PO Box 2345, Beijing 100023, China World J Gastroenterol 2005;11(10):1433-1438www.wjgnet.com World Journal of Gastroenterology ISSN 1007-9327
[email protected] 2005 The WJG Press and Elsevier Inc. All rights reserved.
Impact of pre-operative transarterial embolization on thetreatment of hepatocellular carcinoma with liver transplantation Yu-Fan Cheng, Tung-Liang Huang, Tai-Yi Chen, Yaw-Sen Chen, Chih-Chi Wang, Sheng-Lung Hsu, Leo Leung-Chit Tsang,Po-Lin Sun, King-Wah Chiu, Bruno Jawan, Hock-Liew Eng, Chao-Long Chen Yu-Fan Cheng, Tung-Liang Huang, Tai-Yi Chen, Sheng-Lung 100% at 3 years, which was significantly better than the Hsu, Leo Leung-Chit Tsang, Po-Lin Sun, Department of Diagnostic others who showed <85% tumor necrosis (57.1% at Radiology, Kaohsiung Medical Center, Chang Gung Memorial 3 years) or who did not have TAE (75% at 3 years).
Hospital, Chang Gung University, Kaohsiung 83305, Taiwan, ChinaYaw-Sen Chen, Chih-Chi Wang, Chao-Long Chen, Department CONCLUSION: TAE is an effective treatment for HCC
of Surgery, Kaohsiung Medical Center, Chang Gung Memorial before LT. Excellent long-term survival was achieved in Hospital, Chang Gung University, Kaohsiung 83305, Taiwan, China patients that did not fit Milan criteria. Our results broadened King-Wah Chiu, Department of Hepatogastroenterology, Kaohsiung and redefined the selection policy for LT among patients Medical Center, Chang Gung Memorial Hospital, Chang GungUniversity, Kaohsiung 83305, Taiwan, China with HCC. Meticulous pre-LT TAE helps in further reducing Bruno Jawan, Department of Anesthesiology, Kaohsiung Medical the rate of dropout from waiting lists and should be Center, Chang Gung Memorial Hospital, Chang Gung University, considered for patients with advanced HCC.
Kaohsiung 83305, Taiwan, ChinaHock-Liew Eng, Department of Pathology, Kaohsiung Medical 2005 The WJG Press and Elsevier Inc. All rights reserved.
Center, Chang Gung Memorial Hospital, Chang Gung University,Kaohsiung 83305, Taiwan, China Key words: Hepatocellular carcinoma; Liver transplantation;
Supported by Project Grant NHRI-EX94-9228SP from the National Health Research Institutes and NSC 93-2314-B-182A-084from the National Science Council, Taiwan, China Cheng YF, Huang TL, Chen TY, Chen YS, Wang CC, Hsu Correspondence to: Chao-Long Chen, M.D., Department of SL, Tsang LLC, Sun PL, Chiu KW, Jawan B, Eng HL, Chen Surgery, Chang Gung Memorial Hospital, 123 Taipei Road, Niao- CL. Impact of pre-operative transarterial embolization on the Sung, Kaohsiung 83305, Taiwan, China. [email protected] treatment of hepatocellular carcinoma with liver transplantation.
Received: 2004-09-18 Accepted: 2004-10-08 World J Gastroenterol 2005; 11(10): 1433-1438 http://www.wjgnet.com/1007-9327/11/1433.asp AIM: To determine the effectiveness of pre-liver transplant
(LT) transarterial embolization ( TAE) in treating Hepatocellular carcinoma (HCC) is the most common form hepatocellular carcinoma (HCC) and the patient categories, of primary liver cancer worldwide and has been the leading which are likely to have a good outcome after LT.
cause of cancer death in Taiwan in recent years. HCC causedby the current epidemic of hepatitis B virus-related cirrhosis METHODS: Twenty-nine patients with hepatitis-related
claims the lives of 5 000 people each year in Taiwan. The cirrhosis and unresectable HCC after LT were studied over number of new cases is still steadily increasing[1]. For a 7-year period. The patients were divided into twogroups: group A patients (19/29) received pre-LT TAE, patients with early disease, primary treatment is surgical whereas group B (10/29) underwent LT without prior TAE.
resection whenever possible. Unfortunately, in patients with According to Milan criteria, group A patients were further large and multiple tumors at the time of initial presentation, subdivided into: group A1 (12/19) who met the criteria, surgery is not feasible and their overall survival is usually and group A2 (7/19) who did not. Patient survivals were less than 6 mo[2]. With the advance of surgical techniques in the past few years, LT is now commonly accepted as theoptimal therapeutic measure because not only does it RESULTS: In the explanted liver, CT images correlated
remove the cancer, but it also treats the underlying disease well with pathological specimens showing that TAE with eradication of the cirrhotic tissue that may progress to induced massive tumor necrosis (>85%) in 63.1% of dysplastic nodules or HCC in the future[3]. The current United patients in group A and all 7 patients in group A2 exhibited Network of Organ Sharing (UNOS) policy for organ tumor downgrading that met Milan criteria. The overall allocation among patients with HCCs favors those potential 5-year actuarial survival rate was 80.6%. The TAE group recipients with limited number and diameter of tumor nodule had a better survival (84% at 5 years) than the non-TAE defined by Milan criteria: (A) solitary tumor <5 cm, or B) (75% at 4 years). The 3-year survival of group A2 (83%) three or less lesions, none of them >3 cm[4]. LT can therefore was also higher than that of group A1 (79%). Tumor be offered with a good chance of success to only a relatively necrosis >85% was associated with excellent survival of small proportion of patients, and there is a need for 1434 ISSN 1007-9327 CN 14-1219/ R World J Gastroenterol March 14, 2005 Volume 11 Number 10 associated treatment regimens to improve the operation liver before embolization. The 4 F catheter was advanced rate and to diminish the incidence of recurrence after into the feeding artery as distally as possible. Throughout this study, coaxial 3F catheter was used in all patients. By Various non-surgical therapeutic options for advanced using syringe pump (Razel Scientific Instruments Inc., HCC have been introduced, including TAE, percutaneous Stamford, CT) which can control the injection rate ranging ethanol injection, systemic chemotherapy, hormone therapy, from 0.1 to 1.2 mL/min, a mixture of iodized oil/ethanol immunotherapy, and radiotherapy, among which TAE plays (99.5%) in the ratio of 2:1 was infused selectively into the the major role as a widely accepted treatment[5]. Transarterial supplying artery at a flow rate of 0.5 to 1 mL/min until the embolization (TAE) is a procedure involving the injection adjacent portal branches of the segmental or lobar liver of lipiodol and chemotherapeutic agent into the hepatic were demonstrated. The process was under remote manual artery, followed by embolization with absorbable gelatin fluoroscopic guidance outside the angiographic room.
particles. It produces a selective ischemic and pharmacologic The results of embolization were evaluated by CT in all injury to the tumor that relies mainly on the arterial patients 2 wk after the procedure. We classified the results circulation. TAE was first introduced as a palliative treatment as complete if lipiodol occupied the whole tumor (100%), for patients with inoperable disease and achieved good above 85% as partial embolization, 85% or below as results. In the past few years, the concept of blocking incomplete embolization. All cases with partial or incomplete collateral blood supply to the tumor through complete embolization received second embolization 3 to 4 wk later embolization of liver tissue surrounding the tumor to achieve after liver function was resumed. Following radiological curative treatment for hepatic malignancies has been restaging after TAE, the patients underwent liver proposed. Moreover, the transarterial administration of a transplantation when a graft became available either from mixture of lipiodol and ethanol to create dual hepatic arterial a cadaveric or a living donor. The discovery of extrahepatic and portal venous embolization to attain the effect of lobar tumor either during radiological staging or at laparotomy ablation has been documented[6]. More importantly, TAE has also been applied to improve the resectability of primaryunresectable tumors[7] because it effectively decreases tumor Histopathologic and radiologic studies
size, causes compensatory hepatic hypertrophy, and The explanted liver specimens were examined for features improves ICGR15 that allows a wider range of patients to of tumor disease, including the size, number of nodules, undergo liver surgery with the achievement of a better presence of portal vein thrombosis and percentage of tumornecrosis. The tumor size and number were also measured survival. Pre-transplant adjuvant treatments, therefore, plays on the pre-TAE/LT sonography and CT. The size and an important role in reducing the dropout rate of the waiting number of the tumor on the explanted liver were taken as list for LT. Hence, not only is TAE the treatment of choice the basis for staging to be compared with Milan criteria.
for unresectable HCC to induce tumor necrosis and to Downgrading was defined as the size and number of the control tumor progression, it may also be beneficial for tumors in the explanted liver fully fit the criteria: A) solitary enlisted patients for LT while waiting for the suitable grafts.
The aim of this study is to evaluate the effect of pre- the initial pretreatment images exceeded these criteria.
transplantation TAE on patients with HCC.
Post transplantation management and follow-up
Immunosuppressive therapy after LT consisted of a triple Patient selection
drug regimen of tacrolimus, corticosteroids, and eitherazathioprine or mycophenolate mofetil. Corticosteroids were Patients with histologically proven HCC or a clinical and gradually tapered and were discontinued in 3 mo. All patients radiological presentation strongly suggestive of HCC were were followed up weekly in the outpatient clinic in the first considered for the protocol. All were deemed unresectable, few months after discharge. The frequency of the outpatient either because of anatomic considerations or inadequacy clinic visits thereafter varied according to the patients’ of hepatic reserve. The absence of metastatic tumor was conditions and types of complications. Screening for tumor documented with computed tomography (CT) of the chest, recurrence was assessed by the measurement of serum abdomen, and pelvis. Tumor invasion of the portal vein alpha fetal protein (AFP) and abdominal sonography every was assessed with ultrasound, CT angiography and magnetic 2-3 mo. CT scans of the abdomen and chest were performed resonance scans. Invasion to portal vein was an exclusion criterion. If the patients fully fit the Milan criteria and livergraft was available, then LT proceeded. Otherwise, the Statistical analysis
patients were included into the TAE group. TAE was The biomedical statistical program Statistica 4.0 (Statsoft, performed in the absence of contraindications and poor Tulsa, OK) was used for statistical analysis where appropriate.
liver function in the Child’s class C. If the TAE was well The Kaplan-Meier method was used to calculate survival tolerated, it was repeated if necessary until a donor organ and groups were compared with the log-rank test. P value less than 0.05 was considered significant.
Method of embolization
All patients received complete celiac and superior mesenteric
artery injection for the localization of hepatomas in the In the 8-year period from 1996 to 2003, 29 patients in our program underwent LT treatment for histologically invasion to the portal vein was found in 2 cases that were confirmed HCC associated with cirrhosis. There are 28 underestimated by the pre-operative imaging studies.
male and 1 female with age of 50.03±8.93 years (mean±SD, Pathological evaluation of the explanted liver shows no range: 24-67). The nature of underlying liver cirrhosis was discrepancy between the clinical staging and pathological hepatitis B in 21 (HBsAg positive), hepatitis C (determined finding. Downgrading of HCC was achieved in all 7 patients by HCV RNA testing) in 7, and combined hepatitis B in group A2 to meet the Milan criteria (Figure 1).
In group A, 19 patients (19 males and 0 female, age: 52.4±7.61 years) with sufficient hepatic function underwentTAE in the treatment of HCC before LT. Of these 19 Patient’s tumor and size and distribution (n = 29) patients, 12 met the Milan criteria (group A1) and 7exceeded the criteria (group A2). In group B, 10 patients (9 males and 1 female, age: 45.5±9.89 years) received LT without prior TAE because of available liver graft. Of these 10 patients who met the criteria for transplant, 4 had inadequate liver function for TAE. The mean waiting time from diagnosis to LT was 19.7±18.2 mo in the TAE group and 12.6±12.7 mo in the non-TAE group (Table 1 and Figure 1 Staging of hepatocellular carcinoma before and after TAE.
Twenty-nine patients received embolization before liver transplantation.
Seven patients exceeding criteria (group A2) (outside the box) were Demographics of patients with hepatocellular carcinoma downgraded to acceptable limits (inside the box with arrow).
TAE (group A, %) No TAE (group B, %) P Patient survival and disease-free survival
After LT, all 29 patients were followed for 747.83±391.66 d (mean±SD, range: 204-1920) in the outpatient clinic with ultrasound, CT, and liver function tests. The overall 5-year actuarial survival rate was 80.6% (Figure 2). The survival rates were different between group A (i.e., TAE group) and group B (i.e., non-TAE group) with the former showing a better 5-year survival (84%) than the 4-year survival in the latter (75%) (Figure 3). The 3-year survival of the 7 patients who exceeded the Milan criteria pre-LT and were downgraded by TAE (group A2) was 83% which is better than the patients that met the criteria pre-LT (n = 22) (Figure 4).
In group A1, one patient suffered from lung metastasis 6 mo after LT and died one year later. Microscopic tumor invasion to the portal vein was also noted in the explanted liver of that patient. The other mortality occurred 2.2 years after LT in the downgraded group (group A2). However, the mortality was due to primary lung cancer unrelated to recurrent HCC. In the non-TAE group (group B), one patient was lost due to the recurrence of hepatitis C.
Above Milan criteria before 71 (group A2) 1All downgraded below Milan criteria after TAE.
Histopathologic and radiologic findings
The explanted liver of all 19 patients in group A with pre- LT TAE showed tumor necrosis. Significant tumor necrosis from >85% to 100% was observed in 12 of the 19 patients (63.1%) after TAE. In the other 7 cases, <85% of tumor necrosis was found. The estimated median percentage oftumor necrosis was well correlated with the post-TAE CT Figure 2 The 5-year actuarial survival rate of patients with hepato-
finding and pathological specimen. Microscopic tumor cellular carcinoma after liver transplantation.
1436 ISSN 1007-9327 CN 14-1219/ R World J Gastroenterol March 14, 2005 Volume 11 Number 10 Although the outcome of LT has proved encouraging in the treatment of advanced HCC, the shortage of organs dissuades the policy for organ allocation for malignant disease in Taiwan. The number and size of tumors are considered major factors associated with the risk of tumor recurrence and survival[4]. For patients with liver tumor size and number exceeding the Milan criteria for LT, TAE was beneficial in controlling tumor growth, effectively decreasing tumor size, and allowing a wider range of patients to undergo liver surgery and achieve better survival. Downgrading or totalnecrosis of the tumor induced by TAE was also associated Figure 3 Patient and graft survival by Kaplan-Meier analysis shows
with improved disease-free survival after resection. In this higher 4-year survival in hepatocellular carcinoma that received study, we investigated the influence of TAE on patients pre-transplantation TAE (group A) compared to non-TAE (group B).
undergoing LT for HCC associated with liver cirrhosis.
Although the overall 5-year survival in LT for HCC is 80.6%,which is far behind the overall patients’ survival (afterundergoing LT in our program) of 95% at 5 years, preoperative TAE followed by LT is associated with a better outcome and may be a sensible therapeutic strategy for selected patients with HCC. In our study, TAE before LT appears to be most useful in patients who exceed selection criteria of a single lesion smaller than 5 cm or three lesions smaller than 3 cm. Response to TAE in the form of downgrading or necrosis >85% of the tumor was observed in 63% (12/19) of patients and associated with increased disease-free survival. Response to TAE in these patients has important clinical implications as patients with large tumors are generally considered poor candidates for LT,especially when presenting with multinodular disease. Our Figure 4 Patient and graft survival by Kaplan-Meier analysis shows
results showed that downgrading by TAE is associated with a higher 3-year survival in patients with hepatocellular carcinomapreviously above the Milan criteria and downgraded by TAE (group low incidence of recurrence after LT comparable to that in A2) than the patients that originally met the criteria (group A1 + patients with smaller tumors and should be regarded as a strong argument for patients with advanced HCC to proceedto LT.
The significance of the role of TAE in pre-LT treatment was further underscored by the fact that although group A patients had more advanced HCC and were significantly older compared to those in group B (P<0.05, Table 1), the former actually enjoyed a better survival rate than the latter Cadaveric LT is an excellent treatment for early HCC.
Its use, however, is limited by the shortage of grafts. As a result of prolonged waiting period before transplantation, tumor progression may counteract the benefit of LT. An estimated 30% of patients develop contra-indications to the procedure while waiting for a suitable donor and up to 10% of patients with HCC on transplant waiting list diebefore undergoing LT[8,9]. Surgical resection of the tumor is Figure 5 Patient and graft survival by Kaplan-Meier analysis shows
an optimal bridging treatment, which has been anecdotally a significantly higher 3-year survival in patients with hepatocellularcarcinoma with tumor necrosis >85% compared to those with tumor proposed in many centers[10]. However, acceptable liver necrosis <85% after TAE. Log-rank: P = 0.060.
function is the prerequisite for hepatectomy or tumorresection. In fact, less than 30% of patients who haveadvanced liver cirrhosis would tolerate liver resection[1,2].
Among the 12 patients, whose tumors had undergone So TAE is another treatment of choice in these cirrhotic necrosis >85%, no recurrent tumor was found and their patients to halt or delay tumor progression and to reduce disease-free survival (100% at 3 years) was significantly the impact of a long waiting list and donor shortage. Presence better than the others who showed <85% tumor necrosis of vascular invasion, number of satellite nodules, natural (57.1% at 3 years) (Figure 5) or who did not have TAE history of tumor behavior and response to TAE are powerful predictors of survival in patients with HCC.
Angiography and TAE can demonstrate and offer that the tumor until dual hepatic artery and portal vein additional information. Patients with poor prognostic criteria embolization, early distant metastasis still cannot be prevented.
may be removed from the waiting list.
Unfortunately, the diagnosis of microscopic vascular From the experience using animal model, the nature of invasion can only be made under microscope in vitro and the injected material and the rate of injection had a cannot be predicted or detected by any laboratory tests, significant impact on the actual amount of embolizer that imaging modalities, and even invasive procedures such as reaches the tumor, the adjacent parenchyma, and the portal biopsy and angiography. Since advanced HCC (stage 4) may vein. The pharmacokinetics is especially important for those still achieve 20% 5-year survival post-LT in comparison liquid materials that are not soluble in blood, such as lipiodol/ with 100% mortality without operation[13], all HCC patients ethanol mixture, to pass from the hepatic artery and to the without extrahepatic spread should be offered LT. The portal vein through the presinusoidal communication to create major limiting factors have been organ shortage and cost.
a dual artery and portal vein embolization[11,12]. On the On the basis of the probability of early recurrence, kinetics of the flow, slow injection can produce small droplets candidates with vascular invasion should be excluded from of the liquid embolizer that are carried along with the high velocity main stream towards the feeding vessels of the Pathologic analysis showed that the percentage of tumor tumor. When the velocity of the main blood flow slows necrosis correlated with the results of post-TAE CT. Besides, down during embolization, the embolizer will be evenly post-TAE CT, with lipiodol stasis in HCC, can show nodules distributed inside the tumor and also the adjacent liver previously ignored by CT, ultrasound, and angiography, parenchyma according to the velocity of the blood vessels.
contributing to a more accurate staging of the disease[14,15].
Our results suggest that preoperative TAE can achieve better It indicated that post-TAE CT is a good examination results than those cases with similar tumor sizes but received modality that can be used in the pre-transplant survey that LT without prior TAE. It indicates that the therapeutic effect includes patient selection and outcome prediction after LT.
of the transhepatic artery approach by using lipiodol/ethanol Precise assessment of the size, number, and percentage of mixture is an effective modality in the treatment of HCC tumor necrosis after TAE are among the most powerful predictors of survival in patients with HCC. In addition to Significant tumor necrosis is an important factor that these factors, natural history of tumor behavior can be contributed to the excellent outcome after TAE in our study.
incorporated into future treatment planning. Uncontrolled Our data revealed that recurrence was infrequent in those tumor growth after TAE that does not meet the criteria patients with TAE-induced extensive tumor necrosis who and macroscopic vascular invasion may not be good showed an excellent 100% disease-free survival at 3 years.
candidates for transplantation and could therefore be It is superior to the incomplete embolization group with removed from the waiting list. Other patients with less than 85% tumor necrosis (57.1% at 3 years) or who insufficient tumor necrosis after TAE but within the criteria did not have TAE (75% at 3 years) before LT. Almost all may be selected for early transplantation.
of our patients showed a marked response to pre-transplant In conclusion, our results show a low risk of recurrent TAE, 63% (12/19) of the patients had >85% tumor necrosis HCC in patients treated with preoperative TAE before LT.
or at least greater than 50% tumor size reduction in the These results also provide evidence to redefine the current explanted livers. This high response rate can possibly be rationale behind organ allocation for malignant liver diseases.
explained by the superselective embolization, slow injection The combination of the improved survival rate noted in of the embolizer, dual hepatic artery and portal vein this study and the development of living donor LT may embolization, and the strategy of repeated TAE sessions potentially revolutionize the current scoring system and within a short period of time to achieve maximal necrosis.
scheme of organ allocation that would advocate organ The procedure was well- tolerated in the majority of patients allocation for patients with advanced HCC. For those and caused almost no significant complications.
patients, Pre-LT TAE may be considered the therapeutic Hepatic artery injury during TAE is considered a risk strategy of choice that may reduce their dropout rate for factor for LT that may impair post-transplant survival LT to achieve better patient survival and quality of life.
especially in the living donor liver transplant. Delicateinterventional technique, highly specific selection of intrahepatic artery by using microcatheter, and slow injection Lin TM, Chen CJ, Tsai SF, Tsai TH. Hepatoma in Taiwan. J
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anastomosis. No graft loss due to hepatic artery injury was Study of 850 patients. Cancer 1985; 56: 918-928
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T, Fishbein TM, Emre S, Miller CM, Schwartz ME. Adult liv- In addition to the tumor size and number, vascular ing donor liver transplantation for patients with hepatocellu- invasion is another important predictor of outcome after lar carcinoma: Extending UNOS priority criteria. Ann Surg transplant. Early lung metastasis was also noted in one of 2004; 239: 142-149
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A,
our cases with microscopic tumor invasion to the portal Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari vein. Although TAE was performed by slowly infusing the L. Liver transplantation for the treatment of small hepatocel- mixture of lipiodol and ethanol into the artery supplying lular carcinomas in patients with cirrhosis. N Engl J Med 1996; 1438 ISSN 1007-9327 CN 14-1219/ R World J Gastroenterol March 14, 2005 Volume 11 Number 10 334: 693-699
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