Surgery for hepatocellular carcinoma
Dr KC Tan, Gleneagles Medical Centre, 6 Napier Road, Suite #04-14/15, Singapore 258499. Email: email@example.com
Abstract Today there is an array of therapeutic modalities available for the patients with hepatocellular carcinoma (HCC). However, surgery, be it resection or transplantation, offers the only hope of long-term disease-free survival. Unfortunately, because the majority of HCC in Asia is associated with cirrhosis, surgical resection is restricted to only a small proportion of these patients. However, in selected candidates resection may offer a 5-year survival of up to 70%. With the clinical application of adult-to-adult living donor liver transplantation, an increasing number of patients with small HCC and decompensating cirrhosis are undergoing transplantation.
© 2002 Blackwell Publishing Asia Pty Ltd
Hepatocellular carcinoma (HCC) remains one of the most common malignant tumors in Asia. Due to the prevalence of viral hepatitis, more than 80% of HCC in Asia is associated with cirrhosis. Like most cancers, early detection is elusive yet crucial for successful treatment. However, unlike most solid organ cancers where the tumor and its extent determine the treatment and prognosis, in HCC the management and outcome are greatly affected by the associated liver cirrhosis. Not infrequently, the cause of death is due to the cirrhosis and its sequelae rather than the tumor. Until recently, due to the shortage of cadaveric donor livers in Asia, the only surgical option for the patient with HCC was resection. Unfortunately, surgical resection is possible only in <10% of patients due to late diagnosis and associated cirrhosis. With the recent development of adult-to-adult living donor liver transplantation (ALDLT), an increasing number of patients with HCC and cirrhosis are undergoing transplantation.
Resection for hepatocellular carcinoma
With improved surgical techniques and better perioperative management, extensive resections of very large HCC are being performed with low morbidity and mortality.
The main factor determining resectability is the presence of cirrhosis and the degree of liver dysfunction. It is extremely important to determine the liver reserve and, in particular, its relation to the extent of surgical resection. In Asia, surgeons often use Indocyanine green retention rate to assess liver function;1,2 however, the group in Barcelona have used portal pressure and bilirubin as parameters to select candidates for resection.3,4 In their series, patients without clinically relevant portal hypertension (CPRH) and normal bilirubin have a 75% survival rate 5 years after resection. This decreased to 50% in the intermediate group (with CPRH and normal bilirubin) and to 25% in the poor candidates (with CPRH and raised bilirubin).
Therefore, surgical resection is most useful for the patient with HCC without cirrhosis and those in whom the cirrhosis is well compensated. Recurrence rates are high and can range from 47% at 3 years5 to 100% at 5 years6 due to the multifocality of HCC in cirrhosis.6,7 In addition to tumor size (>5 cm), increased risk can be predicted by pathologic findings of poor differentiation, satellites and vascular invasion. The patients should be closely followed up with repeated scans and α-fetoprotein measurement. Because the majority of the recurrences are intrahepatic, transarterial chemoembolization and repeated resections should be performed8 if liver reserve and clinical condition permit.
Transplantation for hepatocellular carcinoma
For the patients with HCC and decompensating cirrhosis, total hepatectomy and transplantation should be the treatment of choice. Only orthotopic liver transplantation (OLT) has the potential to cure both the tumor and cirrhosis. The early results of OLT for HCC were disappointing because of the high rates of perioperative mortality and tumor recurrence. A 75% recurrence rate with a 25% 3-year survival was reported from Pittsburgh.9 The Cincinnati Transplant Tumor Registry reported a disappointing 18% 5-year survival.10 These results were not acceptable given the high cost of the procedure and the limited resource of suitable donor livers. It was clear that many of the patients with recurrences underwent transplants with tumors that were deemed too large to be resected. Often these tumors were complicated by vascular invasion and lymph node metastasis. The observation that small incidental HCC is associated with low tumor recurrence rate provided the impetus to perform transplants in patients with small HCC.11–13 With the improvement in perioperative survival rate coupled with better case selection, tumor-free survival was significantly improved. The Mazzafero criteria of solitary tumors not exceeding 5 cm and no more than three tumors with none greater than 3 cm13 are widely used as a guideline for selection of candidates for OLT. They reported a 4-year overall and tumor-free survival rates of 85% and 92%, respectively. By re-stricting OLT to candidates with early stage tumors, survival rates have approached that of patients with non-malignant disease.14 Recently, Yao et al. have suggested that the Mazzafero criteria may be too stringent. In their series of 70 consecutive patients in which tumor size limits were expanded, survival was not adversely affected.15 Patients with solitary tumor <6.5 cm and no more than three nodules with the largest <4.5 cm and total tumor diameter <8 cm, had survival rates of 90% and 75.2% at 1 and 5 years, respectively. This appears to provide support to earlier studies that satisfactory patient survival can be achieved with more liberal criteria for selecting candidates with HCC for OLT.16,17 Clearly, factors other than tumor burden (size and number) may be important in determining recurrence and outcome after OLT and remain to be studied.
The greatest limitation to expanding the usage of OLT for patients with HCC is the severe shortage of suitable donor livers worldwide. The average waiting period in the West for most blood types is more than a year.15 Given the rapid progression of the disease, including vascular invasion and extrahepatic spread within the year,18 many initial candidates will become ineligible for OLT. Many centers have adopted aggressive pretransplant antitumor treatment that includes trans-arterial chemoembolization as a ‘bridge’ to OLT.19–21 In addition to tumor control, the other rationale for this approach is the elimination of tumor cells that may be shed during surgery and the presence of micrometastases. Results have appeared promising but the series was small and not randomized.
Recent studies have shown that the superiority of OLT as a treatment option for patients with HCC and cirrhosis is significant only if the waiting period for a suitable donor liver is short.4,22 In an intention-to-treat analysis for early HCC, Llovet et al. found that if the waiting period is more than 6 months, the outcome was significantly worse than that of resection for the best candidates.4 This is due to almost 25% of the patients becoming ineligible due to progression of their disease during the waiting period. The situation is even more serious in the rest of Europe and the USA, with their longer waiting period and higher dropout rate.23,24
Today ALDLT has been shown to be a feasible alternative to cadaveric OLT.25–27 In the West it has been estimated that ALDLT could ultimately benefit 20% of candidates.28 In Asia, almost all liver transplants are being performed with a graft from a living donor.26,27 Prior to the development and widespread clinical application of ALDLT in Asia, very few patients with HCC and decompensating cirrhosis benefited from OLT. Today, notwithstanding ethical and logistical concerns, an increasing number of ALDLT are being performed for this group of patients. It is likely that the criteria for performing transplants in patients with HCC will be more liberal, with aggressive adjuvant antitumor treatment and even salvage transplantation for failed resection.
In carefully selected patients with HCC, good survival results can be obtained following both surgical resection and transplantation. With the rapid deployment of ALDLT, particularly in Asia, an increasing number of such patients are undergoing transplantation. Combined with aggressive adjuvant antitumor treatment, it is likely that the criteria for transplantation will be liberalized. Currently, the prognosis and choice of treatment are largely based on the crude parameters of tumor burden (number and size of tumor) and the presence of vascular invasion. If these parameters could be combined with molecular profiling and genetic analyses of HCC to determine the biologic behavior of the tumor, perhaps the choice of treatment would be better defined with more consistent results.