What is the treatment for residual diffuse IDH (Isocitrate Dehydrogenase) mutant astrocytoma of the insula?

Treatment of Residual Diffuse IDH-Mutant Astrocytoma of the Insula

For residual diffuse IDH-mutant astrocytoma following incomplete resection, radiotherapy (50-54 Gy in 1.8-2 Gy fractions) followed by PCV chemotherapy (procarbazine, lomustine, vincristine) is the standard of care, based on RTOG 9802 trial data showing overall survival prolongation from 7.8 to 13.3 years. 1

Treatment Algorithm Based on Grade and Patient Factors

For WHO Grade 2 IDH-Mutant Astrocytoma with Residual Disease:

Primary recommendation: Radiotherapy (50-54 Gy in 1.8-2 Gy fractions) followed by adjuvant PCV chemotherapy 1

• This regimen is specifically indicated for patients with incomplete resection and/or age >40 years 1
• Temozolomide chemoradiotherapy is an acceptable alternative when PCV toxicity is a concern, though evidence is less robust 1
• For younger patients (<40-45 years) who are asymptomatic or have seizures only after gross total resection, observation alone may be considered, but this does NOT apply to residual disease 1

Key evidence: The RTOG 9802 trial demonstrated major survival benefit across all histological subgroups, including IDH-mutant astrocytomas, with benefit observed in patients aged 18-39 years with subtotal resection/biopsy OR patients ≥40 years regardless of resection extent 1

For WHO Grade 3 IDH-Mutant Astrocytoma with Residual Disease:

Primary recommendation: Radiotherapy (54-60 Gy in 1.8-2 Gy fractions) followed by adjuvant temozolomide 1

• This is based on the CATNON trial and represents Level II evidence 1
• PCV is also acceptable but temozolomide is preferred for grade 3 tumors 1

Critical Considerations for the Insula Location

Second surgery should always be considered first before proceeding to adjuvant therapy, even for insular tumors, though clinical benefit may be limited to cases where gross total resection can be achieved 1

• Maximal safe resection remains the best initial therapeutic approach, and re-resection should be evaluated before committing to radiotherapy 1
• The insular location does not change the fundamental treatment algorithm, but surgical feasibility must be carefully assessed given eloquent cortex involvement 1

Important Caveats and Pitfalls

Avoid premature radiotherapy in young patients with complete resection: Early radiotherapy prolongs progression-free survival but has NOT been shown to improve overall survival compared to radiotherapy at progression 1

Do not use watch-and-wait for residual disease: Observation strategies should only be considered in exceptional situations and specifically after gross total resection in younger patients, NOT with residual tumor 1

Recent contradictory evidence on adjuvant radiotherapy timing: A 2025 retrospective study of 450 patients showed markedly diminished overall survival with adjuvant radiotherapy compared to deferred radiotherapy (HR 2.90, p<0.001), even in high-risk subgroups 2. However, this conflicts with established guideline recommendations and requires prospective validation before changing practice 2

Temozolomide-induced hypermutation risk: Alkylating agents may induce hypermutator phenotype associated with malignant transformation, particularly concerning in IDH-mutant gliomas with longer life expectancy 3, 4

Treatment Sequence

1. Re-evaluate surgical options for additional resection of residual disease 1
2. If further resection not feasible: Initiate radiotherapy within 12 weeks of diagnosis 5
3. Radiotherapy dosing: 50-54 Gy for grade 2,54-60 Gy for grade 3, delivered in 1.8-2 Gy fractions 1
4. Adjuvant chemotherapy: PCV for grade 2 (or temozolomide if toxicity concern), temozolomide for grade 3 1

At Progression or Recurrence

Standard treatment: Temozolomide (or nitrosourea) is the standard chemotherapy at progression after initial surgery and radiotherapy 1

• Treatment choice depends on neurological status, patterns of progression, and first-line therapy received 1
• Second surgery should always be reconsidered at progression 1