Maria Russell, MD

LIVER TRANSPLANT offers the highest rates of long-term survival for patients with hepatocellular carcinoma, according to Maria Russell, MD, Assistant Professor of Surgery at Emory University, Atlanta. At the 2017 Debates and Didactics in Hematology and Oncology Conference at Sea Island, Georgia, Dr. Russell described the latest trends in liver transplantation. 

The other potentially curative option is surgical resection, and choosing between the two modalities is not always simple. “Patients don’t always fall into nice slots,” she admitted. If both modalities are available to the patient with hepatocellular carcinoma, selection takes into account the degree of cirrhosis, the size and number of lesions, the presence of portal hypertension and comorbidities, and insurance/citizenship status.  

“Liver transplant offers the best 5-year survival, with studies demonstrating 70% to 80% survival rates,” Dr. Russell said. 

Determining Eligibility for Transplant 

TRANSPLANT OUTCOMES among patients with cirrhosis and early-stage hepatocellular carcinoma were evaluated in a landmark 1996 study, in which 48 unresectable patients were stratified by preexisting criteria.¹ These factors, which became known as the Milan criteria, were the presence of a tumor ≤ 5 cm in patients with a single lesion and no more than 3 lesions, each lesion ≤ 3 cm in diameter, in patients with multiple tumors. The investigators determined overall and recurrence-free survival at 4 years for patients who met and did not meet these criteria. Overall survival was 85%, and recurrence-free survival was 92% for patients who met the criteria, dropping to 50% and 59%, respectively, for those who did not. 

Liver transplant [for hepatocellular carcinoma] offers the best 5-year survival, with studies demonstrating 70% to 80% survival rates.

— Maria Russell, MD

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The study concluded that liver transplantation is an effective treatment for small, unresectable hepatocellular carcinoma in patients with cirrhosis, especially those meeting the Milan criteria. Thus, the Milan criteria became the standard for determining eligibility for transplant. 

Proposed Changes to Eligibility Criteria 

SINCE THE MILAN CRITERIA are seen by some specialists as too restrictive, moderate expansion of the criteria has also proposed, which would increase the proportion of patients eligible for transplant. Such approaches have been found to result in good outcomes but with an increased risk of tumor recurrence, as shown in a recent review by Sapisochin and Bruix.² For example, the authors of the Milan criteria have proposed an “Up-to-7” protocol, which allows for transplant when seven is the sum of the size of the largest lesion and the number of tumors. In a review of this approach, the disease-free survival rate was 64% at 4 years, and overall survival was 75%.³ Under the standard Milan criteria, 4-year disease-free survival in the study was 92%, and after transplantation, it was 85%. 

“You’ll notice that posttransplant survival goes down, suggesting we can take patients with worse disease, but we won’t necessarily achieve the same benefit we get under the Milan criteria,” Dr. Russell said. 

The MELD (Model for End-stage Liver Disease) score is used to determine which patients receive organs. In an attempt to allocate livers to patients who will most benefit from them, the following changes have been proposed⁴: 

• Candidates with small lesions (2–3 cm) and alpha-fetoprotein (AFP) < 20 ng/mL should undergo local-regional therapy prior to applying for a standardized MELD exception, which has traditionally been extended to patients with hepatocellular carcinoma. 
• Since AFP > 1,000 ng/mL portends for a worse prognosis, these patients are not candidates for the MELD exception criteria. 
• Candidates are eligible for inclusion in a downstaging protocol if they have one lesion > 5 cm and ≤ 8 cm; 2 to 3 lesions each < 5 cm, with a total diameter of all lesions ≤ 8 cm; or 4 to 5 lesions each < 3 cm, with a total diameter of all lesions ≤ 8 cm. 

Issues With Downstaging 

DOWNSTAGING (often via radiofrequency ablation or transarterial chemoembolization) can render patients eligible for transplant. Outcomes were reported from a 2008 study in which 43 patients met criteria for downstaging; 33 received a deceased donor liver transplant, and 2 received a living donor transplant.⁵ At 25 months, 33 patients were alive without recurrence, and 2 had died of unrelated causes. The main predictor of treatment failure was AFP ≥ 1,000 ng/mL, which conveyed a sevenfold risk (P < .0001). 

Whether downstaged patients have survival as good as those meeting the Milan criteria at baseline is not clear, based on a systematic review revealing mixed results.⁶ This study, however, led to the current University of California San Francisco protocol, which includes the following criteria for transplant after downstaging: 

• Single tumors > 5 and ≤ 8 cm 
• Multiple (2–3) tumors, each ≤ 5 cm, with the sum of diameters ≤ 8 cm 
• No vascular invasion observed on computed tomography 
• AFP reduced to < 500 ng/mL if initially > 1,000 ng/mL, and subsequent levels remaining this low 

Proposals for Increasing Donor Volume 

“THE PROBLEM WITH TRANSPLANTATION is organ allocation. There are not enough livers to go around,” stated Dr. Russell. Novel surgical techniques can increase the availability of livers for transplantation—including whole-liver grafts from deceased cardiac donors, living-donor liver transplantation, and split livers— but the effect of these techniques on patients with hepatocellular carcinoma is still not clear. 

“There are pros and cons with each,” he said. “Living-donor transplant offers an unlimited source of grafts, but obviously, it’s a big deal for the donor. That surgery has to be flawless,” Dr. Russell noted. 

Although waiting times are shortened by using livers obtained after cardiac death and by splitting livers, risk for biliary complications is increased in both cases, and there is concern about more graft loss with the former and tumor recurrence due to regeneration with the latter. 

Surgical Resection 

CANDIDATES FOR RESECTION generally include patients without cirrhosis or with well-compensated cirrhosis (Child-Pugh A disease), without portal hypertension, and with a MELD score < 10. Since the liver is not totally removed, recurrence rates are higher, but it is not clear whether survival is affected. A study from Dr. Russell’s group at Emory, comparing resection with transplant in patients meeting Milan criteria, found that transplant yielded higher 5-year survival (65.7% vs 43.8%; P = .005) and recurrence-free survival (85.3% vs. 22.7%; P < .001).⁷ 

Outcomes after resection were favorable, however, when patients meeting Milan criteria had a MELD score < 8 or Child-Pugh class A disease. “Maybe we should focus our resection on those subsets,” Dr. Russell suggested. 

Other surgical advances include the use of portal vein embolization before liver resection, which improves technical and clinical success; the use of laparoscopic resection, extending it beyond benign conditions; and robotic resection, although the benefits to this new surgical technique have yet to be proven. ■ 

DISCLOSURE: Dr. Russell reported no conflicts of interest. 

REFERENCES 

1. Mazzaferro V, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693-699, 1996. 

2. Sapisochin G, Bruix J: Liver transplantation for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 14:203-217, 2017. 

3. León Díaz FJ, et al: Up-to-7 criteria for hepatocellular carcinoma liver transplantation. Transplant Proc 48:2969-2972, 2016. 

4. Elwir S, Lake J: Current status of liver allocation in the United States. Gastroenterol Hepatol (NY) 12:166-170, 2016. 

5. Yao FY, et al: Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation. Hepatology 48:819-827, 2008. 

6. Pomfret EA, et al: Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 16:262-278. 2010. 

7. Squires MH 3rd, et al: Transplant versus resection for the management of hepatocellular carcinoma meeting Milan Criteria in the MELD exception era at a single institution in a UNOS region with short wait times. J Surg Oncol 109:533-541, 2014.