Summary: Managing Hepatocellular Carcinoma Beyond Milan Criteria
Speaker: Prof. Francis Yao, MD, FAASLD | University of California, San Francisco (UCSF)
1. Main Clinical Topics Discussed
- Liver transplantation (LT) eligibility criteria for hepatocellular carcinoma (HCC) beyond Milan criteria
- Expansion of transplant criteria (UCSF criteria, "Up-to-Seven" criteria)
- Role of local regional therapy (LRT) as bridge and downstaging tool
- Tumor biology markers (AFP, treatment response) in candidate selection
- UCSF downstaging protocol and its adoption into national transplant policy
2. Key Learning Points, Guidelines, and Recommendations
Milan Criteria (Mazzaferro, 1996) — Foundation:
- Single lesion ≤5 cm, or 2–3 lesions none >3 cm
- Projected 5-year post-transplant survival: 65–75%
UCSF Criteria (Yao et al., 2001) — Expansion:
- Single lesion ≤6.5 cm, or 2–3 lesions none >4.5 cm, total tumor diameter (TTD) ≤8 cm
- Extended upper size limits by ~1.5 cm vs. Milan
- Projected 5-year survival: 60–70%
"Up-to-Seven" Criteria (Mazzaferro):
- Sum of largest nodule diameter (cm) + number of nodules ≤7
- Projected 5-year survival: ~60%
Metro Ticket Concept:
- The further tumor burden extends beyond Milan criteria, the higher the risk of post-transplant recurrence
- Supported by pathologic registry data from >1,000 patients
Shift Toward Tumor Biology:
- Modern selection moving beyond morphology (size/number) toward biological markers:
- Response to local regional therapy ("ablate and wait" principle)
- Serum AFP levels
- Both downstaging response and AFP are now formally integrated into U.S. national transplant policy
Current U.S. Priority Listing Eligibility:
- Tumors within Milan criteria (T2 lesions; excludes T1 <2 cm)
- Tumors successfully downstaged to within Milan criteria using the UCSF downstaging protocol
3. Specific Clinical Data and Study Results
UCSF Downstaging Protocol (latest publication):
- 118 patients enrolled; 64 underwent LT after successful downstaging
- Mandatory minimum 3-month observation period post-LRT before transplant
- Median follow-up: ~4 years
- 5-year post-transplant survival: ~80% (nearly identical to Milan group)
- 5-year recurrence-free survival: >90%
- Tumor recurrence rate: <10%
- Intention-to-treat survival (including waitlist mortality): 56%
- Successful downstaging probability: ~68% in prospective studies; <50% in higher tumor burden cohorts
- Average post-transplant tumor recurrence rate across studies: ~15–16%
Predictors of Treatment Failure (Mehta et al., multicenter study):
- Independent predictors on multivariable analysis:
- Child-Pugh B cirrhosis (vs. Child-Pugh A)
- AFP ≥1,000 ng/mL
- Patients with both risk factors had a 100% treatment failure rate → should be excluded from LT consideration
Trends in Local Regional Therapy (Kuang et al., national analysis):
- Over 90% of U.S. LT candidates currently receive LRT pre-transplant
- Since 2012: marked increase in Y-90 radioembolization, surpassing TACE as the most commonly used modality (Salem et al.)
Mazzaferro Phase 2B/3 RCT (Italian multicenter):
- Patients beyond Milan, no vascular invasion, Child A/B, projected 5-year survival ≥50%
- 45 responders (