What are the pros and cons of starting Stereotactic Radiosurgery (SRS) before, during, or after IPINIVO (ipilimumab + nivolumab) treatment in a patient with stage 4 metastatic melanoma, brain metastases, and pelvic lymph involvement, who is currently on dexamethasone (corticosteroid) therapy?

Timing of SRS with Ipilimumab/Nivolumab in Metastatic Melanoma Brain Metastases

For patients on dexamethasone requiring brain metastasis treatment, you must first taper steroids to ≤2 mg daily before starting ipilimumab/nivolumab, then initiate concurrent SRS with immunotherapy to optimize both intracranial control and survival. 1

Critical Steroid Management: The Primary Determinant

Your current dexamethasone use fundamentally alters treatment sequencing and outcomes:

• Patients requiring >4 mg dexamethasone daily experience dramatically reduced intracranial response rates of only 16.7%, median intracranial PFS of 1.2 months, and median OS of 8.7 months 2
• If continuous steroid dependency (>10 mg prednisolone equivalent) exists at treatment initiation, targeted therapy is preferred over immunotherapy 1
• CheckMate 204 allowed up to 4 mg dexamethasone provided the dose was stable for 10 days before starting immunotherapy, but asymptomatic patients required complete steroid cessation 10 days prior 1
• The response rate in CheckMate 204 was only 22% in symptomatic/steroid-dependent patients compared to 59% in the COMBI-MB targeted therapy trial 1

Algorithmic Approach to Steroid Management:

1. If currently on >4 mg dexamethasone: Prioritize immediate SRS for symptomatic lesions while tapering steroids, then initiate ipilimumab/nivolumab once ≤2 mg daily is achieved 1, 2
2. If on ≤4 mg dexamethasone and stable: Taper to ≤2 mg over 10 days, then start concurrent SRS + immunotherapy 1
3. If steroid-free or on ≤2 mg: Proceed directly to concurrent SRS + ipilimumab/nivolumab 2

Optimal Timing: Concurrent SRS with Immunotherapy

SRS with concurrent immunotherapy appears safe and provides superior outcomes compared to sequential approaches 1:

Evidence Supporting Concurrent Treatment:

• Concurrent SRS and nivolumab achieved 69% intracranial PFS at 6 months and 42% at 12 months, significantly better than SRS with ipilimumab (48% and 17%, respectively; p=0.02) 3
• Concurrent pembrolizumab with SRS resulted in 70% complete or partial response at first follow-up (median 57 days), compared to 32% with ipilimumab and 22% without immunotherapy 4
• A Korean randomized study showed equivalent median OS between upfront SRS (14.6 months) versus upfront chemotherapy (15.3 months; p=0.418), but SRS demonstrated trends toward longer CNS PFS and lower symptomatic brain progression 1
• Systemic therapy can be given concurrently with SRS with minimal myelosuppression, though grade 3-4 neurotoxicity occurred in 4% of patients, with higher rates when using immunotherapy 1

Biological Rationale for Concurrent Treatment:

The combination offers potential synergy through radiation-induced immune stimulation, increased antigen presentation, and enhanced immune cell infiltration 2

Pros and Cons by Timing Strategy

SRS BEFORE Ipilimumab/Nivolumab:

Pros:

• Immediate local control of threatening brain metastases while awaiting steroid taper 1
• Allows symptomatic relief before systemic therapy initiation 1
• May prime immune system for subsequent immunotherapy response 2

Cons:

• Delays systemic treatment of extracranial disease 1
• Misses potential synergistic effects of concurrent treatment 3, 4
• No survival advantage demonstrated over concurrent approach 1

SRS DURING (Concurrent with) Ipilimumab/Nivolumab:

Pros:

• Superior intracranial control: 69% PFS at 6 months with nivolumab versus 48% with sequential approaches 3
• Exploits radiation-immune synergy for enhanced tumor control 2
• 7-year overall survival of 48% with ipilimumab/nivolumab in asymptomatic patients 5
• Treats both intracranial and extracranial disease simultaneously 1
• Intracranial response rate of 54% achievable if steroid-free or on ≤2 mg dexamethasone 2

Cons:

• Increased radiation necrosis risk: 15% overall, with most events in immunotherapy patients 3, 6
• Severe, surgically refractory radiation necrosis reported with concurrent ipilimumab/nivolumab and 30 Gy in 5 fractions 7
• 55% incidence of grade 3-4 immune-related adverse events (pneumonitis, hepatitis, colitis, nephritis, endocrinopathies) 2

SRS AFTER Ipilimumab/Nivolumab:

Pros:

• Allows assessment of immunotherapy response before radiation 1
• May avoid radiation in patients with excellent systemic response 1

Cons:

• Risks symptomatic brain progression during immunotherapy induction (typically 3-4 months) 1
• Unacceptable for symptomatic or steroid-dependent patients 1
• Delays definitive local control 1

Radiation Necrosis: The Critical Toxicity Concern

Radiation necrosis represents the most significant toxicity of concurrent treatment and requires specific mitigation strategies:

• Overall incidence: 15% with concurrent immunotherapy 3
• Single-fraction SRS carries 20% necrosis risk for lesions >3 cm versus 8% with fractionated approaches 8
• Multi-fraction SRS (3 × 9 Gy) showed significantly better intracranial PFS than single-fraction (70% versus 46% at 6 months; p=0.01), especially with nivolumab 3
• Severe, surgically refractory radiation necrosis has been reported with concurrent ipilimumab/nivolumab and 30 Gy in 5 fractions, requiring bevacizumab, steroids, or immunotherapy discontinuation 7

Radiation Necrosis Mitigation Algorithm:

1. For lesions <3 cm: Use standard single-fraction SRS (acceptable 5-10% necrosis risk) 8
2. For lesions >3 cm: Use fractionated SRS (27 Gy in 3 fractions or 30 Gy in 5 fractions) to reduce necrosis to 8% 8, 3
3. Monitor closely with MRI every 2-3 months for first year 8
4. Distinguish necrosis from progression using MR spectroscopy, perfusion, or PET 8

Recommended Treatment Algorithm for Your Patient

Given stage 4 melanoma with brain metastases, pelvic lymph involvement, and current dexamethasone use:

Step 1: Steroid Optimization (Days 1-10)

• Taper dexamethasone to ≤2 mg daily over 10 days 1, 2
• If unable to taper below 4 mg due to symptoms, proceed to Step 2 with understanding of reduced immunotherapy efficacy 1

Step 2: Concurrent SRS + Ipilimumab/Nivolumab Initiation (Day 10-14)

• Initiate ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 3 mg/kg every 2 weeks 5
• Perform SRS within 1 week of first immunotherapy dose 3, 4
• Use fractionated SRS (3 × 9 Gy or 27 Gy in 3 fractions) for any lesions >3 cm 8, 3
• Use single-fraction SRS for lesions <3 cm 8

Step 3: Monitoring and Salvage (Ongoing)

• MRI brain every 2-3 months for first year 8
• Monitor for immune-related adverse events (55% grade 3-4 incidence) 2
• Salvage options: repeat SRS for new lesions, bevacizumab for radiation necrosis, surgery for large symptomatic lesions 8, 7

Critical Pitfalls to Avoid

• Never start ipilimumab/nivolumab while on >4 mg dexamethasone—response rates drop to 16.7% 2
• Never use single-fraction SRS for lesions >3 cm with concurrent immunotherapy—necrosis risk reaches 20% 8, 7
• Never delay SRS in symptomatic patients to "see if immunotherapy works"—this risks neurologic deterioration 1
• Never assume radiation necrosis is tumor progression without advanced imaging confirmation 8
• Never ignore the 55% grade 3-4 immune toxicity rate—proactive management is essential 2