Transplantation for Hepatocellular Carcinoma as Part of a Balanced, Multidisciplinary Strategy
Transplantation for Hepatocellular Carcinoma as Part of a Balanced, Multidisciplinary Strategy
Hepatocellular carcinoma (HCC) remains a formidable challenge in the United States due to its increasing incidence, its advanced-stage presentation, and its association with chronic liver disease.[1-3] The few potentially curative treatment options in existence—ie, total hepatectomy with liver transplantation, liver resection, and liver ablation—all have rather limited applicability due to fairly well-defined restrictions regarding tumor extent, underlying liver function, and degree of portal hypertension. The majority of patients in this country in whom HCC is diagnosed present in advanced tumor stages or with severe liver function impairment, and may not qualify for any therapy. Unfortunately, no highly effective systemic treatment has been identified to date, and recent advances with targeted therapeutics such as sorafenib (Nexavar) still carry limitations regarding liver function and performance status.
It is therefore sensible that Hanish and Knechtle, in their comprehensive review of liver transplantation for HCC, discuss the implications of earlier diagnosis and screening in cohorts of high-risk patients. While it is clear that earlier diagnosis of HCC would create better treatment options for affected persons, the optimal utilization of screening modalities remains unclear. The review lists the shortcomings of ultrasound and alpha-fetoprotein (AFP) measurements, and it suggests contrast-enhanced ultrasound and MRI as potential future options because of their greater sensitivity and specificity. Of course, reliable detection of small HCC lesions is the ultimate goal, but this is also the greatest challenge. For practical purposes, and for the here-and-now, it has become clear that semiannual ultrasound surveillance provides better results than annual testing. In a recent meta-analysis of 19 studies, ultrasound surveillance had a pooled sensitivity of 94% but performed less well for early HCC detection. While AFP measurements did not yield any added benefit compared to ultrasound alone in this analysis, it is important to acknowledge that ultrasound remains highly operator-dependent, and exams of high quality, as were likely obtained in the trials reviewed, are not universally available. For this reason, semiannual surveillance with ultrasound and AFP measurements should remain an acceptable approach. The biggest obstacle to early HCC detection remains the fact that surveillance in high-risk patients appears to be underutilized: in one study examining US population data, fewer than 20% of patients with newly diagnosed HCC had undergone testing within 3 years prior, and only half of those tested underwent ultrasound.
In their discussion of liver transplantation for HCC associated with chronic liver disease, Hanish and Knechtle make it clear that transplantation is the only modality able to address the therapeutic needs arising from both the tumor and the underlying liver disorder; it thus needs to play a central role in the process of treatment determination. For this reason, superior survival outcomes after transplantation compared to other local treatment approaches may appear plausible, although patients obviously are selected quite differently for transplantation than for other modalities. The authors also provide ample evidence that transplantation benefits are not just limited to HCCs that meet the Milan criteria. In fact, evidence is growing that transplantation for HCCs that do not meet the Milan criteria can yield survival results similar to the results for HCCs within these criteria; we expect that carefully designed studies will ultimately lead to an expansion of the transplantation indications for HCC in the future. However, there are some serious limitations that curtail the wider application of transplantation for HCC, including organ shortage, high costs, need for life-long immunosuppression, and the potential risks to live donors in cases of living donations. The situation is worsened by the fact that patients with HCC appear to be advantaged in the current organ allocation system compared with patients who have liver cirrhosis but no HCC, a problem that may call for future remediation. In addition, living donations do not seem to be a solution to the organ availability problem in the intermediate term, because of ethical challenges and concerns about a possibly greater rate of HCC recurrence. For all these reasons, transplantation needs to always be carefully balanced against other available local therapy options for localized HCC.
Recent developments have widened the possibilities for resection of HCC, even in carefully selected patients with cirrhosis or multifocal disease. Liver volumetry, preoperative portal vein embolization, and lack of tumor size constraints such as are in place for transplantation render hepatectomy an important and valid alternative to transplantation for certain HCC conditions.[13,14] Post-resection survival can compare well to post-transplant outcomes when the liver resection has been performed in a center of excellence. However, a more appropriate comparison appears to be an intent-to-treat comparison, since a significant subset of patients awaiting transplantation will drop off the transplant eligibility list over time. In several series, such an intra-institutional comparison has shown no differences between transplanted and resected patients—ie, no general superiority of the transplantation approach to HCC.[16,17] The preferred choice of primary treatment for transplantable HCC is therefore still debatable and will realistically depend in part on local factors of therapeutic expertise, organ availability, and system support, as well as on individual patient factors of comorbidity and disease characteristics. Importantly, novel forms of induction therapy or bridging treatment prior to possible transplantation—such as radioembolization, drug-eluting bead embolization, stereotactic radiotherapy, or other forms of ablation—will increasingly have a role in this general decision-making process.
Currently acceptable indications for transplantation as treatment for HCC in patients with chronic liver disease have been well articulated by Hanish and Knechtle; the possibility of wider indications beyond the Milan criteria in the future has also been well described. In addition, the authors review the intriguing prospect of possible adjuvant oncologic benefits from targeted immunosuppressive therapies, for which hopefully more evidence will emerge. However, since for now there is no clear separation between some potentially overlapping indications for transplantation and resection, one should conclude that all patients who qualify for either therapy should be offered a formal evaluation for transplantation as well as for resection options. This multidisciplinary process must first and foremost serve one goal: to obtain the best possible outcome for each individual patient, given available resources and specialty expertise. Multidisciplinary evaluation, treatment, and surveillance of patients at risk should preferably take place in centers with specific programmatic dedication and proven excellence. Under these conditions, transplantation and other therapeutic tools will continue to be refined and hopefully better coordinated within a balanced multidisciplinary strategy, for the ultimate benefit of the patient with HCC.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27:1485-91.
2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300.
3. Schwarz RE, Smith DD. Trends in local therapy for hepatocellular carcinoma and survival outcomes in the US population. Am J Surg. 2008;195:829-36.
4. Schwarz RE, Abou-Alfa GK, Geschwind JF, et al. Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement. HPB (Oxford). 2010;12:313-20.
5. Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology. 2008;47:97-104.
6. Santi V, Trevisani F, Gramenzi A, et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J Hepatol. 2010;53:291-7.
7. Singal A, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther. 2009;30:37-47.
8. Davila JA, Morgan RO, Richardson PA, et al. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology. 2010;52:132-41.
9. Guiteau JJ, Cotton RT, Washburn WK, et al. An early regional experience with expansion of Milan Criteria for liver transplant recipients. Am J Transplant. 2010;10:2092-8.
10. Yi NJ, Suh KS, Kim T, et al. Current role of surgery in treatment of early stage hepatocellular carcinoma: resection versus liver transplantation. Oncology. 2008;75 Suppl 1:124-8.
11. Washburn K, Edwards E, Harper A, Freeman R. Hepatocellular carcinoma patients are advantaged in the current liver transplant allocation system. Am J Transplant. 2010;10:1643-8.
12. Pomfret EA, Peter ALJ, Villamil FG, Siegler M. 2010 consensus conference on liver transplantation for HCC: Should we use living donor grafts for patients with hepatocellular carcinoma (HCC)? ethical consideration. Liver Transpl. 2011.
13. Vauthey JN, Dixon E, Abdalla EK, et al. Pretreatment assessment of hepatocellular carcinoma: expert consensus statement. HPB (Oxford). 2010;12:289-99.
14. Jarnagin W, Chapman WC, Curley S, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB (Oxford). 2010;12:302-10.
15. Cha CH, Ruo L, Fong Y, et al. Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg. 2003;238:315-21; discussion 21-3.
16. Cherqui D, Laurent A, Mocellin N, et al. Liver resection for transplantable hepatocellular carcinoma: long-term survival and role of secondary liver transplantation. Ann Surg. 2009;250:738-46.
17. 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 (Oxford). 2009;11:398-404.