Can conversion to resection be considered after neoadjuvant therapy with gemcitabine, cisplatin, and nab-paclitaxel for borderline resectable cholangiocarcinoma (CCA)?

Conversion to Resection After Neoadjuvant Gemcitabine, Cisplatin, and Nab-Paclitaxel for Borderline Resectable CCA

Neoadjuvant gemcitabine, cisplatin, and nab-paclitaxel (GAP) therapy should be considered for patients with borderline resectable cholangiocarcinoma (CCA) as it can facilitate conversion to resectability in approximately 46% of cases, potentially improving survival outcomes. While high-level evidence from randomized controlled trials is lacking, emerging data from phase II studies and real-world experience demonstrate the feasibility and safety of this approach.

Rationale for Neoadjuvant Therapy in Borderline Resectable CCA

• Current guidelines support neoadjuvant therapy for borderline resectable disease:
  • NCCN guidelines recommend neoadjuvant therapy over immediate surgery for borderline resectable pancreaticobiliary malignancies 1
  • The putative benefits include:
    • Increased likelihood of margin-free resection (conversion to resectable status)
    • Selection of patients with stable or responsive disease for surgery
    • Early treatment of micrometastases 1

Evidence Supporting Neoadjuvant GAP Therapy

• The NEO-GAP phase II trial demonstrated:

  • 73% of patients with high-risk intrahepatic CCA completed all chemotherapy and surgery
  • 23% partial response rate and 67% stable disease rate
  • Median overall survival of 24 months for the entire cohort and was not reached in resected patients 2

• Recent real-world experience with gemcitabine, cisplatin, and durvalumab showed:

  • 46.2% conversion rate to resection in borderline resectable CCA
  • Significantly longer overall survival in resected versus non-resected patients (median OS not reached versus 20.8 months) 3

• Similar regimens have shown promise:

  • Gemcitabine/S-1 neoadjuvant chemotherapy for borderline resectable perihilar CCA achieved:
    • 71% resection rate with 81% R0 resection
    • Median survival of 50.1 months for resected patients versus 14.8 months for unresected patients 4

Treatment Algorithm for Borderline Resectable CCA

1. Initial Assessment:

   • Confirm diagnosis with biopsy
   • Determine borderline resectability status through high-quality imaging
   • Evaluate patient's performance status and comorbidities

2. Neoadjuvant Treatment:

   • Preferred regimen: Gemcitabine, cisplatin, and nab-paclitaxel
     • Gemcitabine 800 mg/m², cisplatin 25 mg/m², nab-paclitaxel 100 mg/m² on days 1 and 8 of a 21-day cycle
     • Target: 4 cycles before reassessment 2

3. Response Assessment:

   • Repeat imaging after completion of neoadjuvant therapy
   • Multidisciplinary team evaluation for resectability

4. Surgical Approach:

   • If converted to resectable: Proceed with curative-intent resection
   • If still borderline or unresectable: Consider additional chemotherapy or alternative approaches

Potential Pitfalls and Considerations

• Toxicity Management:

  • Monitor for neutropenia (occurs in >50% of patients) and diarrhea
  • Approximately 50% of patients require dose reductions 2

• Surgical Considerations:

  • Extended resections may be necessary, including extrahepatic bile duct resection and vascular reconstruction
  • Postoperative morbidity (≥grade III) can be significant (up to 50%) 3

• Patient Selection:

  • Best results are seen in patients with good performance status
  • Treatment should preferably be administered at or coordinated through high-volume centers 1

• Adjuvant Therapy:

  • Consider additional chemotherapy after surgery based on response to neoadjuvant therapy and pathologic findings 1
  • Adjuvant capecitabine for 6 months is standard for resected CCA 1

While the evidence for neoadjuvant therapy in borderline resectable CCA is still evolving, the available data suggest that gemcitabine, cisplatin, and nab-paclitaxel can effectively downstage tumors and enable successful conversion to resection in a significant proportion of patients, potentially improving survival outcomes in this challenging disease.