "The immediate postoperative MRI remains important for complications and extent of resection but is not the RANO 2.0 response baseline after radiotherapy.",
    "no_measurable_baseline_rule": "A patient without measurable disease at baseline cannot achieve radiologic CR, PR or MR; the best radiologic result before new growth is SD."
  },
  "MRI_and_measurability_gate": {
    "protocol": "Use a standardized brain-tumor MRI protocol with consistent contrast dose, timing, sequences, field strength, slice geometry and plane across timepoints.",
    "two_dimensional_measurable": "A clearly marginated enhancing or nonenhancing lesion with both perpendicular diameters at least 10 mm on one slice, visible on at least two slices preferably no more than 4 mm apart with no interslice gap.",
    "thicker_slice_rule": "When thicker slices are unavoidable, both perpendicular minimum dimensions equal two times the sum of slice thickness and interslice gap; record the derived threshold.",
    "volumetric_measurable": "If a protocol prespecifies volumetry, measurable disease is at least 1 cm in each of three orthogonal dimensions.",
    "cavity_rule": "Do not measure a cyst or surgical cavity. Tumor around it is generally nonmeasurable unless a nodular component is at least 10 by 10 mm.",
    "nonmeasurable": [
      "one_dimension_only",
      "unclear_margins",
      "both_perpendicular_diameters_below_10_mm",
      "cavity_rim_without_10_by_10_mm_nodule"
    ],
    "failure_rule": "If coverage, contrast, motion, sequence comparability or margins prevent reproducible measurement, return not evaluable or a supported qualitative state rather than inventing exact tumor burden."
  },
  "target_and_measurement_model": {
    "primary_2D_metric": "Sum of products of perpendicular diameters in the plane with the largest lesion extent; use the same declared method longitudinally.",
    "optional_3D_metric": "Prespecified total tumor volume is allowed, with 65-percent reduction for PR and 40-percent increase for PD corresponding to the 2D thresholds.",
    "target_count_single_phenotype": "Select at least two and no more than three measurable lesions when multiple lesions exist for an enhancing-only or nonenhancing-only assessment.",
    "target_count_mixed": "Select no more than two measurable enhancing and two measurable nonenhancing lesions when both components are assessed.",
    "selection_rule": "Prefer the largest enlarging and most reproducibly measured lesions; increasing lesions take priority in multifocal disease even when not the largest.",
    "nontarget_rule": "Record remaining lesions. A nonmeasurable lesion must grow by at least 5 by 5 mm to become at least 10 by 10 mm before its measurable progression contribution is added to total burden.",
    "reference_rule": "Use baseline for response and the smallest valid measurement at baseline or after therapy for PD. Preserve the dates and exact sums or volumes."
  },
  "phenotype_branch": {
    "enhancing": "Measure contrast-enhancing disease for IDH-wild-type glioblastoma. Routine nonenhancing progression is excluded from most such trials unless antiangiogenic or permeability-altering therapy makes it relevant.",
    "nonenhancing": "Measure T2/FLAIR tumor for IDH-mutated nonenhancing glioma and uncommon nonenhancing glioblastoma, excluding edema, radiation change and other non-tumor signal.",
    "mixed": "A protocol can assess enhancing and nonenhancing components in parallel. CR requires both to disappear; a response in one component requires the other to be at least stable; progression in either supported component makes the overall result PD.",
    "antiangiogenic_guard": "Reduced enhancement can be pseudoresponse. Evaluate nonenhancing disease when the agent materially changes vascular permeability and the protocol requires it."
  },
  "response_rules": {
    "CR": {
      "burden": "Complete disappearance of all applicable measurable, nonmeasurable and nontarget enhancing and or nonenhancing tumor; no new lesion; any prior enhancement required by the nonenhancing branch has resolved.",
      "duration": "Sustained for at least 4 weeks; without confirmation it is preliminary CR and the best confirmed response remains SD.",
      "steroids": "Off corticosteroids or receiving physiologic replacement only.",
      "clinical": "Stable or improved.",
      "output_code": "CR"
    },
    "PR": {
      "burden": "At least 50 percent decrease in 2D sum of products or at least 65 percent decrease in prespecified volume versus baseline, with no new lesion and no progression of nonmeasurable or nontarget disease.",
      "duration": "Sustained for at least 4 weeks; without confirmation it is preliminary PR and the best confirmed response remains SD.",
      "steroids": "Dose no greater than at baseline.",
      "clinical": "Stable or improved.",
      "mixed_rule": "If response is driven by enhancing disease, nonenhancing disease must be at least stable and vice versa.",
      "output_code": "PR"
    },
    "MR": {
      "burden": "For nonenhancing disease only, a decrease from 25 percent through less than 50 percent in 2D sum of products, or from 40 percent through less than 65 percent in volume, versus baseline.",
      "duration": "Sustained for at least 4 weeks; without confirmation it remains preliminary and confirmed best response is SD.",
      "additional_requirements": [
        "no_new_lesion_or_new_enhancement",
        "no_progression_of_nonmeasurable_or_nontarget_disease",
        "steroid_dose_not_above_baseline",
        "clinical_status_stable_or_improved",
        "enhancing_component_at_least_stable_if_present"
      ],
      "output_code": "MR"
    },
    "SD": {
      "burden": "Does not meet CR, PR, MR or PD and has stable applicable target burden, no new lesion and no supported progression of nonmeasurable or nontarget disease.",
      "steroids": "Dose not greater than baseline; if increased for symptoms without imaging progression, continue close assessment and do not call PD from dose alone.",
      "clinical": "Stable or improved.",
      "output_code": "SD"
    }
  },
  "PD_any_trigger_algorithm": [
    {
      "trigger": "target_burden",
      "rule": "At least 25 percent increase in 2D sum of products or at least 40 percent increase in volume versus the smallest valid baseline or on-treatment burden, on stable or increasing steroid dose and not attributable to radiation effect, edema or comorbidity.",
      "output_code": "PD"
    },
    {
      "trigger": "new_measurable_lesion",
      "rule": "A credible new enhancing or applicable nonenhancing lesion at least 10 by 10 mm is PD unless a confirmation pathway is required.",
      "output_code": "PD"
    },
    {
      "trigger": "definite_leptomeningeal_disease",
      "rule": "New definite leptomeningeal tumor is PD.",
      "output_code": "PD"
    },
    {
      "trigger": "nonmeasurable_progression",
      "rule": "A prior nonmeasurable lesion grows by at least 5 by 5 mm and becomes at least 10 by 10 mm, then is added to total target burden; overall total must meet the 25-percent area or 40-percent volume progression threshold.",
      "output_code": "PD"
    },
    {
      "trigger": "nontarget_progression",
      "rule": "Unequivocal nontarget growth is added to total burden and establishes PD only when the combined burden reaches the applicable progression threshold; isolated minor change does not override SD or PR.",
      "output_code": "PD"
    },
    {
      "trigger": "clinical_deterioration",
      "rule": "Definite neurologic deterioration attributable to tumor and not to steroid reduction, treatment toxicity, seizure, infection, vascular event or another cause can establish PD.",
      "output_code": "PD"
    },
    {
      "trigger": "disease_related_failure_to_return",
      "rule": "Death or deterioration that prevents evaluation is PD unless a documented non-tumor cause explains it.",
      "output_code": "PD"
    }
  ],
  "progression_confirmation_state_machine": {
    "mandatory_window": "For clinically stable patients with suspected enhancing progression within 12 weeks after completing radiochemotherapy, require repeat MRI after at least 4 weeks, commonly 4 to 8 weeks, or histopathologic evidence of unequivocal recurrent tumor.",
    "preliminary_state": "The first qualifying scan is preliminary PD, not confirmed PD, while therapy and close observation continue under the protocol.",
    "confirmation_rule": "Confirmed PD requires further increase of at least 25 percent in area or 40 percent in volume relative to the preliminary scan or another protocol-valid confirmation; backdate PD to the preliminary scan.",
    "nonconfirmation_rule": "If the confirmation scan is SD, MR, PR or CR, label the initial change pseudoprogression and continue using the smallest valid preliminary or later burden as the future comparison baseline according to protocol.",
    "small_new_lesion_rule": "A new lesion below 10 by 10 mm in a confirmation-required setting is added to the total burden and observed; it is not immediately converted into confirmed PD.",
    "outside_window": "Confirmation is generally optional after the early post-radiotherapy window and for recurrent tumors, but remains appropriate for equivocal imaging or therapies with a high pseudoprogression rate.",
    "nonenhancing_rule": "Confirmation is usually unnecessary for nonenhancing progression because pseudoprogression predominantly affects enhancement."
  },
  "steroid_and_clinical_rules": {
    "steroid_increase_alone": "An increased corticosteroid dose without tumor-related clinical deterioration or qualifying imaging progression is not PD.",
    "steroid_decrease_guard": "Apparent radiologic worsening on a reduced steroid dose can be downgraded to SD when permeability change plausibly explains it; record the dose and rationale.",
    "deterioration_examples": [
      "KPS_100_or_90_to_70_or_lower_for_at_least_7_days",
      "KPS_drop_at_least_20_points_from_80_or_lower",
      "KPS_to_50_or_lower",
      "ECOG_or_WHO_0_or_1_to_2_or_2_to_3"
    ],
    "attribution_rule": "Clinical decline must be attributed by the treating team; an imaging agent must preserve alternative causes and must not infer tumor progression from symptoms alone when attribution is unresolved."
  },
  "management_and_risk_context": {
    "management_rule": "RANO 2.0 is a trial response framework and does not independently order treatment continuation, discontinuation, biopsy, reoperation or a new regimen. Decisions require neuro-oncology review and the governing protocol.",
    "early_progression_rule": "Prematurely calling confirmed PD during the post-radiotherapy pseudoprogression window can stop effective therapy; missing true PD can prolong ineffective therapy. Preserve confirmation status explicitly.",
    "risk_rule": "CR, PR, MR, SD and PD are response states, not individualized survival estimates. Molecular subtype, grade, therapy, performance status and subsequent course remain necessary for prognosis."
  },
  "output_contract": [
    "RANO_2_0_or_named_legacy_variant",
    "adult_glioma_molecular_and_treatment_context",
    "newly_diagnosed_or_recurrent_setting_and_radiotherapy_dates",
    "baseline_nadir_and_current_MRI_dates",
    "enhancing_nonenhancing_or_mixed_branch",
    "2D_products_or_prespecified_3D_volumes_with_target_lesion_identifiers",
    "relative_change_against_baseline_and_nadir",
    "new_nonmeasurable_nontarget_and_leptomeningeal_disease",
    "corticosteroid_dose_and_clinical_status_at_each_timepoint",
    "CR_PR_MR_SD_PD_or_not_evaluable",
    "preliminary_confirmed_or_pseudoprogression_status_when_relevant",
    "no_autonomous_treatment_or_prognostic_claim"
  ],
  "missing_input_behavior": [
    "If the response baseline or radiotherapy timing is unknown, do not substitute the immediate postoperative scan without naming a legacy protocol.",
    "If tumor phenotype or IDH context is unknown, report which enhancing and nonenhancing branches remain unresolved.",
    "If steroid dose or clinical status is missing, return the imaging-only threshold state and withhold a fully qualified RANO response.",
    "If a lesion is below measurability or its margins are not reproducible, preserve it as nonmeasurable and do not inflate it to 10 by 10 mm.",
    "If progression occurs in a confirmation-required window, output preliminary PD and the required next evidence rather than confirmed PD.",
    "If edema, radiation change, seizure or treatment effect cannot be separated from tumor on T2/FLAIR, preserve uncertainty and request expert adjudication or protocol-supported follow-up."
  ],
  "interpretation_limits": [
    "RANO 2.0 was designed for adult glioma clinical trials; clinical-practice use should preserve its protocol assumptions and confirmation logic.",
    "Bidimensional and volumetric methods are alternatives that must be prespecified; their measurements and thresholds must not be mixed within a longitudinal series.",
    "Conventional MRI cannot always separate viable tumor from pseudoprogression, radiation necrosis, postoperative change or treatment-related permeability effects."
  ],
  "supporting_sources": [
    {
      "role": "legacy_RANO_HGG",
      "citation": "Wen et al. J Clin Oncol. 2010;28:1963-1972",
      "doi": "10.1200/JCO.2009.26.3541"
    },
    {
      "role": "current_RANO_2_0",
      "citation": "Wen et al. J Clin Oncol. 2023;41:5187-5199",
      "doi": "10.1200/JCO.23.01059",
      "pmid": "37774317",
      "pmcid": "PMC10860967"
    }
  ],
  "source_locator": "Wen et al. RANO 2.0, PMC10860967: Definitions, Measurable and Nonmeasurable Disease, Target Lesions, Baseline MRI, Criteria for Recurrent/Progressive Disease, Definition of Radiologic Response and Progression, Tables 1-4, Neuroimaging for Confirmation, Nonenhancing Progression and Assessment of Clinical Deterioration; legacy boundary from Wen et al. 2010, DOI 10.1200/JCO.2009.26.3541."
}