In the majority of cases, hepatocellular carcinoma develops in the setting of cirrhosis. Treatment with curative intent is possible in only 20% to 25% of cases and consists of resection or liver transplantation.
The rise of infection with hepatitis C virus worldwide and the lack of effective treatment for this infection has led to a rise in the incidence of hepatocellular carcinoma (HCC). Moreover, it is now accepted that the cirrhotic liver, regardless of etiology, is a nidus for tumor formation. A landmark study of 60 patients by Mazzaferro et al, published in 1996, forever changed the way in which surgeons approach this disease. The Milan criteria (one lesion < 5 cm or three lesions < 3 cm each) were adopted by the United Network for Organ Sharing in 2002 as the criteria by which patients would be given exception points for liver transplantation for HCC. Resection for HCC in the cirrhotic patient has poor outcomes, and many patients' livers cannot be resected due to underlying portal hypertension and thrombocytopenia. Results of transplantation are excellent, with an 80% 5-year survival. Finally, it has been demonstrated that the use of sirolimus for immunosuppression management in these patients may improve long-term disease-free survival; however, no consensus has been reached across the transplant community.
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death. In the majority of cases, HCC develops in the setting of cirrhosis. Treatment with curative intent is possible in only 20% to 25% of cases and consists of resection or liver transplantation.
The incidence of HCC continues to rise worldwide, due in large part to the rising number of persons who are positive for infection with hepatitis C virus (HCV). HCV is an RNA virus that infects around 300 million persons worldwide, with approximately 4 million new cases per year. At this time, there is no effective therapy that can reliably cure the infection, nor is there a preventive vaccine. Current therapy with interferon and ribavirin is often difficult to tolerate because of the side effect profiles of both agents. Moreover, the majority of patients are infected with HCV genotype 1, which exhibits the lowest response to therapy-namely, a 50% sustained viral response (SVR) after 48 weeks of therapy, compared with the 80% SVR after 24 weeks of therapy that is seen with genotypes 2 and 3. In the setting of HCV infection, the odds ratio of HCC developing in a patient with cirrhosis is 6.1 compared with a non-cirrhotic, with a yearly incidence of 2% to 8%. These data come from a clinic-based study, which also showed that the patients who were HCV-positive were at a 20-fold increased risk of developing HCC compared with the HCV-negative cohort.[3-5] In the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) study, the 5-year risk of non-cirrhotic HCV-positive patients developing HCC was 4.8%.
Infection with hepatitis B virus (HBV) also portends a risk of HCC, but not to the same degree as HCV infection. In one study by Beasley et al, the annual incidence in HBV-positive patients was 0.5%; in the setting of known cirrhosis, the incidence was 2.5%, with a relative risk (RR) of 100 compared with non-infected matched controls.[7,8] Interestingly, Asian carriers of the virus continue to have a risk of HCC even in the setting of normal liver morphology. This trend is not seen in Caucasians who have cleared the virus and have normal morphology. Therefore, surveillance for HCC is not warranted in non-cirrhotic HBV-positive Caucasian patients. In contrast, surveillance should be continued from age 40 onward in Asian men of similar status, in whom there is an annual incidence of HCC of 0.2%. Of course, in patients co-infected with either HCV or HIV, the incidence of HCC is exponentially greater, necessitating surveillance in these patients.[6-8]
The most rapidly rising cause of cirrhosis, especially in the developed world, is non-alcoholic fatty liver disease.[8,9] The incidence of HCC in the non-viral cirrhotic is not accurately known. In older studies, the presence of alcoholic liver disease and cirrhosis accounted for 32% of HCC cases.[10,11] Whether or not these cohorts were infected with HCV as well is not known. What can be said, based on a review of all relevant studies, is that any form of cirrhosis increases the risk of HCC developing in the native liver. Genetic hemochromatosis is also known to pose a high risk of HCC, with a RR of 20 and a yearly incidence of 3% to 4%.[12-14] Lastly, autoimmune hepatitis is associated with a 1.1% incidence of HCC per year, and end-stage primary biliary cirrhosis poses the same risk as HCV infection. In these latter groups, yearly surveillance is recommended.
The tests used to diagnose HCC include radiologic imaging and alpha-fetoprotein (AFP) serology. We will limit our discussion to those patients with cirrhosis because the incidence of HCC in the non-cirrhotic is quite low. Given the current sensitivity/specificity of MRI, a biopsy is rarely, if ever, needed.
Algorithm for the Work-Up of Patients With Cirrhosis in Whom Hepatocellular Carcinoma (HCC) is Supected
There are no blood tests that are currently validated for use in the diagnosis of HCC. AFP levels have long been known to lack the sensitivity and/or specificity needed to diagnose HCC. AFP levels can be elevated in a number of conditions, including intra-hepatic cholangiocarcinoma and HCV infection. Because of this, AFP serology is no longer recommended as a diagnostic test for HCC; thus, the diagnosis is dependent on the radiologic appearance.[16,17]
Currently, most screening for HCC is done by ultrasound. Conventional ultrasound lacks the sensitivity and specificity needed to accurately diagnose small HCCs, and in fact, the American Association for the Study of Liver Diseases (AASLD) recommends that two imaging modalities be used if ultrasound is one of the tests.[18,19] Only contrast-enhanced ultrasound (CE-US) has the diagnostic sensitivity and specificity to be used as a screening tool. Unfortunately, ultrasound is so user-dependent that it has not been adopted globally as the preferred screening test. In a consensus conference hosted by the American Hepato-Pancreato-Biliary Association (AHPBA) in 2009, CE-US was left off as a possible surveillance modality because of this limitation. To prove the unreliability of US as a screening modality, a 1997 European study looked at 43 cirrhotic patients with multiple liver lesions (50 regenerative nodules, 6 benign lesions, 13 HCCs). All 43 patients received US, CT, and MRI imaging within 2 weeks; the lesions detected in the US group were as follows: 1/50 regenerative nodules, 2/6 benign lesions, and 2/16 HCCs. As is apparent from these numbers, US does a poor job of screening for HCC in the cirrhotic liver. This is especially true in the case of small lesions, where the sensitivity of US in one reported study was as low as 14%.
Multi-detector computed tomography (MDCT) and MRI are now the modalities of choice when screening for HCC in the cirrhotic liver (Figure 1). MDCT uses radiation and iodinated contrast to opacify the liver during the arterial phase, the portal venous phase, and the hepatic vein phase. The downside of MDCT is the nephrotoxicity caused by the contrast agent and the radiation exposure to the patient. The radiation exposure from just two CT scans is about 40 mSV, which is equivalent to the radiation exposure 2.4 km from Hiroshima's ground zero. Most large series demonstrate a sensitivity of about 70% (65% to 78%) for CT scanning in the detection of HCC in the cirrhotic liver. The benefit of CT is its more universal acceptance; also, image acquisition is not as onerous as with MRI.
Unlike MDCT, MRI is limited only by the code and acquisition sequences that the radiologist can envision. MRI is a non-invasive and non-radioactive imaging modality that views the human body at the tissue level. In multiple large series, the sensitivity of MRI in detecting small HCCs approaches 90%, and in lesions > 2 cm, it has a sensitivity of 100% and a specificity of 99%, with an overall accuracy of 99.1%. These data were prospectively collected and pathologically correlated. The benefit of MRI is truly realized when we compare its ability to detect small HCCs to that of CT. The sensitivity of CT in patients with small HCCs is around 50%, and in some series no better than 36%. Moreover, recent work by Martin et al shows that liver lesions > 2 cm on MRI can be diagnosed with greater than 99% accuracy without a liver biopsy.[25-37] Given these levels of sensitivity, specificity, and diagnostic accuracy, the usefulness of any additional imaging modality is questionable, and the pursuit of biopsy for pathologic correlation should be discouraged.
The initial treatment decision in patients with HCC and cirrhosis is still based on the basic principles of hepatic surgery: inflow, outflow, and parenchymal reserve. The most important issue in the cirrhotic patient is the functional liver remnant (FLR). Most experts agree that in the cirrhotic liver, an FLR of 40% of the total liver volume is the minimum required for safe resection. The presence of portal hypertension and thrombocytopenia can complicate the picture: both of these negatively affect the outcomes of resection. For these reasons, and based on review of multiple center-specific series, the AHPBA said in their 2010 consensus statement that liver transplantation is the preferred approach for patients with HCC and cirrhosis, or in patients with Child A cirrhosis in the absence of portal hypertension.
The early experience with liver transplantation for large HCCs was marred by a high tumor recurrence rate both in the liver and in extrahepatic locations. However, proper patient selection based on pre-transplant imaging has rendered liver transplantation the most effective long-term therapy for small HCCs, and it has become the standard of care in patients who meet the Milan criteria.
In 1996, Mazzaferro et al published a series of 60 patients with small HCCs (1 lesion < 5 cm or 3 lesions < 3 cm each on pre-transplant imaging). These data showed that the 5-year survival was > 70%, with a recurrence rate of < 15%. Since 2002, the Milan criteria have been accepted in the United States by the United Network for Organ Sharing (UNOS) and other parties as the standard by which liver transplantation should be offered. Because donor livers are allocated according to the modified end-stage liver disease (MELD) scoring system, patients with HCC meeting the Milan criteria are granted a MELD “exception" of 22 points, which increases their likelihood of receiving a donor liver. If they do not receive a transplant within 3 months, such patients qualify for a further increase in MELD score-to 25. Use of this liver allocation system in the United States has made liver transplantation a commonly used treatment for HCCs that meet the Milan criteria.
Survival after orthotopic liver transplantation (OLT) for patients with TNM stage II disease has been shown to be excellent, with 5-year survival ranging from 60% to 80%. Importantly, with the addition of the MELD exception, the number of transplants for HCC has grown from 8.8% prior to 2002 to 22% in 2009. The disease-free survival (DFS) in patients undergoing transplantation is far better than the DFS in those undergoing partial resection (which is only 20% after 10 years). Lastly, recent multi-institutional data have shown that partial hepatectomy in patients with portal hypertension stratified by platelet count is associated with a 75% morbidity rate. Therefore, in patients with HCC in the setting of chronic liver disease, the intervention that is most successful at improving both the quality and length of life is OLT; it must be borne in mind, however, that not all patients will pass the rigorous medical, social, and financial screening necessary to receive an OLT.
Soon after the Milan criteria were accepted as the means for determining which patients should be offered liver transplants, aggressive OLT centers began extending the criteria and performing transplants in patients with higher-stage disease. Their rationale was that 13 of the 48 patients in the Milan paper had had disease beyond stage II disease. The 4-year outcomes in the subset of patients with more advanced disease were worse than those in patients with disease that met the Milan criteria. Interestingly, however, the University of California San Francisco (UCSF) has been able to expand the Milan criteria to include a single lesion < 6.5 cm or 1 to 3 HCCs each < 4.5 cm, with a total tumor size < 8 cm (Figure 2). The 1-year survival in the patients who met these UCSF criteria was shown to be 90%, with a 5-year survival of 75%. Therefore, in very select patients, OLT can be offered to patients with stage III disease.[40,42,43]
The University of Toronto has shown that in tumors as large as 10 cm, OLT can be performed successfully, with acceptable 5-year survival. The Toronto criteria employ a protocol biopsy for tumors that do not meet the Milan criteria, and in those patients with well differentiated or moderately differentiated tumors, transplant-along with aggressive bridging therapy-is offered. Factors associated with a worse outcome in this cohort were AFP level > 400 ng/mL, the number of nodules, and total tumor diameter. However, using multivariate analysis, only AFP level > 400 ng/mL had a significant impact on DFS, with a RR of 2.3, compared with patients whose tumors met the Milan criteria. The overall 5-year survival was 72%, with a DFS of 68%. There was no difference between the two groups in 5-year survival (72% vs 70%, P = .63) or in DFS (70% vs 66%, P = .25). This study challenges the current dogma that tumor size and number affect overall survival (OS); however, to date the Milan criteria remain the standard of care in most UNOS regions.
The above data, and the recognition that local therapy was effective at treating small HCCs, led the transplant community to adopt a policy of down-staging HCCs so that they would meet the Milan criteria. Multiple single-center studies have been performed showing the efficacy of either transarterial chemoembolization (TACE) with doxorubicin beads (deb-TACE) or radiofrequency ablation.[3,40,44] The choice of local therapy is usually based on center-specific expertise. The AHPBA supports the use of Deb-TACE as the preferred method of treating patients with unresectable HCC or as a bridge to transplant. In a recent report, pre-transplant TACE was used effectively to downstage 18 of 76 patients (23.6%) with otherwise unresectable or non-transplantable stage III/IV disease. This led to transplant in 17 out of 18 patients, with a DFS and OS of 94% at 19.6 months of follow-up. Therefore, most transplant centers support the use of neoadjuvant deb-TACE to downstage patients into the Milan criteria. Built into these protocols is a mandatory waiting period of 3 to 6 months, during which time patients are observed to ensure that disease does not progress. Patients with stable hepatic-only disease, without evidence of progression for 3 to 6 months, should be considered for OLT.
Comparison of the Milan Criteria and the University of California San Francisco (USCF) Criteria for Orthotopic Liver Transplantation in Patients With Hepatocellular Carcinoma (HCC
The use of local-regional therapy as a bridge to transplant has several therapeutic goals. Specifically, these are (1) to avoid HCC progression and drop-out from the waiting list; (2) to increase tumor-free survival; and (3) to downstage the disease in those patients who present with advanced disease. Currently, there are no data that pre-transplant therapy affect DFS or OS. Moreover, recent data suggest that local therapy to prevent drop-out only shows benefit in patients with wait-times greater than 240 days. On average, most large studies show a drop-out rate of approximately 2% per month regardless of treatment status.
No review of liver transplantation for HCC would be complete without mentioning the role of liver resection. The use of resection as a bridge to transplant has been used with acceptable long-term results in very select series of patients who came to “salvage transplant." In Asia, this strategy is often used. However, it is not recommended that hepatic resection be used for down-staging, as will be explained below. Moreover, recent publications have shown that liver resections in the setting of thrombocytopenia are associated with significant morbidity.
Liver resection for HCC in the setting of normal liver morphology is supported and is not germane to the scope of this review. The real debate concerns those patients who have chronic liver disease and HCC. Multiple experts have stated that hepatic resection should not be entertained unless the FLR is > 40%. Liver resection is not recommended in patients with platelet counts < 100,000/Î¼L, splenomegaly, paraesophageal varices, or other signs of clinically significant portal hypertension. In patients with viral hepatitis, the removal of the tumor burden does not change the field effect caused by the rest of the cirrhotic liver, and therefore the recurrence rate in such patients exceeds 70%.[45,46] For this reason, liver transplantation offers the best long-term cure for both malignancy and underlying liver disease. Lastly, resection of the lesion, unlike local therapy, negates the UNOS exception score; patients are therefore disadvantaged from an allocation perspective if their tumor is resected.
The use of adjuvant therapy to prevent recurrence of HCC is a novel idea and one that is not universally supported by the oncology community. What is accepted is that post-OLT maintenance needs to include some sort of anti-rejection medication. If that anti-rejection medication also had anti-tumor effects, then two goals could be met with one therapy. There are no large randomized trials comparing one anti-rejection regimen to another with respect to their effect on recurrence or survival. In one recent Italian study of 69 OLT patients with HCC, cyclosporine was used exclusively and showed a lower mortality rate and lower recurrence rate in the first year in a dose-dependent fashion.Multivariate analysis showed that the only independent prognostic determinant of recurrence was the blood level of cyclosporine.
Mentioned in This Article
Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.
The mammalian target of rapamycin (mTOR) inhibitors, sirolimus (Rapamune) and everolimus (Afinitor), are immunosuppressive agents that also have anti-tumor properties: they inhibit the clonal expansion of interleukin-2–activated T lymphocytes via blockade of mTOR. There are few studies that show the efficacy of sirolimus in OLT patients; however, in one Canadian study, 40 consecutive liver transplant patients with HCC that met either the Milan criteria (n=19) or extended criteria (n=21) received a sirolimus-based regimen. The survival rates were similar in the two groups and the recurrence rates remained low in both cohorts. There is also a large registry-based trial that showed that sirolimus monotherapy was associated with improved survival after OLT for HCC. Lastly, there are two studies showing improved survival rates in patients who received sirolimus-based therapy compared with those who received conventional calcineurin-based therapy.[49,50] Therefore, in patients with poor prognostic factors on explant (eg, vascular invasion, tumors that do not meet the Milan criteria, low differentiation grade, or presence of satellite nodules), it is acceptable to use a sirolimus-based regimen at the onset.
For patients with HCC and cirrhosis, liver transplantation offers the best long-term survival and excellent DFS. The Milan criteria transformed the landscape of what can be offered to this difficult-to-treat cohort of patients. In the future, as local-regional therapy improves or as novel anti-tumor medications become available, this modality may be able to be made available to patients whose disease does not meet the current Milan criteria while still providing them with acceptable long-term outcomes.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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