Medical Management of Melanoma

Article:

Hyngstrom JR. Neoadjuvant Therapy: Changes in the Management of Macroscopic Stage III/Resectable Stage IV Melanoma. Surg Oncol Clin N Am. 2025 Jul;34(3):375-392. 

What is neoadjuvant therapy?

"Neoadjuvant" means treatment given before surgery. Traditionally, melanoma that has spread to lymph nodes (stage III) or nearby areas was treated with surgery first, then medication afterward (adjuvant therapy). But recent research shows that giving immunotherapy before surgery dramatically improves outcomes.

Why give treatment before surgery? 

When you have bulky, visible melanoma in lymph nodes or nearby skin, immunotherapy before surgery offers several benefits:

1. Better long-term control: Your immune system learns to fight melanoma while the tumor is still present, priming it to recognize and destroy remaining cancer cells after surgery

2. Shrinks tumors: Makes surgery easier and sometimes less extensive

3. Predicts outcome: How the tumor responds to treatment tells doctors how aggressive to be with further therapy

What the landmark studies show 

Two major trials have revolutionized stage III melanoma treatment:

SWOG 1801: Patients receiving just 3 doses of pembrolizumab (an immune checkpoint inhibitor) before surgery, followed by 15 doses after, had a 72% chance of being disease-free at 2 years, compared to only 49% for those who had surgery first then all 18 doses. Same total treatment, dramatically better results just by moving some doses before surgery.

NADINA: Patients getting 2 doses of nivolumab plus ipilimumab (combination immunotherapy) before surgery had an 84% chance of being event-free at 1 year versus 57% for those treated with surgery first. Even more impressive: 59% had such a good response that they needed no further treatment after surgery.

Understanding pathologic response 

After neoadjuvant treatment, pathologists examine the removed tumor under a microscope to measure how much cancer remains:[1]

- Complete response (pCR): No viable cancer cells left—associated with 96% disease-free survival at 2 years

- Major response: Less than 10% viable tumor—also excellent outcomes

- Partial or no response: More cancer remains—may need more aggressive treatment

This "report card" helps doctors personalize your next steps.

Treatment options 

Most neoadjuvant regimens use 6–8 weeks of treatment before surgery:[1]

- Pembrolizumab alone: Typically 2–3 doses; lower side effect risk (12% serious), 38% complete response rate

- Nivolumab + ipilimumab: 2 doses; higher response rate (47–57% complete response) but more side effects (30–47% serious)

- Nivolumab + relatlimab: 2 doses; excellent response (57% complete) with remarkably low serious side effects (0% in one study)

For patients with BRAF-mutated melanoma, targeted therapy (dabrafenib-trametinib) produces high initial response rates but worse long-term outcomes than immunotherapy, so it's generally not recommended as neoadjuvant treatment.

Surgery after neoadjuvant treatment 

Studies show neoadjuvant therapy doesn't make surgery significantly more difficult or increase complication rates compared to upfront surgery. In some cases, patients with excellent responses may avoid extensive lymph node removal, reducing side effects like lymphedema.

Take Home Message:

If you have resectable stage III or limited stage IV melanoma, neoadjuvant immunotherapy is now considered standard of care—not experimental. It significantly improves your chances of long-term survival compared to traditional surgery-first approaches, with the added benefit of knowing how well the treatment is working before you finish therapy.