Liver transplantation for recurrent hepatocellular carcinoma in Europe

Transcription

1 J Hepatobiliary Pancreat Surg (2001) 8: Liver transplantation for recurrent hepatocellular carcinoma in Europe Sven Jonas, Thomas Steinmüller, Utz Settmacher, Jan Langrehr, Andrea Müller, and Peter Neuhaus Department of General, Visceral and Transplantation Surgery, Charité Campus Virchow Klinikum, Humboldt University, Augustenburger Platz 1, Berlin, Germany Abstract Background. Patient death after liver resection for hepatocellular carcinoma in cirrhosis is caused by tumor recurrence as well as by complications of cirrhosis. Liver transplantation represents the only simultaneous treatment of tumor and primary liver disease. Certain criteria regarding the number (up to three) and size (up to 5cm) of tumor nodules have to be observed in order to ensure a low risk of extrahepatic spread or vascular infiltration. Liver transplantation, as treatment for recurrent hepatocellular carcinoma, has to observe the same rules. Only few patients have undergone liver transplantation for recurrent hepatocellular carcinoma in cirrhosis. The reason for this restraint is not fully evident. Poor survival rates after liver transplantation as therapy for advanced hepatocellular carcinoma in the 1980s and an increasing shortage of donor grafts are certainly two factors. Methods. We report on two cases from our experience and review the European literature. Results. Outcome in a few selected patients has been rather favorable, despite varying approaches. Conclusions. The only conclusion that can be drawn is that tumor control by liver transplantation is possible in individual patients suffering from recurrent hepatocellular carcinoma. Adult living donor liver transplantation is one way to overcome graft shortage. Other strategies, for example, salvage transplantation, are presented. Key words Recurrent hepatocellular carcinoma Liver transplantation Resection Introduction In contrast to the prognosis of many other visceral carcinomas, the postoperative prognosis of hepatocellular Offprint requests to: P. Neuhaus Received: April 20, 2001 / Accepted: May 11, 2001 carcinoma (HCC) in cirrhosis is not fully determined by tumor recurrence. In the course after liver resection, almost half of the patients die of complications related to the underlying liver cirrhosis. 1 In patients with a recurring HCC, the recurrence does not necessarily mean that the original tumor has either been resected incompletely or that it has spread into the systemic circulation. More likely, tumors develop as de-novo HCC, because liver cirrhosis, as the precancerous risk factor, persists or even exacerbates after resection or any other type of local treatment. Recurrence after liver resection has been reported in more than half of the patients. 2 Among those, with recurrence, intrahepatic recurrence is most common, with a frequency of 80%. 3 5 Extrahepatic recurrence is primarily located in the lungs and skeletal system. Despite this relatively high rate of intrahepatic recurrent HCC, rates of repeat resection rarely exceed 20%. 6 9 In general, unfavorable location of the tumor nodules and progressively impaired liver function, as well as scientifically unjustified nihilism towards recurrent malignancies, are the main reasons for this low figure. Liver resection for recurrent HCC can be a potentially curative intervention. As in hepatic surgery for colorectal cancer metastases, survival figures do not differ from those obtained after primary resection. Moreover, even the patient who is not cured by a repeat resection may have a benefit with respect to quality of life and also to survival. However, resection is precluded in many patients in whom deteriorating liver function or increasing portal hypertension is shown. 10 Today, liver transplantation is the only simultaneous treatment that can be for cirrhosis as well as HCC. A crucial factor for outcome after liver transplantation is the appropriate selection of patients. The most favorable survival figures originate from groups which apply selection criteria that do not adhere stringently to the tumor-node-metastasis-classification (TNM), but rather, to criteria of the size and number of tumor nod-

2 S. Jonas et al.: LT for recurrent HCC in Europe 423 ules Patients suffering from HCC and cirrhosis with three or fewer tumor nodules, a maximum tumor diameter not exceeding 5cm, and no apparent signs of vascular invasion have posttransplant 5-year-survival rates of more than 70%. However, liver transplantation is only rarely considered as treatment for recurrent HCC. Several factors may explain this cautious attitude: 1. Only few recurrent HCC meet the tumor selection criteria. 2. If a patient suffers from recurrent HCC in cirrhosis after liver resection, there may have been a contraindication for liver transplantation as primary treatment. This contraindication, e.g., severe chronic cardiopulmonary disease, advanced age, and active alcohol abuse, also holds for liver transplantation as rescue treatment. 3. In many malignant conditions, recurrence implies a dissemination of tumor cells, either via a shedding into the circulation or locally via the manipulation or incompelete resection of the tumor. 14 Tumor cell dissemination is a major problem in graft recipients because of the immunosuppressive treatment which renders recurrence more likely and reduces tumor volume doubling-times Tumor recurrence can also be observed in noncirrhotic livers. Primary HCC in non-cirrhotic livers occur considerably less frequently than in cirrhosis and these fewer tumors are much more advanced. The consistent rates of posttransplant 5-yearsurvival reported by Pichlmayr et al. and Iwatsuki et al. were only 25%. 16,17 In the rare case of early HCC in non-cirrhotic livers, resection as well as repeat resections can be performed straightforwardly because of a normal functional reserve. In addition, the postoperative prognosis over the long-term is not impaired by complications associated with liver cirrhosis either A recurrent tumor may be more aggressive than the primary. It has demonstrated its capacity to resist to the host environment. Therefore, a recurrent HCC may not meet the selection criteria for liver transplantation because it is too advanced. The main risk factor for patients undergoing liver transplantation is a vascular tumor infiltration. Recurrence may be an indicator not only of an already existing dissemination but also for the potential of a tumor to infiltrate a vessel. Unfortunately, it is still impossible to differentiate a recurrent tumor from a de-novo HCC in a cirrhotic liver, or to detect a microscopic vascular infiltration. Therefore, the decision for liver transplantation has to be individualized after assessment of the likelihood of a de-novo tumor not infiltrating the vascular system. As a contribution to a more empirical and less theoretical concept, we report on two patients with recurrence, out of 120 patients in whom liver transplantation for HCC in cirrhosis had been performed. Case 1 A 57-year-old man suffering from a small recurrent HCC in a non A-non B liver cirrhosis was admitted for liver transplantation. The cirrhosis was advanced to stage B according to the Child-Pugh classification. The previous intervention had been a non-anatomic wedge resection of segment 5, carried out 2 years previously, for a solitary HCC with a diameter of 3.5cm. The recurrent tumor consisted of two nodules, 2.5 cm and 1.5 cm in diameter, respectively. The liver transplantation and the patient s postoperative course with a sequential cyclosporine-based quadruple immunosuppressive regimen, using antithymocyte globulin (ATG), were all uneventful. The highly differentiated tumor (G1) was staged as T3N0M0 or IIIa according to the Union Internationale contre le Cancer (UICC) classification. Three years posttransplant, a myocardial infarction was successfully treated by a percutaneous transluminal coronary angioplasty of the left anterior descending artery. Seven years posttransplant, a signet-ring carcinoma was detected in an ulcer of the gastric corpus. The patient underwent gastrectomy and lymphadenectomy. The tumor stage was T3N2M0 with a local peritoneal carcinomatosis and a poor histopathological grading (G3). Intraoperatively and on all follow-up visits, there were no signs of intra- or extrahepatic recurrence of the HCC. The patient died of recurrent gastric cancer 1 year after gastrectomy, 8 years posttransplant. Case 2 A 50-year-old man presented with a recurrent HCC in a non-cirrhotic liver. Five years, 3 years, and 1 year prior to this admission, he had undergone right hemihepatectomy, left-lateral sectorectomy, and non-anatomic wedge resections of two nodules in the hypertrophic remnant segment 4, respectively. On admission, three nodules, with a maximum diameter of 2.5 cm, were detected and considered non-resectable. Extrahepatic manifestation of the tumor was ruled out. Intraoperatively, lymph nodes from the hepatic hilum to the celiac axis were dissected, and on frozen biopsy, confirmed to be free of tumor infiltration. Total hepatectomy, i.e., resection of the remaining segments 1 and 4, and liver transplantation, were performed uneventfully. The patient s postoperative course was uncomplicated as well. The initial immunosuppression consisted of a

3 424 S. Jonas et al.: LT for recurrent HCC in Europe cyclosporine-based quadruple induction regimen with ATG. Pathological examination of the resected liver disclosed a total of nine tumor nodules. The maximum diameter was confirmed to be 2.5 cm. The histological grading was classified as moderate (G2). The stage was T4N0M0 or IVa according to the UICC system. Four years posttransplant, a metastasis was detected in the superior lobe of the left lung. Other metastases were ruled out, and a pulmonary wedge resection was performed. The patient s intra- and postoperative course was uneventful. On histopathological examination, the resected specimen was confirmed to be a metastasis of an HCC. Four years later, or 8 years posttransplant, another left pulmonary mass was evident during follow-up and was confirmed as a metastasis after wedge resection. The patient had an apoplectic stroke extending to the cerebellum and the medulla oblongata 1 month after this resection. The symptoms were predominantly dysphagia, Horner s syndrome, and vertigo, but these symptoms completely resolved in the further course. Today, i.e., 12 years posttransplant, the patient is well, without any signs of recurrent tumor, during his annual follow-up visits. Discussion The two case reports above pertain to two entirely different concepts of liver transplantation for recurrent HCC. First, an early HCC in cirrhosis; and, second, an irresectable HCC after multiple resections in a noncirrhotic liver. Both patients had in common the assumption that the disease appeared to be limited to the liver. The second patient developed pulmonary metastases, and this demonstrates how erroneous such an assumption can be. However, the patient has had a considerable benefit in terms of survival, which could not be expected without liver transplantation. The features in the first patient are characteristic of what today would generally be accepted as an indication for transplant. Unfortunately, a de-novo gastric cancer occurred in this patient and this is a reminder of the fact that tumor recurrence is not the only problem to jeopardize a patient during follow-up. The only conclusion that can be drawn from case reports is that tumor control by liver transplantation is possible in individual patients suffering from recurrent HCC. Reports of patients from other German centers, in Hannover and Heidelberg, add to this rather favorable experience. 19 However, there are no recent reports on liver transplantation for recurrent HCC. The overall numbers in Europe do not exceed an estimated 30 to 40 patients, including 4 patients from Barcelona and 12 patients from Paris, Geneva, and Milan. 20,21 Many case reports originating from the early 1990s describe patients who had undergone liver transplantation even back in the 1980s. In the early 1990s, the general attitude toward liver transplantation as a treatment for hepatic malignancies, even including cholangiocarcinoma and metastatic tumors, was different from the attitude today. Bismuth et al. 22 were the first to show that, in this early era, the surgical strategy for the treatment of HCC in cirrhosis had followed a misconception in terms of selecting patients who had advanced, and therefore unresectable cancers, as transplant candidates. Even groups that have advocated liver transplantation as a therapeutic option for selected patients with unresectable liver tumors of various anatomical origins have recommended the exclusion of patients with UICC stage III and IV HCC from liver transplantation. 16 Based on the United Network of Organ Sharing (UNOS) and European Liver Transplant Registry (ELTR) data, patient survival was poor, and reached only 30% at 5 years posttransplant. Conversely, small HCC in cirrhosis, with diameters of less than 3cm, comprising only one or two nodules (i.e., tumors frequently suitable for resection), showed a favorable outcome. 22 One reason that transplant centers exercise restraint when they consider liver transplantation for recurrent HCC is graft shortage. When outcome after liver transplantation for primary HCC is considered not in terms of posttransplant survival, but by an intention-totreat analysis of all patients with an HCC on the transplant waiting list, the figures become considerably lower because of drop-outs during an increasing waiting time. 20 The reason is tumor progression with a 1-year probability of 70%. The 1-year rates for vascular invasion and extrahepatic spread are 21% and 9%, respectively. 23 The situation may be changed by a broader introduction of living-donor liver transplantation among adults. The most important difference from cadaveric transplantation is that a graft is uniquely available for one recipient. Allocation according to the most favorable outcome, which would generally be anticipated for benign liver diseases, rather than HCC, is not only not necessary but is even impossible. At least in Germany, legislation covers living-donor organ transplantation only between closely related persons. The prognosis of a patient with an HCC that is too advanced with respect to the above-described selection criteria should not be compared with the expected outcome of other potential graft recipients, but with the prognosis provided by other therapeutic options. There are no reports on outcome after adult living-donor liver transplantation for extended or even critical indications regarding HCC. Nevertheless, it can be expected that indications for transplantation in patients with recurrent HCC in

4 S. Jonas et al.: LT for recurrent HCC in Europe 425 cirrhosis after resection will become less stringent. The most important caveat is the risk of complications in the donor, who is not a patient but a healthy individual. Another strategy for overcoming graft shortage, especially in patients suffering from HCC in cirrhosis, has been reported by a group in Geneva, Switzerland, Majno et al., 24 as salvage transplantation. The rationale is to perform resection in patients who are assumed not to require transplantation, in terms of survival, and to avoid first-line liver transplantation for those HCCs that are close to the limits of the transplantation criteria. The poor prognosis of these patients is, in the view of Majno et al., 24 reflected by a 30% mortality rate after liver transplantation during the first few years posttransplant. Hence, liver resection is offered as first-line therapy, and liver transplantation only in patients with deteriorating liver function or a recurrent tumor that fulfill the usual criteria for transplantation. Their report, however did not include results obtained from a treatment study, but used a Markov model of calculated probabilities. 25 This theoretical model presumes a life expectancy of 8.8 years for primary liver transplantation compared with 7.8 years for primary resection and salvage transplantation. The calculated requirement for grafts is markedly reduced from 52% in primary liver transplantation to 23% in salvage transplantation. However, the 30% posttransplant mortality rate is due only in part to tumor recurrence; further the underlying assumptions of these calculations are indefinable and the model does not include a quality-of-life analysis. Nevertheless, the concept may at least indicate a growing acceptance of liver transplantation for recurrent HCC, provided the criteria do not differ from those applied prior to primary transplantation. References 1. Jonas S, Bechstein WO, Kling N, Guckelberger O, Neuhaus P (1997) Therapy of primary hepatocellular carcinoma. Dtsch Med Wochenschr 122: Belghiti J, Panis Y, Farges O, Benhamou JP, Fekete F (1991) Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg 214: Ikeda K, Saitoh S, Tsubota A, Arase Y, Chayama K, Kumada H, Watanabe G, Tsurumaru M (1993) Risk factors for tumor recurrence and prognosis after curative resection of hepatocellular carcinomas. Cancer 71: Yamanaka N, Okamoto E, Toyosaka A, Mitunobu M, Fujihara S, Kato T, Fujimoto J, Oriyama T, Furukawa K, Kawamura E (1990) Prognostic factors after hepatectomy for hepatocellular carcinomas. A univariate and multivariate analysis. Cancer 65: Okada S, Shimada K, Yamamoto J, Takayama T, Kosuge T, Yamasaki S, Sakamoto M, Hirohashi S (1994) Predictive factors for postoperative recurrence of hepatocellular carcinoma. Gastroenterology 106: Shuto T, Kinoshita H, Hirohashi K, Kubo S, Tanaka H, Tsukamoto T, Okuda T (1996) Indications for, and effectiveness of, a second hepatic resection for recurrent hepatocellular carcinoma. Hepatogastroenterology 43: Nagasue N, Kohno H, Hayashi T, Uchida M, Ono T, Yukaya H, Yamanoi A (1996) Repeat hepatectomy for recurrent hepatocellular carcinoma. Br J Surg 83: Farges O, Regimbeau JM, Belghiti J (1998) Aggressive management of recurrence following surgical resection of hepatocellular carcinoma. Hepatogastroenterology 45 (Suppl 3): Poon RT, Fan ST, Lo CM, Liu CL, Wong J (1999) Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Ann Surg 229: Bruix J, Castells A, Bosch J, Feu F, Fuster J, Garcia Pagan JC, Visa J, Bru C, Rodes J (1996) Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 111: Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334: Llovet JM, Bruix J, Fuster J, Castells A, Garcia Valdecasas JC, Grande L, France A, Bru C, Novasa M, Ayuso MC, Sole M, Real MI, Vilana R, Rimola A, Visa J, Rodes J (1998) Liver transplantation for small hepatocellular carcinoma: the tumor-nodemetastasis classification does not have prognostic power. Hepatology 27: Jonas S, Bechstein WO, Steinmüller T, Herrmann M, Radke C, Berg T, Settmacher U, Neuhaus P (2001) Vascular invasion and histopathological grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 33: Wong IH, Lau WY, Leung T, Yeo W, Johnson PJ (1999) Hematogenous dissemination of hepatocellular and tumor cells after surgical resection of hepatocellular carcinoma: a quantitative analysis. Clin Cancer Res 5: Yokoyama I, Carr B, Saitsu H, Iwatsuki S, Starzl TE (1991) Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation. Cancer 68: Pichlmayr R, Weimann A, Oldhafer KJ, Schlitt HJ, Klempnauer J, Bornscheuer A, Chavan A, Schmoll E, Lang H, Tusch G (1995) Role of liver transplantation in the treatment of unresectable liver cancer. World J Surg 19: Iwatsuki S, Starzl TE, Sheahan DG, Yokoyama I, Demetris AJ, Todo S, Tzakis AG, Van-Thiel DH, Carr B, Selby R (1991) Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 214: Bismuth H, Chiche L, Castaing D (1995) Surgical treatment of hepatocellular carcinomas in noncirrhotic liver: experience with 68 liver resections. World J Surg 19: Neuhaus P, Kling N (1996) Local recurrence in hepatocellular carcinoma. Akt Chir 31: Llovet JM, Fuster J, Bruix J (1999) Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30: Majno PE, Adam R, Mazzaferro V, Regalia E, Mentha G, Morel PH, Bismuth H (1999) Liver transplantation for recurrence after resection of solitary hepatocellular carcinoma (abstract). Liver Transpl Surg 5:S Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A (1993) Liver resection versus transplantation for hepatoecllular carcinoma in cirrhotic patients. Ann Surg 218: Lau WY, Leung TW, Ho SK, Chan M, Machin D, Lau J, Chan AT (1999) Adjuvant intra-arterial iodine-131-labelled lipiodole for

5 426 S. Jonas et al.: LT for recurrent HCC in Europe resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 353: Majno PE, Sarasin FP, Mentha G, Hadengue A (2000) Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: an outcome-oriented decision analysis. Hepatology 31: Naimark D, Krahn MD, Naglie G, Redelmeier DA, Detsky AS (1997) Primer on medical decision analysis: part 5 working with Markov processes. Med Decis Making 17: