Resection prior to liver transplantation for hepatocellular carcinoma: A strategy of optimizing the role of resection and transplantation in cirrhotic patients with preserved liver function
Abstract
Objective
To evaluate the feasibility and postoperative course of liver transplantation (LT) in cirrhotic patients who underwent liver resection prior to LT for HCC.
Summary Background Data
Although LT provides longer survival than liver resection for treatment of small HCCs, donor shortage and long LT wait time may argue against LT. The feasibility and survival following LT after hepatic resection have not been previously examined.
Methods
Between 1991 and 2001, among 107 patients who underwent LT for HCC, 88 met Mazzafero's criteria upon pathologic analysis of the explant. Of these, 70 underwent primary liver transplantation (PLT) and 18 liver resection prior to secondary liver transplantation (SLT) for recurrence (n = 11), deterioration of liver function (n = 4), or high risk for recurrence (n = 3). Perioperative and postoperative factors and long-term survival were compared.
Results
Comparison of PLT and SLT groups at the time of LT revealed similar median age (53 vs. 55 years), sex, and etiology of liver disease (alcohol/viral B/C/other). In the SLT group, the mean time between liver resection and listing for LT was 20 months (range 1-84 months). Overall time on LT waiting list of the two groups was similar (3 vs. 5 months). Pathologic analysis after LT revealed similar tumor size (2.2 vs. 2.3 cm) and number (1.6 vs. 1.7). Perioperative and postoperative courses were not different in terms of operative time (551 vs. 530 minutes), blood loss (1191 vs. 1282 mL), transfusion (3 vs. 2 units), ICU (9 vs. 10 days) or hospital stay (32 vs. 31 days), morbidity (51% vs. 56%) or 30-day mortality (5.7% vs. 5.6%). During a median follow-up of 32 months (3 to 158 months), 3 patients recurred after PLT and one after SLT. After transplantation, 3- and 5-year overall survivals were not different between groups (82 vs. 82% and 59 vs. 61%).
Conclusions
In selected patients, liver resection prior to transplantation does not increase the morbidity or impair long-term survival following LT. Therefore, liver resection prior to transplantation can be integrated in the treatment strategy for HCC. (Ann Surg 2003;238:885–893.) (Liver Transpl 2004;10:813–815.)
Resection Prior to Liver Transplantation for Hepatocellular Carcinoma. , , , , , , et al. Ann Surg 2003; 238: 885–893. (Reprinted with permission from Lippincott Williams & Wilkins)
Abbreviation
HCC, hepatocellular carcinoma.
Comments
Liver transplantation is a well-established treatment for solitary hepatocellular carcinoma (HCC) < 5 cm in diameter (or two or three tumor nodules, all < 3 cm in diameter) with no gross vascular invasion (Milan criteria) in patients with Child-Turcotte-Pugh B or C cirrhosis.1 For HCC associated with Child-Turcotte-Pugh A cirrhosis, partial hepatic resection has been the mainstay of curative treatment, and recent studies have demonstrated improved survival results after hepatic resection for HCC.2, 3 However, hepatic resection for HCC in cirrhotic patients is associated with a high risk of tumor recurrence, which is partly attributed to multicentric hepatocarcinogenesis in cirrhosis. Hepatic resection for HCC < 5 cm in diameter in patients with Child-Turcotte-Pugh A cirrhosis could provide a 5-year survival of 60% to 70%, but the 5-year disease-free survival was only 24% to 48%.4-6 The overall 5-year survival rate after hepatic resection for early HCC in patients with Child-Turcotte-Pugh A cirrhosis seems to be comparable to that after transplantation,1, 6, 7 but the 5-year disease-free survival rate is worse than that of 60% after transplantation.6-8 Hence, some authors advocated that transplantation is a better treatment option than hepatic resection for early HCC associated with Child-Turcotte-Pugh A cirrhosis.9 However, other authors argued that hepatic resection is still the preferred treatment.5, 6
There is no doubt that liver transplantation provides the best curative treatment for early HCC, because it not only removes the tumor but also cures the underlying cirrhosis. However, transplanting all Child-Turcotte-Pugh A cirrhotic patients who have early HCC is not practicable because of the severe shortage of donor organs. Furthermore, this may not be a rational approach, since a significant proportion of patients may survive for 5 years or more without tumor recurrence after hepatic resection. While resection is associated with a high incidence of tumor recurrence, liver transplantation is associated with a risk of graft rejection and the need for long-term immunosuppression, which may lead to problems such as opportunistic infections and new neoplasms, thus compromising the long-term survival. This explains why the overall survival after transplantation for HCC was similar to that after hepatic resection in some studies, despite a lower tumor recurrence rate after transplantation. It may be preferable if liver transplantation can be deferred in some patients with Child-Tucotte-Pugh A cirrhosis until tumor recurrence or deterioration of liver function after hepatic resection, and avoided in some patients who can survive long-term without tumor recurrence after hepatic resection. Hence, we proposed resection followed by salvage transplantation for tumor recurrence or deterioration of liver function as a more rational strategy to optimize the role of hepatic resection and transplantation in the treatment of early HCC in patients with preserved liver function.10 We have demonstrated that this strategy may be feasible because 80% of tumor recurrences were still transplantable by the Milan criteria, and this fact was corroborated by another study.5 However, for this strategy to become a viable option, it is important to demonstrate that the long-term survival is not compromised after transplantation for recurrent tumors. Recently, Belghiti et al.11 reported that the posttransplant long-term survival of 18 patients with prior liver resection followed by transplantation for recurrent HCC, deterioration of liver function, or high risk of recurrence was comparable to that of 70 patients with primary transplantation for HCC. The 5-year survival after transplantation was 61% and 59% in the two groups, respectively, and there was no significant difference in the recurrence rate either. After a median follow-up of 32 months, only one patient in the secondary transplantation group developed tumor recurrence. Furthermore, there were no significant differences in morbidity (56% vs. 51%) and 30-day mortality (5.6% vs. 5.7%) after primary and secondary transplantation. However, there was a higher incidence of reoperations in the secondary transplantation group, suggesting that transplantation after prior resection is technically more difficult than primary transplantation. To minimize the potential technical difficulty of future transplantation, Belghiti et al. suggested that transthoracic resection should be considered for tumors adjacent to the diaphragm, and when transabdominal resection is indicated, segment-oriented resections are preferred.
The study by Belghiti et al. demonstrated that prior resection does not compromise the survival results following transplantation when the tumors recur or when liver function deteriorates. In fact, if the mean interval of 20 months from the time of resection to listing for transplantation had been included in the secondary transplantation group, the overall survival from the time of initial surgical treatment in this group would have been better than that of the primary transplantation group. The low tumor recurrence rate observed in the secondary transplantation group was encouraging, because the main theoretical concern of the strategy of salvage transplantation for tumor recurrence is that some of the recurrent tumors may represent metastatic disease rather than multicentric tumors, and hence may lead to worse prognosis even when salvage transplantation is performed. However, it has to be noted that in the series of 18 patients with secondary transplantation in the study by Belghiti et al., only 11 had tumor recurrence. Although tumor size and number of the 11 recurrent tumors were similar to those tumors treated by primary transplantation, no data on tumor differentiation or pathological features of tumor invasiveness such as microscopic vascular invasion and microsatellite nodules were provided. Nonetheless, the results of the study will certainly encourage other groups to perform salvage transplantation for recurrent HCC after previous hepatic resection, and further studies may provide better insight into the treatment.
Despite the favorable results reported by Belghiti et al., the role of salvage transplantation following resection of HCC remains a controversial issue. In a study of 17 patients with secondary transplantation following previous resection by another group,12 secondary transplantation resulted in a higher operative mortality and poorer survival compared with primary transplantation. The operative mortality of 23.5% in the latter study was much higher than that of Belghiti's study and could have significantly reduced the overall long-term survival rate. Furthermore, if survival from initial hepatic resection rather than survival from secondary transplantation was considered, the survival of patients with resection followed by transplantation would appear to be similar to that after secondary transplantation in that study.
While a randomized trial of resection followed by transplantation versus primary transplantation is practically impossible, further studies should provide intention-to-treat comparison of the survival results between patients who are treated with hepatic resection with a plan for salvage transplantation for recurrence or deterioration of liver function, and patients who are listed for primary transplantation. Dropout because of tumor progression before transplantation is an important limitation of the strategy of primary transplantation.13 The use of living donor transplantation has been proposed for patients with early HCC associated with Child-Turcotte-Pugh A cirrhosis.12 However, in our experience, living donors are not available for about half of the patients with transplantable HCC, for various reasons.14 Furthermore, it is arguable whether it is ethically acceptable to risk the life of a living donor for a Child-Turcotte-Pugh A cirrhotic patient with an early HCC who has an alternative option of resection with comparable overall long-term survival. It may be more acceptable for the relatives to volunteer liver donation when resection has failed due to tumor recurrence or deterioration of liver function. The study by Belghiti et al. has provided some preliminary data supporting the strategy of salvage transplantation following hepatic resection. However, whether Child-Turcotte-Pugh A cirrhotic patients with an early HCC should receive resection, transplantation, or resection followed by transplantation will continue to be an issue of debate until further data based on a large sample size and intention-to-treat analysis become available.
