Transplant Versus Resection for Hepatocellular Carcinoma

Provided by Dr. I-Chen Tsai, Taichung Veterans General Hospital, Taichung, Taiwan.

Although liver transplantation may be a more ideal treatment option compared with resection for many patients with hepatocellular carcinoma (HCC), donor availability remains a major limiting factor to its widespread incorporation. Variations in outcomes between patients treated with resection and transplantation, along with a potential strategy to increase donor availability while maintaining outcomes, were the focus of two recent studies published in theJournal of the American College of Surgeons.^1,2

Overall, results from the first study, led by William C. Chapman, MD, indicated that liver transplantation does have an overall and disease-free survival advantage over resection among patients who qualify for both treatment modalities.¹However, due to resource limitations, liver resection often remains the recommended therapy for patients with resectable HCC.

A second study, led by Mizuki Ninomiya, MD, PhD, shed light on the potential for living donor liver transplantation (LDLT) to offer an increased source of donors for patients with unresectable HCC.²In their study designed to compare centers utilizing LDLT versus deceased donor liver transplantation (DDLT) as a primary treatment choice, HCC recurrence rates appeared similar regardless of graft source.²

These studies help to improve local therapies for patients with HCC, which is increasingly being diagnosed at earlier stages as a result of routine screening in patients with cirrhosis.³Despite more patients being diagnosed at earlier stages, the estimated 5-year survival rate in the United States remains less than 12%, emphasizing the need for improved therapeutic options for patients with HCC.⁴

“Liver transplantation and liver resection are the mainstays of surgical therapy for HCC,” Chapman, and colleagues noted in their report comparing resection with transplantation.¹However, most of the patients presenting with HCC also have associated chronic liver disease,⁵which may impact their eligibility for these procedures. In fact, only 25% to 40% of US patients undergo some form of curative therapy upon presentation.⁶

Pros and Cons of Liver Resection

Liver resection with partial hepatectomy is currently the standard of care for patients with HCC who have well-compensated cirrhosis and no evidence of portal hypertension.¹In the population of patients without chronic liver disease, resection can yield 5-year overall survival rates around 50%.⁷

“Liver resection is an attractive therapy because it is immediately available, allows for pathologic assessment of the tumor and background liver, and does not require use of an increasingly scarce donor liver that could be used for the overall transplant pool,” the authors added.¹In addition, there is evidence to suggest that resection may be more cost-effective than liver transplantation.⁸

Despite these benefits, liver resection is not without its limitations, as 60% to 80% of patients experience intrahepatic recurrences of HCC in the remnant liver by year 10 of follow-up.⁸Additionally, effective treatment options for post-resection recurrence remain poorly defined. In fact, some reports suggest that patients undergoing salvage transplantation after post-resection recurrence may have worse outcomes versus those undergoing initial liver transplant.⁹

Pros and Cons of Liver Transplantation

In contrast to liver resection, Chapman and colleagues noted, “liver transplantation offers a more ideal treatment for HCC because it achieves removal of the tumor and also the potential sites of recurrence in the diseased liver.”¹

Rates of survival post liver transplantation have greatly improved following incorporation of the Milan criteria, which provides a strict standard for patient selection and limits transplant to those in earlier stages of disease. These criteria exclude liver transplantation in individuals with vascular invasion involving intrahepatic portal or hepatic veins, or those with evidence of metastases.¹

Unfortunately, “given the rigorous selection process and the ever-present scarcity of donor organs,” Chapman added, “liver transplantation as the treatment of choice for HCC is not feasible in a significant number of patients who present with [the disease].”¹

Benefits of Transplant Versus Resection

It is important to note that studies comparing the outcomes of liver resection versus transplantation in patients with HCC are impacted by the fact that patient eligibility—and thus baseline patient characteristics—often differ between the 2 treatment groups.¹“Patients with normal background liver (ie, no fibrosis or cirrhosis) almost never undergo transplantation,” Chapman and colleagues explained, while “those with decompensated cirrhosis and/or portal hypertension almost never undergo hepatic resection.”¹

While the use of liver transplantation is “almost never considered in patients with normal background liver,” most HCC patients do present with chronic liver disease, which often confounds treatment selection, especially among individuals who qualify for both treatment options.¹For the subset of patients with early stage malignancy and well-compensated cirrhosis or hepatic fibrosis, both transplant and resection may be feasible; unfortunately, for these individuals, controversy remains as to which approach is ideal.

One study in 2013 indicated that liver resection yields significantly greater rates of disease recurrence, where the 10-year recurrence risk was 83% following resection versus only 20% following liver transplant.¹⁰Ten-year survival rates in this study were also higher for liver transplant compared with resection, at 49% versus 33%, respectively.¹⁰

Despite these findings, other intention-to-treat analyses have countered that overall survival rates are similar between liver resection and transplantation in this setting.^11,12Data from randomized controlled trials directly comparing the 2 treatment modalities are not available at this time.

To address this residual controversy, Chapman and colleagues completed an extensive retrospective study, gathering data from 5 large US liver centers spanning over 20 years of clinical practice.¹The study included patients with HCC who were surgically treated via either liver resection or transplantation between January 1, 1990, and August 31, 2011. “We were especially interested in patients with background liver disease who might potentially qualify for either surgical therapy,” the authors noted.¹

“Our results suggest that, controlling for patient characteristics that often confound analyses of outcomes from retrospective data, liver transplantation had significantly greater overall and disease-free survivals,” concluded Chapman.¹This outcome was particularly notable among cirrhotic patients with tumors meeting Milan criteria, “who theoretically, would have been candidates for either therapy.”¹

In this patient population, 5- and 10-year overall survival rates were 74.3% and 53.7% for liver transplantation compared with 46.5% and 15.2% for liver resection.¹Similar results were obtained for disease-free survival, reaching 71.8% and 53.4% for liver transplant at 5 and 10 years compared with 18.4% and 3.0% for liver resection, respectively. These trends remained unaffected by age or the presence of cirrhosis.¹

Taken together, the authors concluded that “patients with HCC and background liver disease are likely to have better outcomes in short- and long-term follow-up by undergoing liver transplantation, if they qualify.”¹These findings suggest that ideally, liver transplantation should be encouraged as an initial therapy for HCC in the setting of background liver disease, even among individuals suitable for resection.

Unfortunately, despite poorer treatment outcomes following resection, Chapman and colleagues concluded that, from a “resource use standpoint,” candidates who qualify for either therapy might still need to be managed via resection rather than transplant.¹

This recommendation is necessary to “lessen the impact of liver transplantation on the overall donor pool,” the authors explained, “which is already compromised with the ever expanding waiting list of patients needing [transplant] and for whom no other options exist.”¹They urgently called for additional strategies, such as adjuvant therapy, in an effort to lessen the gap in treatment outcomes between resection and transplant.¹

Additional strategies are especially important for those who do not qualify for liver transplantation. Based on tumor size and the presence of cirrhosis, only around 10% of patients in the Chapman study who underwent liver resection would have met the criteria for liver transplant.¹

Increasing Options for Liver Transplantation

Even if recurrence rates following liver resection could be improved, many patients with HCC may have more advanced, unresectable disease. “In the United States alone,” wrote Ninomiya and colleagues, “approximately 7,000 new patients with HCC are put on the waiting list for DDLT each year, and 15% die during the waiting period…due to the relative shortage of deceased donors.”²

Due to the extended waiting periods and consequent risk of tumor progression associated with DDLT, Ninomiya and other researchers proposed LDLT as an alternative.²The use of LDLT has the potential to increase the supply of organs available for transplant; however, controversy remains as to whether this approach can maintain overall and disease-free survival rates comparable to those achieved with DDLT.^13,14

In the United States, DDLT accounts for the large majority of liver transplantation procedures, especially among patients who meet Milan criteria.^2,15As LDLT is often reserved for those excluded from DDLT, many studies in the United States may be subject to bias. In contrast, many Asian countries resort to LDLT as a primary therapy for patients with unresectable HCC, due to the limited supply of deceased donors.^2,15

Taking this into consideration, Ninomiya and colleagues set out to compare outcomes of LDLT versus DDLT in settings where each procedure would be the “first treatment choice” for patients with unresectable HCC.²In summary, 133 patients receiving LDLT from Kyushu University in Japan were compared with 362 patients receiving DDLT from Mount Sinai Medical Center in New York. The authors specified a primary endpoint of recurrence rate after liver transplantation (LT).²

Interestingly, for the primary endpoint of recurrence rate, there was no significant difference between groups over 1, 3, and 5 years of follow-up. This finding led the authors to conclude that “LDLT is a viable treatment option for unresectable HCC, providing similar recurrence rates to those achieved with DDLT.”²

Findings also indicated that the survival rate for patients undergoing LDLT was significantly better compared with those receiving DDLT. However, the authors noted that, due to differing baseline patient characteristics and potential selection bias, “the current results do not necessarily represent superiority of LDLT over DDLT in terms of survival benefits.”²

Looking to the Future

In lieu of strategies to improve resection outcomes in these cases, and in the face of increasing numbers of patients with unresectable disease, alternatives with the potential to increase donor availability are crucial for optimizing treatment outcomes in this setting.

“Given the static supply and the increasing demand for usable organs for transplantation,” Chapman and colleagues concluded, “there is urgency in exploring methods to increase the supply of organs.”¹While present findings offer one potential strategy for improving donor availability, additional efforts to expand the donor pool and improve resection outcomes via adjuvant therapies remain critical to the field.

References:

1.        Ninomiya M, Shirabe K, Facciuto ME, et al. Comparative study of living and deceased donor liver transplantation as a treatment for hepatocellular carcinoma.J Am Coll Surg. 2015;220(3):297-304.e3. doi:10.1016/j.jamcollsurg.2014.12.009.

2.        Chapman WC, Klintmalm G, Hemming A, et al. Surgical treatment of hepatocellular carcinoma in North America: can hepatic resection still be justified?J Am Coll Surg. 2015;220(4):628-637. doi:10.1016/j.jamcollsurg.2014.12.030.

3.        Cicalese L. Hepatocellular Carcinoma. May 2014. http://emedicine.medscape.com/article/197319-overview. Accessed March 12, 2015.

4.        Mittal S, El-Serag HB. Epidemiology of HCC: Consider the Population.J Clin Gastroenterol. 2013;47(0):S2-S6. doi:10.1097/MCG.0b013e3182872f29.

5.        Simonetti RG, Cammà C, Fiorello F, Politi F, D’Amico G, Pagliaro L. Hepatocellular carcinoma. A worldwide problem and the major risk factors.Dig Dis Sci. 1991;36(7):962-972.

6.        Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects.J Hepatol. 2003;38:136-149. doi:10.1016/S0168-8278(02)00432-4.

7.        Belghiti J, Regimbeau JM, Durand F, et al. Resection of hepatocellular carcinoma: a European experience on 328 cases.Hepatogastroenterology. 2002;49(43):41-46.

8.        Lim KC, Wang VW, Siddiqui FJ, et al. Cost-effectiveness analysis of liver resection versus transplantation for early hepatocellular carcinoma within the Milan criteria.Hepatol Baltim Md. 2015;61(1):227-237. doi:10.1002/hep.27135.

9.        Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy?Ann Surg. 2003;238(4):508-518; discussion 518-519. doi:10.1097/01.sla.0000090449.87109.44.

10.      Sapisochin G, Castells L, Dopazo C, et al. Single HCC in cirrhotic patients: liver resection or liver transplantation? Long-term outcome according to an intention-to-treat basis.Ann Surg Oncol. 2013;20(4):1194-1202. doi:10.1245/s10434-012-2655-1.

11.      Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.Hepatol Baltim Md. 1999;30(6):1434-1440. doi:10.1002/hep.510300629.

12.      Facciuto ME, Rochon C, Pandey M, et al. Surgical dilemma: liver resection or liver transplantation for hepatocellular carcinoma and cirrhosis. Intention-to-treat analysis in patients within and outwith Milan criteria.HPB. 2009;11(5):398-404. doi:10.1111/j.1477-2574.2009.00073.x.

13.      Fisher RA, Kulik LM, Freise CE, et al. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation.Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2007;7(6):1601-1608. doi:10.1111/j.1600-6143.2007.01802.x.

14.      Bhangui P, Vibert E, Majno P, et al. Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation.Hepatol Baltim Md. 2011;53(5):1570-1579. doi:10.1002/hep.24231.

15.      Hwang S, Lee S-G, Belghiti J. Liver transplantation for HCC: its role: Eastern and Western perspectives.J Hepato-Biliary-Pancreat Sci. 2010;17(4):443-448. doi:10.1007/s00534-009-0241-0.