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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Hepatocellular cancer: resection or transplantation

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The Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom

Resection or transplantation for hepatocellular carcinoma

Worldwide, hepatocellular carcinoma (HCC) is one of the most common cancers, and remains a leading cause of death. Whereas its incidence in many parts of Africa and the Far East is extremely high, and correlates with the geographical distribution of hepatitis B and C (increased risk × 100), the prevalence in Europe and North America is much less. However, its incidence is undoubtedly rising, with the spread of hepatitis C, although alcohol and haemochromatosis probably also play an important role (Columbo 91; De Boc 94; Curly 1995). A combination of alcoholic liver disease and hepatitis C appears to be a particularly dangerous situation, and of course in Africa the alflatoxins contribute to the development of HCC. (Table II)

Table II. Screening for hepatocellular carcinoma.

Table II

Screening for hepatocellular carcinoma.

Survival of patients with HCC not subjected to surgical intervention is generally less than 6 months, and even with treatment less than 5% of patients survive over 5 years.

Surgical removal of the tumor remains the only realistic treatment offering the prospect of cure for hepatocellular cancer. This may be achieved, either by hepatic resection or complete hepatic removal with liver replacement, i.e. liver transplantation. Of course, those parts of the world with the highest prevalence of hepatocellular cancer are areas where transplantation is rarely possible. In this brief report we review the role of these two treatment modalities in the surgical management of hepatocellular cancer, although recognizing that no prospective randomized trials have been undertaken.

One of the principle determinants affecting outcome is the stage of disease, and the early detection of HCC improves resectability rates. Patients at high risk of developing HCC, especially those with HBV and HCV infection and cirrhosis should undergo routine surveillance, and in communities that have initiated this using alphafetoprotein screening and ultrasound, an increasing number of “small tumors” has been diagnosed (Lee 86; Sheu 85). Indeed, in a patient with cirrhosis the presence of a lesion on ultrasound and an alphafetoprotein of > 1000 is virtually diagnostic of HCC. Unfortunately, a significant proportion of HCC patients do not have elevated alphafetoproteins, and in fibrolamellar tumors, AFP is often normal. In equivocal patients a Lipiodol arteriogram may be needed, and indeed supplemented with CT or MRI scanning. A routine percutaneous biopsy is not recommended because of the risks of tumor seedling, although biopsy of the “normal liver” may be required to assess the degree of cirrhosis (Table II).

For HCC in otherwise normal liver; i.e., without underlying cirrhosis resection if anatomically feasible, remains the mainstay treatment option. In such patients, up to 75% of liver tissue can be removed with relatively low morbidity ensuring adequate tumor clearance (Fan 99). Long-term 5 year survival rates of 40–50% with peri-operative mortality < 5% have been reported by a number of centers (Table III).

Table III. Hepatocellular cancer evaluation.

Table III

Hepatocellular cancer evaluation.

Survival depends on three key factors: Firstly, the stage of the tumor, minimal to moderate disease (stage I and II) confined within the liver is associated with the best long-term outcome. Size of the tumor appears to be an important prognostic factor for recurrence-free survival. Survival after liver resection appears to be better for small (< 5 cm) solitary tumors with negative resection margin and an absence of vascular invasion (Vauthey 95).

At present, liver transplantation does not have an established role in the treatment of HCC in a non-cirrhotic liver. Curative resection of small HCCs (< 5 cm) is associated with good long-term prognosis, and also avoids the morbidity of long-term immunosuppression. (Historically, malignancy used to be a major indication for liver replacement). Our initial philosophy in the 1970s and 1980s was to resect tumors which could be resected, and to transplant those not amenable to resection. The results of liver transplantation for such advanced HCCs were extremely poor, with only 25% of patients alive 2 years post-operatively, and none at 5 years (Ismail 90). Equally disappointing results were reported by other centers (Ringe 91;Iwatsuki 91).

It could be argued that transplantation for advanced HCCs should be regarded as palliative treatment only, offering improved life quality and extended survival compared with the natural course of the disease. However, with uniformly poor results and donor organ shortage such an approach is not justified at present.

There have, however, been no prospective randomized trials to compare resection with liver transplantation.

Tumors developing in non-cirrhotic liver account for only a small proportion of HCCs. Liver cirrhosis is present in up to 90% of patients with HCC (Kew 84; Kinami 86; Bismuth 86), and the optimal surgical approach in cirrhotics is difficult to determine as it depends not only on the stage of the tumor but also the second critical factors, the liver functional reserve, and thirdly, the patient's viral status (Table IV).

Table IV. Liver transplantation for HCC in cirrhotic livers.

Table IV

Liver transplantation for HCC in cirrhotic livers.

In South-East Asia, small (< 5 cm) tumors are regularly resected in compensated Child's A patients with the reported 5 year survival rates between 25–67%, provided that adequate resection margins have been achieved (Yamasaki 91).

The results of liver resection for HCC tumors associated with cirrhosis appear generally better in Japan (26% 5 year survival) than in Europe (10% 5 year survival), although the cause of death is often progression of the liver disease and hepatic failure rather than recurrence.

The result appears to be determined by both the likelihood of cancer recurrence and the functional stability of the cirrhotic liver. Size of the tumor (> 5 cm), presence of multifocal disease and vascular invasion increase the risk of HCC recurrence after liver resection (Nago 86;Pichlmayr 88). However, as 10–20% of patients with cirrhosis and a “small HCC” have multicentric disease not apparent on the pre-operative imaging (Belli 89), and vascular invasion is often present microscopically even in many clinically localized HCCs (Yokoyama 91), tumor recurrence may occur. Furthermore, an unstable liver cirrhosis may be regarded as a “premalignant disease”, and liver resection leaves behind the disease organ, often with an element of hepatocytic dysplasia, and this may lead to the development of metachronous lesions (Gores 93). In patients with chronic viral infection, HCC recurrence may result in multifocal carcinogenesis (Saiho 96).

HCC developing after liver resection may therefore represent either progression of previously undiagnosed disease, or de novo lesions developing in “unstable” residual liver.

In patients with cirrhosis, liver function determines both the extent of liver which can be removed, and the risk of surgery (Cheng-Chung 96), with operative mortality in the presence of cirrhosis significant, at 14% (Vauthey 95).

Patients should therefore be evaluated, and their liver function assessed. Criteria for irresectability include hepatic encephalopathy, refractory ascites and gross impairment of synthetic function (Huguet 92), i.e. advanced cirrhosis. Whereas individuals with well-compensated cirrhosis (Child's A) tolerate hepatectomy relatively well. In those with Child's B and C cirrhosis, major hepatic resection is dangerous, and residual live tissues should be preserved by using segmental or non-anatomical resection. In Child B and C Cirrhosis patients usually only peripherally situated tumors can be resected with adequate tumor clearance and acceptable mortality. Postoperatively, progression of liver disease has significant adverse effect on long term survival. High rates of death due to liver failure in patients free from recurrent tumor have been reported from both Japan and Europe. Less than 25% of patients with Child's group B or C are expected to be alive 5 years postoperatively, with as many having succumbed to complications of cirrhosis as to tumor recurrence (Nagasue 93) (Table V.)

Table V. Surgical options in HCC.

Table V

Surgical options in HCC.

It can therefore be argued that many cirrhotics would be best treated with liver transplantation, which removes not only the tumor but the diseased liver thus preventing both late liver failure and recurred or de novo HCC.

Such an option would, however, be inappropriate in patients with active alcoholism, and careful consideration is needed in patients with underlying viral hepatic disease, which may lead to recurrent hepatitis, post-transplantation cirrhosis and graft failure.

The results of liver transplantation for HCC as the primary indication is difficult to evaluate in the absence of proper prospective trials. Most reports include patients with HCC in non-cirrhotic livers, as well as those with “incidental tumors” in cirrhotic levels. Tumor stage is probably the most important prognostic factor related to early recurrence. The results of liver transplantation for small (< 5 cm) HCCs in cirrhotic patients are good, although hospital mortality in patients with decompensated liver function (Child's group B and C) appears to be relatively high (11%) (Romani 94). However, both patient survival and recurrence-free survival rates are noticeably lower in patients with more advanced large tumors (McPeake 93; Mazzaferro 96). Accurate staging including tumor size, multifocality, vascular involvement and extrahepatic disease is essential to identify those patients who are most likely to benefit from long-term survival without tumor recurrence, (Table VI.)

Table VI. Liver transplantation - HCC.

Table VI

Liver transplantation - HCC.

Some centers have been using adjuvant chemotherapy in order to improve the outcome of liver transplantation for more advanced HCC. Stone et al. (93) reported actuarial survival of 59% and tumor-free survival of 54% at 3 years in patients with large HCCs (> 5 cm, multifocal disease and vascular invasion) treated with Doxorubicin. These results are encouraging, though the protocol has to be regarded as experimental, and its long-term benefits remain to be fully evaluated.

The severe shortage of donor organs inevitably influences the decision process.

Few comparative studies on the outcome of liver resection and transplantation for HCC have been published. Data reported by Bismuth (93) suggest that although 3 year overall survival rates are similar (50% and 47%), however, disease-free survival may be better in patients who have been transplanted (46% versus 27%). However, patient selection may have significantly influenced the outcome.

In subjects with viral hepatitis, reinfection of the graft with HBV or HCV is a common problem. The possibility of subsequent liver failure may limit application of transplantation in this group of patients.

Lamivudine is a new nucleoside analogue with potent antiviral effects against HBV. The study of Bain et al. (96) shows that Lamivudine can effectively inhibit HBV in cirrhotic patients pre-transplant and post-transplant.

Transplant recipients with actively replicating HBV-related cirrhosis may achieve a good outcome after liver transplantation using Lamivudine, but viral resistance is likely to be a significant problem. Also in the study of Grellier and Mutimer et al. (96) passive immunoprophylaxis with HBIg has been shown to decrease the rate of recurrence to 25–50%. In the study carried out by Nymannt et al. (96) they concluded that HBsAg positive patients can be safely transplanted using indefinite, high dose HBIg prophylaxis and it is possible to prevent recurrence in HBV DNA positive patients as well. However, levels of antibody must remain high. The recurrence of HBsAg decreased from 70–100% to between 23–48% (Nymannt et al – 96).

These problems are associated with the use of HBIg for post-transplant prophylaxis: first, intravenous administration with the risk of allergic reaction; second, drug clearances after transplantation are complex, and costly maintenance therapy is required; and third, HBIg is produced from pooled human blood so there is a risk of virus transmission (Grellier et al - 96).

Until conclusive data is available, patients with hepatitis B infection, particularly HBV DNA positive, should be offered transplantation on an experimental basis. Hepatitis C virus is also a major long-term concern after transplantation. Reinfection of the donor liver occurs in virtually all patients with viremia prior to transplantation. No truly effective HCV-specific treatment has been available, but limited success has been achieved with Interferon therapy.

However, recurrent hepatitis C progresses relatively slowly, and clinical manifestation of liver impairment is uncommon during the first 5 years after transplantation (Fishman 96). Therefore, underlying HCV cirrhosis should not be considered as a contraindication to liver transplantation for HCC.

Conclusions

Outcome of surgical treatment for HCC is influenced by the ‘stage’ of the tumor, ‘stage’ of underlying liver disease and, in patients with viral hepatitis ‘stage’ of infection. Therefore, choice of optimal treatment is determined by a careful evaluation of all three variables.

Stage I and II HCC in non-cirrhotic livers are best treated by formal resection. Because the prospect for the underlying liver is good, resection for advanced disease (large tumor, multifocal lesions or vascular improvement, or extra-hepatic spread), with or without underlying cirrhosis, has been associated with very poor long-term results. Because of high recurrence rates, liver transplantation cannot be considered as a curative treatment in such cases, and with the shortage of donor organs it will rarely be recommended as a palliative measure. It remains to be determined whether the development of effective adjuvant chemotherapy could improve the outcome of liver resection and transplantation for advanced HCC.

“Small” tumors in patients with underlying cirrhosis, in a society where transplantation is not available, will be treated, where possible, with liver resection. Hepatectomy in patients with well-preserved liver function (Child's group A) has been associated with relatively good outcome, at least in the medium term.

However, recurrent tumor and progressive decompensation of liver function have a significantly adverse effect on long-term survival.

Liver resection in patients with poor functional reserve (Child's group B and C) may be associated with significant mortality and reduced survival due to progressive liver failure, and will usually be confined to limited resection of peripheral tumors. For small cirrhosis-related HCCs, liver transplantation offers better long-term prospects of cure than resection, as transplantation removes the entire diseased and potentially carcinogenic organ, restores normal liver function, and in the case of a centrally situated lesion, allows adequate removal of tumors not amenable to resection.

Therefore, if liver transplantation is available as an option it should be considered as the treatment of choice in Child B and C, particularly for younger patients with otherwise good life expectancy.

It could be argued that long-term immunosuppression would accelerate tumor recurrence. However, to date experience suggests better disease-free survival occurs after transplantation rather than liver resection (Bismuth 93).

Patients with active virus-induced cirrhosis are at risk of recurrent hepatitis leading to graft cirrhosis and failure. No effective treatment for hepatitis C is as yet available. However, the progress of recurrent HCV hepatitis is relatively slow with late clinical manifestation of the disease (95% 5 year survival - Birmingham 96). Therefore, HCV infection should not be considered a contraindication to liver transplantation. Recurrence of hepatitis B, particularly in HBV DNA positive patients, is often aggressive with progression to cirrhosis. Long-term efficacy of Lamivudine in prevention of hepatitis B recurrence after liver transplantation is urgently being investigated and hyperimmune globulin may be effective (Table VII).

Table VII. Treatment outcome in relation to liver disease.

Table VII

Treatment outcome in relation to liver disease.

Image ch40f1.jpg

Table I. Liver disease and risk of HCC cross sectional studies proportion of patients with HCC by etiology of liver disease in Europe.

Table I

Liver disease and risk of HCC cross sectional studies proportion of patients with HCC by etiology of liver disease in Europe.

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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6871

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