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The Revolution of Neoadjuvant and Adjuvant Immunotherapy
Alexander Eggermont
We spent decades operating first and treating second. Professor Alexander Eggermont opened by turning that on its head. In melanoma, and now in a growing list of other cancers, the order is...
We spent decades operating first and treating second. Professor Alexander Eggermont opened by turning that on its head. In melanoma, and now in a growing list of other cancers, the order is immunotherapy first, and surgery only if it is still necessary. The reason is not comfort. It is cure.
Eggermont walked through why adjuvant therapy after a lymph node dissection delivers so little overall survival benefit, and why the neoadjuvant approach delivers so much. When you take out the positive lymph nodes first, you take away the school where T cells are trained. Leave the primary tumor and its nodal metastases in place, give two cycles of checkpoint blockade, and you build a larger and more diverse army of T cell clones than any adjuvant regimen can. He called it a triple benefit: more cures, shorter treatment, and less surgery. Then he showed the same pattern repeating across skin, breast, lung, gastric, rectal, bladder, and even relapsed glioblastoma.
Key points for clinicians:
Adjuvant therapy after lymph node dissection produces a marginal or absent overall survival benefit in stage 3 melanoma. Real-world data from the Netherlands and Sweden show no population-level survival gain, and a recent UK report found a benefit of only a few percentage points that barely reached significance.
The mechanism is the argument. Minimal residual disease after dissection has too few T cells to expand. Anti-CTLA-4 intensifies T cell priming in intact nodes and anti-PD-1 expands the response, so keeping the primary tumor and nodes in place produces bigger, more diverse, and newly created T cell clones.
In palpable-node melanoma, neoadjuvant anti-PD-1 plus anti-CTLA-4 produced a 60 percent pathologic complete response and a further 15 percent near-complete response. Those patients essentially stop relapsing, a curve never before seen in melanoma.
The SWOG trial showed that just three doses of pembrolizumab before surgery beat a year of standard adjuvant anti-PD-1, and it became standard of care. Adding two cycles of anti-CTLA-4 before planned dissection produced a gain of more than 20 percent in distant metastasis-free survival at 18 months and at two years.
The PRADO trial pushed the logic further. A magnet marks the index node, two cycles of low-dose ipilimumab and high-dose nivolumab follow, and 60 percent reach a pathologic complete or near-complete response in that node. Those patients get no lymph node dissection and no year of adjuvant therapy, and the five-year data show almost no relapse.
The paradigm is not confined to melanoma. Cutaneous squamous cell cancer may move to intralesional anti-PD-1 that spares 80 to 85 percent of facial surgery, head and neck cancer has an FDA-approved perioperative pembrolizumab regimen with a 22-month event-free survival benefit, MSI-high rectal tumors reach roughly 95 percent response and can avoid surgery entirely, neoadjuvant therapy spares half of bladder cancer patients a radical cystectomy, and a single preoperative dose of anti-PD-1 in relapsed glioblastoma at UCLA and UCSF filled the resected tumors with lymphocytes and improved survival.