Hepatectomy vs. liver transplantation: A combination rather than an opposition

About 10 years ago, several studies made it clear that liver transplantation (LT) offers better long-term survival than resection alone for small hepatocellular carcinoma (HCC). Studies with sufficient follow-up clearly demonstrated that the rate of recurrence is lower after LT compared to resection in cases of small HCC, provided there is no vascular invasion. In patients fulfilling the widely used Milan criteria, the results of LT proved to be nearly as good as those obtained in patients without malignancies.1 As a result, LT is generally considered the “gold standard” option. However, during the last 10 years, the chronic imbalance between the increasing number of candidates for LT and a limited organ supply has made it necessary to temper the enthusiasm for LT. Organ shortage results in prolonged waiting time. In turn, prolonged waiting time results in tumor growth with an increasing risk of vascular invasion, a source of post-LT recurrence. In parallel, advances in liver surgery have significantly improved the safety of resection.2 Improvements in the selection process and technical refinements have made it possible to decrease the rate of recurrence after resection, rehabilitating resection as a valuable alternative to LT in cirrhotic patients with preserved liver function. In addition, improvements in surgical techniques have raised the concept of resection as a possible bridge to transplantation.3 On a theoretical basis, however, this concept could have major drawbacks. In particular, it can be anticipated that prior liver surgery might be a source of technical difficulties for LT and can preclude the results of LT. LT, liver transplantation; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; HCV, hepatitis C virus. It has been shown that, in contrast to what could be expected, prior resection neither increases operative morbidity nor impairs survival following deceased donor transplantation.4 For the first time, the study by Hwang and colleagues published in this issue of Liver Transplantation5 shows that living donor liver transplantation (LDLT), a much more complex procedure, can also be safely performed in patients who had prior major resection. The excellent results reported by this group emphasize the advances achieved in the era of LDLT, particularly the technical refinements concerning the need to preserve the inferior vena cava after right hepatectomy. The recommendations from this Korean group concerning recipient liver isolation, outflow reconstruction when the stump of the right hepatic vein is no longer utilizable, the cautious use of the native bile ducts, and the possible use of the left branch of the hepatic artery or the right gastroepiploic artery for arterial reconstruction during LDLT represent a useful contribution for the transplant community. The conclusion that either deceased donor LT or living donor LT is safe in patients who have had prior resection is an incentive to reconsider the place of conventional surgery in patients who otherwise fulfill the stringent selection criteria for LT. In the context of organ shortage, it raises again the issue of whether resection should be the first line option for patients with small HCC, with transplantation as a second-line option, in case of recurrence. The very attractive concept of salvage LT has several advantages. It gives rapid access to an effective therapy, without the need for a donor and, subsequently, without prolonged waiting time. Resection is technically far less complex than LT and less demanding in the long term. In selected patients it offers 5-year survival rates exceeding 50% with a good quality of life.2 Again, it remains possible to perform salvage LT in case of tumor recurrence and/or deterioration of liver function, without a significant decrease in post-LT survival compared to that of patients who primarily underwent LT.4 Finally, since transplantation is performed only at the time of recurrence, exposure to immunosuppressive therapy is delayed. However, such a strategy is applicable only if patients still have a small tumor at the time of recurrence and if they meet the Milan criteria. In the series by Poon et al., 80% of patients remained eligible for salvage LT at the time of recurrence.6 However, it is noticeable that all candidates for salvage LT in this series from Hong Kong as well as all those in the present paper by Hwang et al. had hepatitis B virus infection.5, 6 Unfortunately, we found that this optimistic scenario could not be directly reproduced in Western countries where the majority of patients have hepatitis C virus (HCV) infection. Indeed, we found that among the subgroup of HCV-infected patients with small tumors (within the Milan criteria) who underwent liver resection, tumor recurrence was over the Milan criteria in 60% of cases.7 Possibly due to a different natural history, the majority of HCV-infected patients had multifocal tumors and/or vascular invasion at the time of recurrence. As a result, they were no longer eligible for salvage transplantation at the time of recurrence. Therefore, at least in HCV-infected patients, resection alone could represent a loss of chance, since only a minority would be eligible for salvage transplantation. Such patients could be resected but maintained on the waiting list and transplanted before recurrence. Should these restrictions concerning salvage transplantation in HCV-infected patients condemn the concept of liver resection prior to LT? In our opinion, the answer is no, for several reasons. Resection of HCC can be used as a bridge in patients listed for LT. As a consequence of tumor progression, a sizeable proportion of patients fall outside the Milan criteria while waiting for a donor and must be eventually removed from the waiting list. Furthermore, even if patients can eventually be transplanted, tumor growth increases the risk of recurrence. Compared to radiofrequency ablation and transarterial chemoembolization, resection can be considered the most efficient option for bridging patients to LT, provided that the tumor is peripheral and there is sufficient functional reserve. The use of laparoscopic or transthoracic approaches for peripheral tumors may further contribute to expansion of this strategy by minimizing technical difficulties during the transplant procedure.8, 9 A second justification for resection prior to transplantation is that it helps refine the selection process. Resection, indeed, gives access to detailed pathological examination of the tumor and the surrounding liver parenchyma. Important prognostic information can be obtained from the entire resected tumor, including differentiation (that proved to be heterogeneous within the tumor), satellite nodules, microvascular invasion and capsular effraction. Core biopsy specimens are generally insufficient for these issues to be addressed. As a result, resection may contribute to denial of transplantation in patients with tumors apparently within the Milan criteria but with histological features of especially poor prognosis (undetected macrovascular invasion in particular). On the other hand, resection may help decide transplantation in patients with tumors slightly outside the Milan criteria but with histological features of good prognosis. Finally, resection makes it possible to accelerate LT (by choosing LDLT, for instance) or delay LT according to the risk of early recurrence, on the basis of histological prognostic factors.10 Pushing the limits of resection in patients with tumors markedly over the limits defined by the Milan criteria introduces the more recent concept of downstaging. In many centers, patients who are initially outside the Milan criteria and who return within these criteria after transarterial chemoembolization or radiofrequency are considered to be eligible for transplantation. It has been suggested (but not definitely demonstrated) that patients with downstaging have post-LT survival comparable to that of patients initially within the Milan criteria.11 Since resection does not preclude LT, this technique should also be used in an attempt to obtain downstaging, with the advantage of allowing detailed pathological analysis. It also offers the possibility for appreciation of the natural history of the tumor. Transplantation should be denied in patients with an early and aggressive pattern of recurrence after resection. The expansion of resection in patients with large tumors, whether HCC or other malignancies, obviously has drawbacks. Despite careful selection, postoperative liver failure may occur as a consequence of an insufficient mass of liver parenchyma and/or underlying chronic liver lesions. The prognosis of postoperative failure is especially poor. In this issue of Liver Transplantation, another innovative paper, from Otsuka and colleagues,12 shows that selected patients undergoing liver resection and developing postoperative liver failure can be transplanted in an emergency setting with excellent results. Emergency LT after resection requires a strict selection of the candidate with 2 aspects. First, robust markers of irreversible postoperative liver insufficiency must be present. Apart from patients with massive necrosis of the remnant liver or those with uncontrollable bleeding, it remains very difficult to ascertain the irreversibility of liver insufficiency. A significant increase in international normalized ratio and serum bilirubin within the first postoperative days is part of the natural history of extended resection. Which clinical and biological limits justify rescue transplantation has been a challenging issue. Recently, we have suggested that in the absence of any treatable complication, the absence of significant improvement on postoperative day 5 (bilirubin over 50 μmol/L and prothrombin index below 50% of normal [international normalized ratio >1.7]) may lead to strong consideration of rescue transplantation.13 An underlying issue is to select candidates with a sufficient probability of survival after LT. In some of the patients from the series of Otsuka and colleagues,12 particularly those with large HCC and colon cancer metastasis, the indication for transplantation was questionable. In this context, “rescue” LT should be limited to selected patients below 70 years old, with HCC and no macrovascular invasion, and, possibly, those with small cholangiocarcinoma (<3 cm) without lymph node invasion. There is no indication for transplantation in patients with liver metastasis except those with neuroendocrine tumors. Some patients with chronic liver disease who develop massive ascites along with postoperative deterioration of liver function after nonhepatic surgery (abdominal repair) could also be acceptable candidates for this exceptional procedure. Nevertheless, the 2 papers open a new field for hepatobiliary and liver transplant surgery (Table 1). What can be expected from resection in candidates for transplantation Bridge to transplantation: The patient is on the waiting list for transplantation. Resection is performed for limiting tumor growth during waiting time. Selection before transplantation: The patient is not on the waiting list. Analysis of the resected specimen allows for identification of patients with favorable or unfavorable (vascular invasion, satellite nodules, poor differentiation) histological features. Patients slightly outside the Milan criteria but with favorable histological features are listed. Patients apparently within the Milan criteria but with unfavorable histological features are not listed. Resection as an initial treatment: The patient is not on the waiting list. In patients with a small, single nodule, a favorable cause and favorable histological features, transplantation is delayed and considered only after recurrence or in the case of liver failure. What can be expected from transplantation in patients undergoing resection The salvage transplantation proposed in case of recurrence after resection, provided that the tumor is still within the Milan criteria. Downstaging in patients with tumors initially outside the Milan criteria, and bridge to transplantation with an appreciation of the natural history after resection. Emergency transplantation in case of postoperative hepatic failure, taking into account a good prognosis after LT.