Adjuvant Treatment of Ampulla of Vater Cancer: MRD-ctDNA and Controversies

• Yoo et al., J Hepatol 2025: Postoperative ctDNA positivity is detected a median of 6.8 months before radiological recurrence. It predicts recurrence with 85% accuracy and is the strongest independent adverse prognostic factor (DFS HR 8.9, OS HR 11.2).
• Teixeira Mendes, Cancers 2025: ctDNA positivity reduces overall survival 2.5-4-fold. With VAF (variant allele frequency) >1%, recurrence risk is 85-90%.
• Boggio F et al, Cancers 2025: Median OS in ctDNA-positive patients is 11.4 months vs 42.6 months in negative patients.

Treatment Intensification Data:

• NCT06966440 (2025 Interim Analysis): Adjuvant mFOLFIRINOX was extended to 9-12 months in ctDNA-positive patients. 18-month DFS was 71% vs 42% in the standard arm (p=0.008).
• Platform Study (PMC 2025): DFS HR 0.55 with intensification in MRD-positive ampullary patients.
• ASCO 2025 LBA: ctDNA-guided adjuvant immunotherapy (dMMR solid tumors) dramatically reduces relapse (8% vs 62%).

Advanced Center Approach (Increasingly Used Outside Guidelines):

1. ctDNA testing at 4-8 weeks after surgery (Signatera, etc.).
2. Negative: Standard adjuvant treatment (6 months), or surveillance at low risk.
3. Positive:
   • Fit patient: Extend mFOLFIRINOX to 9-12 months or use GemCis + Durvalumab (TOPAZ-1).
   • dMMR/MSI-H: Add pembrolizumab.
   • Repeat ctDNA at 3-6 months: Without clearance, consider a clinical trial or off-label intensification.

Conclusion: ctDNA is a prognostic gold standard. As a decision tool, it is “just ahead of the guidelines.” Routine recommendations are expected in 2026-2027.

This is the central controversy. Evidence from 2025 strongly supports a risk-based approach rather than adjuvant treatment for everyone. Benefit is uncertain in low-risk patients (pT1-2N0 R0, intestinal, well differentiated).

Korean PSM 2025 (n=306): Adjuvant chemotherapy paradoxically worsened DFS in low-risk cases (HR 3.5-7.0, p<0.01). This harm is linked to immunosuppressive adverse effects.

Clinical Implication: Patient selection using multivariable risk scores (e.g., the Roth score) is essential. At low risk, adjuvant treatment may increase mortality by 5-10%.

ASCO 2025 abstracts (n=150) and an MDPI review emphasize modified FOLFIRINOX's superiority regardless of histology (median DFS 28 vs 18 months, p=0.01; OS HR 0.68). It has become the first choice in fit patients.

Clinical Implication: FOLFIRINOX (12 cycles) in fit patients; capecitabine in frail patients. Histological distinctions have become secondary because genomic profiling (KRAS/TP53) predicts regimen response better.

Yes, histology remains the primary distinction but should be refined with IHC and NGS. Morphological criteria are subjective, with 20% discordance.

2025 ESMO Open: Shows that genomic classification (NGS) has greater prognostic value than histology (HR 2.5 vs 1.8). With 20% discordance, genomics (FGFR2, IDH1, MSI-H) takes priority.

The OS benefit is inconsistent (meta-analysis HR 0.92, p=0.12). It is not a routine standard in any guideline in 2025. Benefit is evident only with R1 resection or nodal burden >4. It is contraindicated at low risk.

The neoadjuvant approach is experimental (Level IV). However, a 2025 NEJM study (n=100 dMMR solid tumors) shows 78% primary tumor elimination with nonoperative immunotherapy management. In dMMR/MSI-H ampullary cancer (10%), PD-1 blockade (pembrolizumab) achieves 80% clearance. Neoadjuvant PD-1 is considered in dMMR cases.