Transplantation for hepatocellular carcinoma

Transplantation

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ORLDWIDE, hepatocellular carcinoma (HCC) is the most common form of primary malignancy of the liver.1 It has an incidence of 500,000 to l,OOO,OOO new cases per annum worldwide. A recent study suggests that the incidence of HCC in the United States has increased from 1.4 to 2.4 per 100,000.2 This increase was primarily in the age group 40 to 60 years. This change in incidence parallels the increasing prevalence of hepatitis C in the United States. While there are a variety of medical conditions associated with the development of HCC, viral hepatitis is the most important numerically. This discussion concentrates on the surgical management of HCC arising in patients with these viral hepatitides. Prior to the advent of transplantation, resection was the only hope for a cure. In the 1970s and 198Os, transplantation of the liver was used in an attempt to cure patients with both early- and advanced-stage disease. From this experience, it became clear that transplantation had no better outcome than resection for patients with late-stage disease, but transplantation did have an important role in the management of those with less advanced disease.3 Since this discovery, there has been controversy about the relative merits of transplantation versus resection in this group of patients. The classic teaching for evaluating patients for Seminars

in Oncology,

Vol 28, No 5 (October),

200 I: pp 497-502

Carcinoma

P. Roberts

resection of HCC was focused on this point: that the planned resection was not futile, ie, (1) there was no extrahepatic disease that would limit the life expectancy despite technically successful surgery, as there appears to be little advantage of palliative surgery in these patients; (2) there was no bilobar disease, so that resection would not leave behind tumor; and (3) the patient should be left with adequate hepatic reserve to allow for survival, which is difficult in the cirrhotic. With these criteria, only a small percentage (~30%) of patients with liver cancer were found to be candidates for resection. With the application of liver transplantation, it was found that criteria no. 2 and 3 were less important as long as the patient met other criteria as a candidate for transplantation and the tumor stage was early. The remaining controversy pertains to the patient who could undergo resection or transplantation. The question is, first, which therapy offers the best chance for long-term survival and, second, which therapy is feasible given the shortage of donor organs? PATHOLOGY Understanding the appropriate therapy for HCC associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requires understanding the pathogenesis of the disease. For both, the time interval between viral exposure and development of HCC is quite long, with intervals as long as 29 years4 from time of exposure via blood transfusion to HCC development. Following exposure to HCV infection, 20% to 25% of patients will go on to develop cirrhosis or serious complie cations, and of these 20% to 25% will develop HCC.5 HCV causes hepatic inflammation, which leads to fibrosis and eventual cirrhosis in chronic cases.

From Guy’s, King’s and St Thomas’ School of Medicine, London, UK; and the University of California San Francisco Medical Center, San Francisco, CA. Address reprint requests to Elka Kashef, MD, Guy’s, King’s and St Thomas’ School ofMedicine, London Bridge, London SE1 1UL, UK. Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2805~0007$35.00/0 doi:10.1053/sonc.2001.26952 497

4%

It is estimated that only 12% of HCC that are surgically resectable develop in a nonfibrotic liver and that only 2% to 3% of patients with resectable HCC have normal liver histology.6 When cirrhosis is established, HCV replication continues, which sustains inflammation and thus increases the rate of cell turnover. This increases the risk of transforming mutations and therefore HCC.7 After cirrhosis is established, approximately 3% of patients will develop HCC on an annual basis.8 The average interval between the diagnosis of cirrhosis and HCC development is about 3 years, but this interval varies depending on a variety of factors, including the viral genotype, smoking status, alcohol consumption, age, and gender of the patient.9 There appears to be a progression of pathology in the liver that leads to the development of HCC, similar to the proposed pathologic progression in the development of colon cancer. As in ulcerative colitis or familial polyposis, where dysplasia may be seen in one area and carcinoma in another area of the colon, the liver frequently exhibits a variety of pathologic states. In adults undergoing transplantation for cirrhosis, HCC was found in 17.5% of the explanted livers of all patients, and in 35% of the livers of patients over the age of 50 years.lO With the presence of HCC, many of which are quite small, there are frequently high-grade dysplastic nodules, which are the precursors of the development of HCC. The presence of a HCC in the liver is a harbinger for the subsequent development of HCC in a different area of the liver because of the presence of unrecognized neoplasia or preneoplastic lesions. The greatest risk factor for the subsequent development of HCC is a pre-existing HCC in the liver, very similar to the situation in breast or colon cancer. Development of a second primary tumor in the liver of a patient following ablation of a HCC is estimated to occur in 44% to 55% of patients 36 months following ablation of the first primary.‘l Using a variety of source literature, Majno et al estimated the yearly recurrence at 20% per year, with a range of 15% to 30%.12 HBV may lead to the development of HCC at a different stage in the disease progression than HCV. Patients with HCC and HBV tend to have less advanced liver disease than patients with HCV, and are more frequently candidates for resection (49% w 7%).i3 Furthermore, patients with HCC and HCV had significantly longer S-year

KASHEF

AND

ROBERTS

disease-free survival after transplant compared with resection (48% v 7%). The incidence of multicentric postoperative reccurrence appears to be higher in patients with HCV-related HCC (53.3%) than in patients with HBV-related HCC (7.7%).14j15 It is uncertain whether there is a difference in outcome following resection between patients with the different etiologies. RADIOLOGICAL

IMAGING

To determine the possibility of a curative resection for a patient with HCC, bilobar disease should be excluded. To this end, preoperative helical computed tomography (CT) with arterial, portal, and hepatic venous phases offers a more informative investigation than conventional CT scanning. There is some controversy regarding the optimal radiologic method, magnetic resonance imaging (MRI) versus helical CT scan, for this purpose. It has been suggested that MRI is the most accurate noninvasive procedure in detecting HCC nodules and can possibly differentiate between regenerative and dysplastic nodules of the liver.i6zi7 An alternative is CT scanning using lipiodol as a contrast agent. This compound is concentrated in the HCC and is suggested to have a high sensitivity. Unfortunately, the uptake in dysplastic or regenerative nodules hinders the specificity of the test.18 Despite advances in radiologic techniques, the sensitivity and specificity of detection of small lesions is low. Comparisons of the radiologic techniques and subsequent careful pathologic examinations of explanted livers following transplantation have demonstrated that small cancers are frequently missed, as are dysplastic nodules.i9j20 It appears that helical CT scan only identifies 40% of tumor nodules. It might be expected that intraoperative ultrasound would be a more sensitive technique to locate small HCCs, and it is our experience that this is true. Unfortunately, given the frequency of associated cirrhosis and severe fibrosis in this population, the intraoperative ultrasound frequently shows a field of nodules, suggesting poor specificity. Determining which nodule could be an HCC is impossible, and biopsy of any single lesion would carry a very high risk of missing the adjacent HCC or dysplastic nodule. The failure of radiologic techniques to accurately determine the presence of disease outside the planned resection margin, coupled with the

TRANSPLANTATION

FOR

HEPATOCELLULAR

CARCINOMA

high incidence of small HCC or dysplastic nodules in these patients, suggests that resection will frequently leave behind either a small HCC or a nodule that will degenerate into a HCC. THERAPEUTIC

TECHNIQUES

Resection The outcome following resection is limited by two factors. The first, which has been discussed above, is the recurrence of HCC in the remaining liver, and the second is progression of underlying liver disease resulting in liver failure. It is estimated that the risk of development of a recurrence of a second primary tumor or recurrence of the index tumor occurs in about 50% of patients by 3 to 4 years following resectionzl An additional percentage will develop liver failure and die before tumor development.22 To predict which patients are at risk for liver failure following resection, several techniques have been advocated. The first is the use of indocyanine green (ICG) clearance to assess the functional mass of the liver. In general, this technique is used in patients with normal biochemical markers of synthetic function such as bilirubin, albumin, and prothrombin time.23 Patients who do not meet these criteria (Child’s class A) are usually eliminated from consideration of removal of more than one or two segments.24 In patients who fit these criteria, ICG clearance may play a role in determing the risk of a major resection. An alternative technique is to measure wedged portal vein pressure.z5 Patients with abnormally high pressures appear to be at increased risk following liver resection. This measurement would exclude patients with radiographic evidence of portal hypertension such as varices, as in this circumstance the portal pressure would be elevated. These tests may be able to select patients with lower perioperative mortality with regard to liver failure, but their ability to predict liver failure in the long term is limited. When resection is considered, a relatively new technique, portal vein embolization, can be used to improve morbidity and mortality rates following resection in patients with underlying liver disease.26 This technique uses a material such as polyvinyl alcohol powder injected into the ipsilatera1 side of the planned resection, which blocks portal flow and encourages growth of the con-

tralateral side. It appears that a significant portion of patients respond with growth of the contralatera1 side as measured by volumetric CT scan. Failure of the contralateral side to respond by growing appears to be a poor prognostic sign for survival following resection. Results following resection for HCC are relatively dismal. The risk of intrahepatic recurrence is on the order of 40% to 60% at 36 months, and longer patient survival is in the range of 25% to 30%.27-29 However, patients with normal synthetic function, with a single tumor smaller than 2 cm, have a 5year survival rate of 80%.30 This represents about 16% of patients undergoing resection for small HCC. Survival at 1, 2, and 3 years among patients who are not candidates for resection, with intermediate-stage disease, followed prospectively, is 80%, 65%, and 50%, respectively, which is not dissimilar from that of patients undergoing resection.31 Ablation Alternatives to resection, including ablation with either alcohol or radiofrequency devices, have been used more frequently in recent years. These offer the advantage of destroying a minimal amount of surrounding tissue while destroying the tumor. This spares functioning parenchyma. The techniques may be used on a repeated basis, eradicating remnants of previously treated lesions or destroying new lesions as they develop. Although radiofrequency ablation may be performed in an open or laparoscopic fashion, this technique and ethanol injection are frequently done percutaneously. The percutaneous approach may save patients with relatively decompensated liver disease from receiving a general anesthetic. Percutaneous access may be limited by the position of the tumor, particularly those located near the right hemidiaphragm. Currently, the results following ethanol ablation are better reported than those of radiofrequency ablation. The recurrence rate following ethanol ablation of small lesions appears somewhat higher than resection, although no randomized trials have been performed. 32 The survival advantage of patients treated by these methods as compared to resection is unclear.33 There is probably a strong selection bias among patients referred for ablation rather than resection; however, despite this bias, the survival results appear to be similar.34

500

If the ability of these techniques to be used repeatedly to control local disease within the liver at an early stage is confirmed, a potential role might be in controlling local disease while the patient is on the waiting list for transplantation. Chemoembolizution The prevention of tumor growth by injection of chemotherapeutic agents into the hepatic arterial supply of the tumor coupled with embolization of arterial flow was an attractive alternative to resection in some patients. Unfortunately, several randomized trials have demonstrated no significant survival benefit to this therapy.35J6 While there appears to be an early improvement in survival suggesting an immediate benefit, overall survival was no better than in the control group. The use of chemoembolization as a measure to stay tumor growth in patients on the waiting list for transplantation is attractive. Theoretically, this approach would take advantage of the early improvement in survival, allowing more patients to get by the long waiting time for transplantation. Transplantation Most reports regarding transplantation for HCC have demonstrated that tumors greater than 5 cm in size, and patients with more than four tumors or with macroscopic portal vein invasion, have 5-year survival rates in the 0% to 30% range. Currently, few centers perform cadaveric transplantation for patients with this late stage disease. Several reports have demonstrated that patients with early-stage disease have excellent survival. Mazzaferro et al reported 85% 5-year survival among patients with a single lesion less than 5 cm or patients with more than one lesion, no more than three lesions and none greater than 3 cm.37 Bismuth et al found that in patients with lesions less than 3 cm, the 5-year survival rate was 66%.3s Another study by Bismuth’s group demonstrated an 83% disease-free survival rate at 3 years in patients with small HCCs, compared with 18% among a similar group of patients undergoing resection.39 Figueras et al found a ii-year survival rate of 75% in patients with tumors less than 5 cm.40 Importantly, Mazzaferro et al have demonstrated that the survival among patients meeting this criteria is equivalent to that of patients undergoing transplantation without the presence of tumors.37 While there appears to be survival advantage

KASHEF

AND

ROBERTS

among patients with early disease, the precise limits of size and number of lesions are unclear. A recent review of patients transplanted at the University of California San Francisco by Yao et al, demonstrated that patients with HCC and a solitary tumor 5 6.5 cm, or 5 three nodules with the largest lesion 5 4.5 cm and total tumor diameter 5 8 cm, had survival rates of 90% and 75.2%, at 1 and 5 years, respectively, after orthotopic liver transplantation, versus a 50% l-year survival and 0% late survival for patients with tumors exceeding these limits.41 PATIENT

MANAGEMENT

Given the discussionabove, it should be clear that transplantation offers a survival advantage that is superior to resection or ablation in patients with early-stagedisease.The major problem with offering this therapy to patients with HCC is that livers for transplantation are offered in an algorithm that emphasizeswaiting time. This means that tumor progressionwill eliminate a large percentage of patients if they need to wait a prolonged time for transplantation. A study using cost-benefit methodology suggeststhat resection is better than transplantation when waiting times exceed 6 to 10 months.‘r2This is becauseof estimatesthat 20% to 30% of patients will have tumor progression during this time that will prevent transplantation, With the advent of living-donor transplantation, the issueof waiting time for those patients who have a donor becomesmoot. This operation should allow the maximum benefit of transplantation for early-stageHCC, asthe results appear to be comparable to cadaveric transplantation and the lossof patients from diseaseprogressionwhile waiting for an organ is minimal. For patients without a living donor, the issueis more difficult. First, these patients should be listed for liver transplantation. The patients need some method of tumor control while waiting. In this situation, resection or ablation should be considered. For patients with normal synthetic function and small tumors, there is some evidence that resection may be better than ablation.30 Careful follow-up should be performed and recurrences ablated as they appear. With some luck, this should allow diseasecontrol until an organ becomesavailable. An alternative strategy of resection with transplantation for those patients who

TRANSPLANTATION

FOR HEPATOCELLULAR

501

CARCINOMA

have recurrent disease has been proposed.12 The success of this strategy is dependent on having the patients who recur after resection being salvaged by transplantation. The true probability of this is unknown, and a strategy of transplanting patients before recurrence seems to be a reasonable compromise. In the future, hopefully a new set of treatments will emerge that will decrease the incidence of HCC. First, vaccination to prevent HBV has already demonstrated a positive effect on the incidence of HCC.43 Interferon may play an important role in controlling HCC in patients infected with HCV,44 as it may be able to reduce the risk of recurrence after liver resection or ablation in these patients.45 Additionally, an acyclic retinoid, polyprenoic acid, has been shown to decrease recurrence and improve survival after tumor ablation.ii,46 If these studies can be replicated with a larger number of patients, the outcome of resection may improve substantially, shifting the therapeutic balance from transplantation to resection.

12. Majno resection plantation

PE, Sarasin

and salvage in patients

noma

and

cision

analysis.

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S, Haim

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