Liver resection and liver transplantation are the

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1 Surgery and Transplantation for Hepatocellular Cancer William J. Wall * and Paul J. Marotta Key Points 1. Curative treatment of hepatocellular carcinoma (HCC) depends on early diagnosis. 2. The cure rate for operable HCC occurring in the absence of cirrhosis is only 10% to 25%. 3. Features of HCC in patients with cirrhosis that are associated with a 5-year survival rate of 75% after liver transplantation include (1) solitary tumor less than 5 cm; (2) 3 or fewer tumors, each less than 3 cm; and (3) absence of vascular invasion. 4. Advanced cirrhosis limits the widespread application of partial hepatectomy to patients with HCC. 5. Neoadjuvant therapy has not yet been proven to improve patient outcome for early-stage HCC that is promptly treated by transplantation. (Liver Transpl 2000;6:S16-S22.) Liver resection and liver transplantation are the treatments of choice for patients with hepatocellular cancer (HCC). When there is no underlying liver disease, partial liver resection is the preferred option. However, HCC commonly occurs in cirrhotic livers, and impaired hepatic reserve often precludes safe partial hepatectomy. Total hepatectomy with transplantation was expected to be the solution to HCC in cirrhotic livers when partial hepatic resection was not feasible. This approach was also used for unresectable tumors in noncirrhotic livers. Experience from single centers and registry data have shown that only early-stage cancer has a high likelihood of cure when treated by total hepatectomy with transplantation. In this report, we discuss the surgical management of HCC in patients with and without cirrhosis. HCC With Cirrhosis Screening practices are now identifying more cancers in patients with cirrhosis for whom either hepatic resection or transplantation are potentially curative options. From the *Multi-Organ Transplant Program and Liver Transplantation, University of Western Ontario, London Health Sciences Centre University Campus, London, Ontario, Canada. Address correspondence to William J. Wall, MD, FRCS(C), Professor of Surgery, University of Western Ontario, Multi-Organ Transplant Program, London Health Sciences Centre University Campus, 339 Windermere Rd, London, ON N6A 5A5, Canada. Telephone: ; FAX: ; william.wall@lhsc.on.ca Copyright 2000 by the American Association for the Study of Liver Diseases /00/ $3.00/0 doi: /jlts A huge emphasis has been placed on imaging techniques to accurately stage the tumors. Concurrently, there has been a marked trend to use neoadjuvant chemotherapy, especially for patients with HCC who are deemed candidates for transplantation. Most centers use a combination of abdominal ultrasonography and serial alphafetaprotein (AFP) levels to screen for HCC. Sensitivity for detecting HCC ranges from 39% to 64%, and specificity ranges from 76% to 91% when AFP levels exceed 20 ng/ml. 1,2 Sensitivity and specificity for ultrasonography have been reported to be 78% and 94% when the tumor was greater than 2 cm in diameter. 2,3 When either AFP level or ultrasonography suggests a tumor, contrast-enhanced computed tomography (CT) with dual-phase imaging should be used to define the size, number, and location of the lesions. 4 When combined with hepatic angiography, the accuracy of identifying small tumors is increased. 5,6 Magnetic resonance imaging has not been used as extensively as the other imaging modalities, but it can detect tumors less than 2 cm in diameter in a high percentage of cases. 7 Lipiodol CT has a greater accuracy for tumor identification than either CT or angiography alone. 8,9 Unfortunately, none of the imaging modalities is perfect, and even with multiple investigations, comparison of the imaging studies with pathological tumor assessment after removal shows that tumors are understaged preoperatively in 25% or more of the cases. 10 Therefore, it is not uncommon for surgery to be performed for lesions that ultimately prove to be more extensive than indicated by preoperative investigations. It has become common practice to use the tumor, node, and metastasis (TNM) classification to define the pathological extent of HCC (Table 1). 11 The primary tumor is defined by the size, number, and location of the tumor nodules in the liver and the presence or absence of vascular invasion. Node involvement and the presence or absence of distant metastases are determined preoperatively or at pathological examination. The International Union Against Cancer (UICC) has used the TNM system to stage HCC as listed in Table Although the TNM classification is useful in its uniformity, when only early tumors are selected for treatment by transplantation, the classification fails to correlate with prognosis. The 2 prognostic factors in the TNM classification that dominate over all others are node involvement and metastatic spread. When tumors in those stages are deliberately excluded from therapeu- S16 Liver Transplantation, Vol 6, No 6, Suppl 2 (November), 2000: pp S16-S22

2 Surgery and Transplantation for HCC S17 Table 1. TNM Classification of HCC T: primary tumor T1: solitary, 2 cm, without vascular invasion T2: solitary, 2 cm, with vascular invasion; solitary, 2 cm, without vascular invasion; multiple, 1 lobe, 2 cm, without vascular invasion T3: solitary, 2 cm, with vascular invasion; multiple, 1 lobe, 2 cm, with vascular invasion; multiple, 1 lobe, 2 cm, with or without vascular invasion T4: multiple, 1 lobe; invasion of major branch of hepatic or portal veins N: hilar lymph nodes N0: nodes negative N1: nodes positive M: distant metastasis M0: no distant metastasis M1: distant metastasis (e.g., lung, bone) tic considerations, the TNM classification is restricted to primary tumor characteristics and loses its discriminatory ability to predict outcome. 10,13 For example, ample evidence shows that increasing tumor size beyond the 2-cm designation of the TNM classification influences prognosis. Registry data and reports from single centers have shown correlations between 5-year patient survival rates and tumor diameters of 3, 4, 5, and 8 cm. 14,15 It is arguable whether a tumor of any size with lymph node involvement (stage IIIB) should be assigned a lesser stage than 2 small tumors that involve both hepatic lobes (stage IVA). Cure is possible after transplantation in the latter situation, but virtually nonexistent in the former. 10,16 Until a better classification is developed, the TNM system should continue to be used, but additional primary tumor features, i.e., size, should also be recorded. Restricting candidacy to tumors believed to be in their early stages has resulted in survival rates after liver transplantation that approximate those achieved by grafting for nonmalignant disease. 10,13,17,18 Studies suggest that transplantation candidacy should be restricted to patients with tumors with the following favorable characteristics: (1) 5 cm if single; (2) 3 cm if multiple, with 3 or fewer lesions; and (3) no gross vascular invasion. Using these criteria, 5-year actuarial patient survival rates after liver grafting in patients with cirrhosis are approximately 75%. 10,13,17,18 The patient survival rates firmly establish the therapeutic role of liver grafting for HCC when rigid selection criteria are applied. Adjuvant and Neoadjuvant Chemotherapy At the same time that the need to restrict selection criteria for HCC for transplantation was recognized, reports of adjuvant chemotherapeutic regimens in transplant recipients appeared that seemed promising. The rationale for systemic chemotherapy is rooted in the observation that HCC recurrence after grafting frequently involves the graft. In addition, malignant cells have been recovered from the portal vein and right atrium during partial liver resection for HCC. 19,20 An assumption can be made that undetectable micrometastases are already present at the time of surgery in many patients, or malignant cells are liberated into the circulation during the surgery. In both cases, perioperative chemotherapy to kill micrometastases has conceptual appeal. The results of several small pilot series of adjuvant systemic chemotherapy are listed in Table Mainly doxorubicin, cisplatin, fluorouracil, and mitoxantrone were used. Impressive 3-year actuarial patient survival rates of 46% to 64% were reported, considerably better than those in historical series of patients who received transplants for HCC. It should be emphasized that patients with either lymph node metastases or evidence of tumor outside the liver were excluded as candidates. This contrasts with historical series that commonly included significant numbers of patients with advanced tumors, i.e., stages IIIB, IVA, and IVB. The exclusion of more advanced cancers from these pilot series makes it impossible to conclude that adjuvant chemotherapy accounted for the improved survival rates. Nevertheless, as a result of these studies, much Table 2. UICC Staging of HCC Based on the TNM System Classification T N M Stage I T1 N0 M0 II T2 N0 M0 IIIA T3 N0 M0 IIIB T1 N1 M0 T2 N1 M0 T3 N1 M0 IVA T4 Any N M0 IVB Any T Any N M1 Abbreviations: UICC, International Union Against Cancer; T, primary tumor; N, hilar lymph nodes; M, distant metastasis.

3 S18 Wall and Marotta Table 3. Liver Transplantation and Adjuvant Chemotherapy for HCC Reference Year No. of Patients Treatment Stone et al Doxorubicin pre-, intra-, and postoperatively Carr et al Intra-arterial doxorubicin and cisplatin preoperatively, systemic postoperatively Cherqui et al Chemoembolization preoperatively with doxorubicin, radiotherapy, mitoxantrone systemically postoperatively Olthoff et al Systemic fluorouracil, doxorubicin, and cisplatin postoperatively * Number of patients listed in parentheses. Either tumor or whole-liver chemoembolization. TNM Tumor Classification* II (6), III (3), IVA (11) III (5), IVA (5), IVB (1) II (1), III (1), IVA (7) I (1), II (5), III (8), IVA (11) Actuarial Patient Survival (%) 59 (3 yr) 91 (1 yr) 64 (3 yr) 46 (3 yr) interest was generated in neoadjuvant and adjuvant chemotherapy. To avoid the toxicities of systemic chemotherapy and deliver the maximum tumoricidal dose of drug, there has been a definite trend toward the use of transarterial chemoembolization (TACE) in patients with HCC before transplantation. Simultaneous, embolization of the tumor with chemotherapy administration enhances tumor necrosis. 26 However, comparing results in which similar criteria were used for selecting patients with early HCC for grafting, good 5-year survival rates (71% to 79%) and low 5-year cancer recurrence rates (3.5% to 8%) have been recorded regardless of whether TACE was performed 10,13 (Table 4). It is clear that for patients who have early HCC and undergo liver transplantation promptly (within 2 months), there is no proven benefit to date of either systemic or selective chemotherapy perioperatively. The true role of neoadjuvant chemotherapy may be in those patients who wait for long periods before transplantation. Data from Barcelona recently showed that nearly one quarter of the candi- Table 4. Results of Liver Transplantation for Early HCC Reference Year No. of Patients Venook et al Tumors, none 5 cm Romani et al cm found on screening Mazzaferro et al cm if single, 3 cmif multiple, not 4 lesions Tumor Characteristics Neoadjuvant Therapy Patient Survival TACE (doxorubicin, cisplatin, mitomycin) TACE (doxorubicin), 3 patients; ethanol injection, 1 patient TACE (doxorubicin ormitoxantrone), 26 patients; ethanol injection, 1 patient Figueras et al cm, localized TACE (doxorubicin) in 31 patients Llovet et al cm solitary, None no vascular invasion 10/13 Disease free at median of 40 mo 71% (3 yr) 75% (4 yr) 79% (5 yr) 74% (5 yr)

4 Surgery and Transplantation for HCC S19 dates dropped out from the waiting list because of tumor progression (none was administered neoadjuvant therapy) during the waiting period when the average waiting time increased to more than 5 months. Therefore, the true value of TACE may be in the prevention of tumor progression during the waiting period. Also, neoadjuvant chemotherapy could downstage the cancer and increase the chance for cure. The latter point will be difficult to prove because of the relative inaccuracies of preoperative imaging. 27 Resection Versus Transplantation for HCC No randomized, controlled trials compare resection with transplantation for HCC. In general, when tumors are judged to be totally removable by partial hepatectomy and the underlying cirrhosis does not preclude resection with an acceptable mortality (Child s class A), resection has been regarded as a reasonable option. Conversely, if multiple lesions are present and their location or the severity of cirrhosis (Child s class B or C) precludes removal by either anatomic or nonanatomic resection, transplantation has been offered. Liver resection can be performed without delay after HCC is diagnosed, but it is associated with a high recurrence rate, whereas liver transplantation has better long-term survival in selected patients, but it is not readily available because of the shortage of donor livers. Most believe that liver transplantation is the best therapy for early HCC, but better intention-to-treat results can be obtained with resection in properly selected patients when the dropout rate associated with patients awaiting transplantation is taken into account. 27 In addition, there is an economic benefit to immediate resection if the wait for liver transplantation exceeds 6 to 10 months. 28 The debate over the appropriateness of hepatic resection versus transplantation for HCC in patients with cirrhosis who satisfy selection criteria for either surgery cannot be resolved without a randomized trial. Such a trial is unlikely to be completed because of the large number of cases that would be required and the need to stratify for stage, chemotherapy, and waiting time. The results from 7 centers that reported their experiences with resection and transplantation for HCC are listed in Table 5. 27,29-34 In every series, the decision to resect or transplant was related to tumor extent, severity of the underlying cirrhosis, and philosophical biases favoring 1 treatment over the other. Other variables, such as patient age, cause of cirrhosis, and comorbid disease, contribute to the extreme heterogeneity of the cases at the different centers. It may be meaningless to compare the results among centers, but based only on survival rates, arguments can be made for either transplantation or resection. Three-year patient survival rates after transplantation vary from 18% to 69%, whereas the survival rates after resection range from 31% to 51%. In some centers, neither treatment had superiority over the other. From an oncological viewpoint, the HCCs most suitable for resection are the same tumors that should have the best results when treated by transplantation, i.e., small localized tumors. Thus, reserving transplantation for more advanced tumors is illogical. At the same time, the inability to offer transplantation as an immediate treatment jeopardizes the outcome in some patients. Although still under evaluation, adult living donor liver transplantation (LDLT) is emerging as a therapeutic option. If the donor safety of LDLT can be ensured, application of LDLT to patients with cirrhosis with early HCC may be a solution to the donor shortage that could improve survival for this group of patients. However, current selection criteria identify suitable donors in only 15% to 25% of the potential Table 5. Resection Versus Transplantation for HCC 3-Year Actuarial Survival Rates Reference Year No. of Patients Resection (%) Transplantation (%) Ringe et al Iwatsuki et al Bismuth et al Tan et al Michel et al * Otto et al Llovet et al * Includes patients from 6 centers in France.

5 S20 Wall and Marotta recipients, limiting the ultimate impact of LDLT on mortality from HCC in patients with cirrhosis. An argument that favors transplantation is the high rate of cancer recurrence or new cancer development in the remnant liver after partial hepatectomy (20% per year). 35 Although transplantation also cures the underlying cirrhosis, this has to be considered in light of the fact that cirrhosis from chronic hepatitis C is now the main indication for hepatic transplantation in adults in most centers, and the graft invariably becomes infected with the hepatitis C virus. The appearance of a de novo HCC in a transplanted liver that developed recurrent hepatitis C was reported. 36 Therefore, the argument that transplantation removes the malignant potential of the cirrhotic liver may lose its validity for transplant recipients who have HCC superimposed on chronic hepatitis C. HCC Without Cirrhosis Patients with HCC who do not have cirrhosis usually present with upper abdominal pain, weight loss, and malaise. Unfortunately, the mere presence of symptoms usually indicates the tumors are advanced at the time of presentation, and surgical approaches with curative intent are not possible in the majority of patients. Partial hepatectomy is the preferred treatment for tumors that are grossly confined to the liver and have an anatomic location, regardless of size, that permits complete excision even if an extended lobectomy is required. The surgical mortality rate for major partial hepatectomy should be less than only 1% to 2% when there is no cirrhosis. Despite excision of the gross tumor, recurrence is common. Five-year survival rates of 25% after resection are reported. 37 Risk factors for recurrence are tumor size, multifocality, inadequate surgical margins, and capsular and vascular invasion. When tumors are too extensive to be completely excised without removal of the entire liver, patients are often referred for consideration of transplantation. During the early years of liver grafting, almost 1 of 3 transplant recipients had a malignant condition The radical nature of total hepatectomy and liver replacement was appealing from an oncological perspective, but it proved to be biologically inadequate treatment for most malignancies. Most patients died of recurrent malignancy within 2 years, with the lungs and liver graft frequent sites of recurrence Registry data reported a 5-year overall survival rate of only 18% in patients with advanced HCC treated by transplantation. 46 The poor results coincided with the introduction of cyclosporine and the shortage of donor organs, which forced transplant specialists to face the reality that transplantation could not be justified as palliative treatment of malignancy. A recent analysis of 16 reported series in the literature has shown that transplantation for HCC in patients without underlying liver disease has only a small chance of cure, undoubtedly because of the advanced stages of the cancers. 47 Tumor sizes ranged from 7 to 24 cm in diameter. The 5-year survival rate of 77 collected patients without cirrhosis who underwent transplantation for HCC was only 11.2%. Such a low survival rate has convinced most surgeons that transplantation is not appropriate treatment for HCC in a noncirrhotic liver that cannot be removed by subtotal hepatic resection. Although there are anecdotal cases of cure of very large hepatocellular malignancies by transplantation, they are so infrequent that it is difficult to defend transplantation for this condition Fibrolamellar Variant of HCC The fibrolamellar variant of HCC is an uncommon, less-aggressive cancer that tends to occur in younger patients, usually in the absence of cirrhosis. 48 The tumors are often bulky and may extend into adjacent structures when first diagnosed. Despite those inherently undesirable features, an aggressive approach toward surgical resection of the tumor and contiguous structures yields good results Even repeated surgery with removal of recurrent localized disease can be associated with very long tumor-free survival. Data from the Cincinnati Tumor Registry showed a 5-year actuarial survival rate after transplantation of 55% for this tumor. 10 A 5-year actuarial survival rate of 48.8% has been reported from Hanover, Germany. 50 In the largest series of cases from the University of Pittsburgh, 41 patients with fibrolamellar HCC were treated by either resection or transplantation. 51 The vast majority of the tumors were advanced TNM stage IVA or IVB, and one third of the patients required resection of adjacent organs. The 10-year actuarial patient survival rates were 70% for resection and 28% for transplantation. The inferior results with grafting were caused by the selection of more advanced tumors for treatment by that modality. Thus, aggressive surgical approaches should be taken for these tumors, but transplantation for advanced tumors is unlikely to be curative. The Future The number of patients in need of life-saving liver transplantation is rapidly increasing, whereas the cur-

6 Surgery and Transplantation for HCC S21 rent supply of donor organs makes it impossible to meet the demands. Patients with nonmalignant diseases are already overwhelming transplant waiting lists, and significant increases in the numbers of patients with HCC found on screening will add to waiting lists and waiting times. Thus, transplantation cannot be considered the solution for all patients with HCC, even if candidacy is restricted to the favorable tumors. If adjuvant therapy was so effective that patients with more advanced tumors could be cured by transplantation, the burden on the waiting list would worsen. LDLT offers the opportunity for timely expedient transplantation. However, using current selection criteria, suitable living donors can only be identified for 15% to 25% of potential recipients. 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