What is the optimal management approach for oligometastatic melanoma with one metastatic lesion in each lung, considering surgical resection versus immunotherapy with agents such as nivolumab (nivolumab) or pembrolizumab (pembrolizumab)?

Management of Oligometastatic Melanoma with Bilateral Lung Metastases

For oligometastatic melanoma with one lesion in each lung, initiate systemic immunotherapy first (pembrolizumab or nivolumab, or ipilimumab/nivolumab combination), followed by surgical metastasectomy only if complete response or excellent partial response is achieved, as this combined approach offers superior long-term survival compared to surgery alone. 1, 2, 3

Primary Treatment Strategy

First-Line Systemic Therapy Selection

BRAF Wild-Type Disease:

• Offer ipilimumab plus nivolumab followed by nivolumab maintenance as the preferred first-line option, achieving durable responses in 45-50% of patients with 10-year overall survival of 43% 1, 2
• Alternative single-agent options include nivolumab or pembrolizumab monotherapy if combination therapy is contraindicated 1

BRAF-Mutated Disease:

• Immunotherapy (ipilimumab/nivolumab, nivolumab, or pembrolizumab) remains the preferred first-line approach for patients with favorable prognostic features (good performance status, normal LDH, slow disease progression) to maximize chances of durable long-term control 1, 2
• BRAF/MEK inhibitor combinations (dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib) should be reserved for patients with poor prognostic features requiring rapid disease control 1, 2

Role of Surgical Metastasectomy

Timing and Patient Selection

• Perform surgical resection only after demonstrating response to systemic immunotherapy, not as initial treatment 1, 2, 3
• The goal must be complete (R0) resection of all disease sites 1, 2
• Ideal candidates are those with isolated, slowly developing metastases who achieve radiographic response to immunotherapy 1, 2
• Case series data demonstrate disease-free survival ranging from 13-67 months when metastasectomy is performed after good response to immunotherapy 3

Surgical Approach

• Both lung lesions must be technically resectable with clear margins achievable 1, 2
• Consider stereotactic radiation as an alternative to surgery for local control, though this should not be used to enhance immunotherapy response outside clinical trials 1
• Continue systemic therapy after metastasectomy as consolidation/adjuvant treatment 3

Treatment Duration and Monitoring

Immunotherapy Duration

• Continue pembrolizumab for up to 24 months or nivolumab beyond 2 years if ongoing response 1
• For patients achieving complete response (confirmed on subsequent imaging at least 4 weeks later) after ≥6 months of anti-PD-1 therapy, stopping treatment can be considered with 85-90% remaining disease-free 1
• For partial response or stable disease, treatment can be stopped after 2 years, though earlier cessation after ≥6 months may be considered if complete metabolic/pathologic response is documented 1

Surveillance After Treatment

• Perform clinical and imaging follow-up every 3-6 months for up to 3 years after stopping immunotherapy 1
• Increase intervals between follow-up visits after 3 years of remission 1
• Late recurrences can occur even after major pathologic response, but are often salvageable with additional therapy 4

Critical Decision-Making Algorithm

Step 1: Confirm BRAF mutation status (mandatory testing) 1

Step 2: Assess prognostic features:

• Performance status (ECOG 0-1 required for aggressive approach) 3
• LDH level 2
• Rate of disease progression 2

Step 3: Initiate systemic immunotherapy based on BRAF status as outlined above 1, 2

Step 4: Reassess after 2-3 cycles (approximately 6-9 weeks):

• If complete or excellent partial response → proceed to surgical evaluation for metastasectomy 1, 3
• If stable disease or minimal response → continue immunotherapy, reassess at 6 months 1
• If progression → switch to alternative systemic therapy (BRAF/MEK inhibitors if BRAF-mutated and not yet used, or alternative immunotherapy combinations) 1

Step 5: If surgery performed, resume systemic therapy postoperatively as consolidation 3

Common Pitfalls to Avoid

• Do not perform upfront surgery without systemic therapy first - this approach is inferior to the combined modality strategy and misses the opportunity to assess treatment responsiveness 2, 3
• Do not delay immunotherapy in BRAF-mutated patients with favorable features - these patients benefit most from immunotherapy's potential for durable long-term control 2
• Do not use single-agent BRAF inhibition - combination BRAF/MEK inhibition is mandatory if targeted therapy is chosen 2
• Do not attempt incomplete resection - only R0 resection provides benefit; incomplete surgery adds morbidity without survival advantage 1, 2
• Do not use radiation to enhance immunotherapy response - while safe to give concurrently for palliation or local control, adding radiation does not improve immunotherapy efficacy 1