What is the recommended treatment regimen for fractionated Stereotactic Radiosurgery (SRS) in patients with brain metastasis?

Fractionated Stereotactic Radiosurgery for Brain Metastases

For large brain metastases (>3 cm), fractionated SRS using 27 Gy in 3 fractions or 30 Gy in 5 fractions is recommended over single-fraction SRS to achieve superior local control while minimizing radiation necrosis risk. 1

Indications for Fractionated vs Single-Fraction SRS

When to Use Fractionated SRS

• Lesions >3 cm in diameter require fractionated delivery to reduce toxicity while maintaining tumor control 2
• Lesions near critical structures (brainstem, optic apparatus) benefit from fractionation to minimize radiation-induced injury 2
• Post-operative treatment to resection cavities, particularly when cavity volumes are large, should utilize fractionation 3

Optimal Fractionation Schemes

• 27 Gy in 3 fractions yields 1-year local control of 91% compared to 77% with single-fraction SRS for large lesions 1
• 30 Gy in 5 fractions is an alternative regimen that achieves similar control with reduced necrosis risk 1
• 24 Gy in 3-5 fractions is commonly used for lesions 10-82 mL in volume, achieving 63% local control at 12 months 4

Evidence Supporting Fractionation

Local Control Benefits

• Multifraction SRS achieves 92.9% 1-year local control for lesions 4-14 cm³ versus 77.6% with single-fraction (though not statistically significant, p=0.18) 5
• For post-operative cavities >14 cm³, multifraction SRS achieves 85.7% 1-year control versus 62.4% with single-fraction (p=0.13) 5
• Single-fraction doses of 24 Gy achieve 85% 1-year control, but lower doses (15-18 Gy) result in <50% control, demonstrating the dose-response relationship 1

Radiation Necrosis Reduction

• Multifraction SRS reduces radionecrosis to 8% versus 20% with single-fraction for large lesions (p=0.004) 1
• For lesions 4-14 cm³, radionecrosis occurs in 7.3% with multifraction versus 23.1% with single-fraction (p=0.003) 5
• No significant difference in radionecrosis rates for post-operative treatment (7.5% multifraction vs 7.3% single-fraction, p=0.85) 5

Treatment Algorithm by Lesion Size

Small Lesions (<3 cm)

• Single-fraction SRS is appropriate, achieving 85% local control at 1 year and 65% at 2 years 2
• Standard single-fraction doses based on tumor diameter: 24 Gy for <2 cm, 18 Gy for 2-3 cm 1

Large Lesions (>3 cm)

• Surgical resection should be considered first for symptomatic lesions with mass effect 2
• If surgery declined or not feasible, use fractionated SRS with 27 Gy/3 fractions or 30 Gy/5 fractions 1, 2
• Avoid single-fraction SRS for lesions >3 cm due to unacceptably high radionecrosis rates (20-23%) 1, 5

Post-Operative Resection Cavities

• SRS to the resection cavity reduces local recurrence and should be used routinely 1
• Fractionated delivery (typically 3000 cGy in 5 fractions) is well-tolerated with 87% local control at 1 year 3
• Cavity volume and number of fractions predict both local control and overall survival (p<0.001 for both) 3

Number of Metastases Considerations

1-4 Metastases

• SRS alone is recommended over whole brain radiotherapy when cumulative volume <7 mL 1
• WBRT should be reserved for salvage therapy to preserve neurocognitive function 1
• Fractionation scheme depends on individual lesion size, not total number of lesions 1

>4 Metastases

• SRS alone improves median overall survival when cumulative volume <7 mL 1
• Consider fractionated delivery for any individual large lesion within the multiple metastases 2

Critical Pitfalls to Avoid

Dose Selection Errors

• Do not use single-fraction doses <18 Gy for large lesions, as this results in <50% local control 1
• Do not attempt single-fraction SRS for lesions >3 cm due to prohibitive necrosis risk (20-23%) 1, 5

Patient Selection

• Patients with KPS <70 should not receive radiation therapy as median survival is <2 months with supportive care only 2
• Melanoma histology predicts higher local failure (32% vs 8-12% for other histologies at 1 year, p=0.02) and may require dose escalation 6

Follow-up and Salvage

• Routine MRI surveillance is mandatory to detect recurrence early for salvage therapy 1
• Distinguish radiation necrosis from progression using MR spectroscopy, perfusion imaging, or PET before salvage treatment 2
• Repeat SRS is reasonable if prior response was durable (>6 months) and imaging confirms active tumor 2

Toxicity Profile

• Grade ≥2 toxicity occurs in approximately 6% of patients with fractionated SRS, including seizures (2.4%) and symptomatic radionecrosis (2.4%) 3
• Radionecrosis risk at 2 years is 17% with fractionated SRS for large lesions 6
• No acute complications are typically observed with fractionated delivery 4