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Living donor liver transplantation for hepatocellular carcinoma
GASTROENTEROLOGY 2004;127:S277–S282
Living Donor Liver Transplantation for Hepatocellular Carcinoma LAURA KULIK* and MICHAEL ABECASSIS† *Departments of Medicine, Division of Hepatology, and †Surgery, Division of Transplantation Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
The incidence of hepatocellular carcinoma (HCC) is increasing at an alarming rate in the United States, such that HCC has become an important indication for liver transplantation. The role of liver transplantation in patients with HCC has evolved over the past 2 decades, and transplantation has become one of the few curative treatment modalities for patients with HCC, especially in selected patients with favorable tumors. The advent of living donor liver transplantation for adult recipients provides another therapeutic venue, in particular for patients with HCC who are disadvantaged by current allocation algorithms for grafts from deceased donors. Living donor transplantation may limit the waiting time and, as a result, may decrease the progression of disease so that intuitively the recurrence rate should be lower than for recipients who wait for an organ from a deceased donor. There are limited data on the efficacy of living donor liver transplantation in the setting of HCC. Based on a limited cohort of patients undergoing transplantation for HCC at Northwestern University Medical Center, a higher recurrence rate, stage for stage, was found in recipients whose transplants were accelerated (“fasttracked”) by performing a living donor transplant, especially in the era in which patients with HCC were disadvantaged by the allocation algorithm. Clearly, the role of living donor liver transplantation in management of patients with HCC requires prospective direct analysis of both recurrence and dropout rates in comparable patient cohorts with HCC undergoing either deceased or living donor liver transplantation.
he incidence of HCC continues to increase at an alarming rate. It is predicted that the burden of HCC will continue to rise in the next 2 decades,1 potentially overwhelming the current number of 18,000 patients listed for orthotopic liver transplant (OLT) in the United States.2 In an effort to bridge the gap between the organ supply and demand, living donor liver transplantation (LDLT) has become an acceptable, alternative treatment option for patients with HCC.
T
Role of Liver Transplantation The role of liver transplantation in patients with HCC has evolved over the last 2 decades as both the medical community and governmental agencies have struggled with the issues of equity and justice versus utility of an increasingly scarce resource (shortage of organs from deceased donors). National allocation policies for these organs have changed significantly because of changing views on the effectiveness of OLT for patients with HCC. Accordingly, in April 2001, the Center for Medicare and Medicaid Services approved a National Coverage Decision expanding the list of covered indications to include HCC. This coverage decision reinforced a recent allocation policy by the United Network for Organ Sharing (UNOS) to assign a relatively higher priority status for patients with HCC awaiting liver transplantation. This optimistic approach to these patients was in sharp contrast to previous pessimism based on published data reflecting a high rate of recurrence and 5-year survival rates of between 18% and 25% in patients with HCC.3,4 These discouraging results of liver transplantation in patients with HCC were because of the lack of appropriate selection of candidates. A pivotal study by Mazzafero et al.6 showed that carefully selected patients with HCC could be successfully transplanted with a survival rate equivalent to patients transplanted without HCC (75% survival at 4 years) and with less than a 10% risk of recurrence.5 This important publication confirmed a similar observation by the transplant community in the United States that led to the change in the UNOS allocation policy for patients with T1 and T2 HCC7 (Table 1). Thus, the Mazzaferro (Milan) criteria (a Abbreviations used in this paper: A2ALL, Adult-to-Adult Living Donor Liver Transplantation Cohort Study; DDLT, deceased donor liver transplantation; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation; UCSF, University of California at San Francisco. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gast.2004.09.042
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Table 1. American Liver Tumor Study Group Modified TumorNode-Metastasis (TNM) Staging Classification Classification TX, NX, MX TO, NO, MO T1 T2 T3 T4a T4b
N1 M1 Stage Stage Stage Stage Stage Stage
I II III IVA1 IVA2 IVB
Definition Not assessed Not found One nodule ⬍ 1.9 cm One nodule 2.0–5.0 cm; 2 or 3 nodules, all ⬍ 3.0 cm One nodule ⬎ 5.0 cm; 2 or 3 nodules, at least one ⬎ 3.0 cm Four or more nodules, any size T2, T3, or T4a plus gross intrahepatic portal or hepatic vein involvement as indicated by CT, MRI, or ultrasound Regional (portal hepatis) nodes involved Metastatic disease, including extrahepatic portal or hepatic vein involvement T1 T2 T3 T4a T4b Any N1, any M1
single lesion ⬍5 cm or 3 lesions ⬍3 cm, without gross vascular invasion) were consistent with the UNOS criteria for HCC. However, waiting time, rather than the patient’s underlying disease severity, remained a major determinant of the local, regional, and national allocation of organs. Therefore, when the National Coverage Decision by the Center for Medicare and Medicaid Services for unresectable HCC within Milan criteria was implemented, there were large regional variations in waiting times and, consequently, in organ availability for patients with HCC, highlighting the need for expanding the donor pool. The first successful LDLT was performed in a child in 1989. Almost a decade later the first successful adult-to-adult LDLT was performed in 1998. The advantage that LDLT offered to patients with HCC was the lack of a lengthy waiting period, which intuitively translates into a decline in the dropout rate because of disease progression. Two decision analysis studies examining the utility and cost-effectiveness of LDLT in patients with HCC published during this time period concluded that LDLT conferred a substantial survival advantage in patients with early stage HCC (3.5 cm) who would otherwise have waited over 7 months for a deceased donor liver transplant (DDLT).8,9 Thus, given that the existing allocation policy for organs from deceased donors clearly placed patients with HCC at a disadvantage, the use of LDLT for patients with HCC represented an excellent treatment option for patients with early stage HCC.
Impact of the Model for End-Stage Liver Disease on Patients With HCC The Model for End-Stage Liver Disease (MELD) adopted by the UNOS on February 27, 2002, changed the allocation of organs from deceased donors dramatically in favor of patients with HCC. A significant advantage was given to patients with T1 (assigned MELD score 24) and T2 (assigned MELD score 29) lesions, who otherwise would not have been transplanted on the basis of synthetic dysfunction alone (calculated MELD score). This assigned priority score had a profound effect on the number of transplants performed for the indication of HCC and also made LDLT less warranted in patients with HCC (within Milan criteria). The trend of a disproportionately high number of patients being transplanted with HCC (23% of DDLT in 11 months) led to a subsequent revision in the assigned priority score given to patients with HCC.10 In February 2003, the assigned MELD score was decreased from 24 and 29 MELD points to 20 and 24, respectively. Subsequently, it was decided that T1 lesions would not be assigned the MELD score advantage. This decision was based on key observations made after the MELD allocation system had been in place for 12 months. Approximately 86% of patients with T1 lesions were being transplanted within 3 months of listing, whereas ⬍10% of patients with T1 lesions were dropping off the list at 1 year because of tumor progression. The downgrading of patients with HCC may make LDLT once again a justifiable procedure as waiting times for the patients increase and as the incidence of HCC rises. There are also growing data that support the superiority of transplantation over resection in selected patients with small tumors which may also play a role in an even further increase in demand for liver transplantation in the setting of HCC.4,11
Living Donor Liver Transplantation in Patients With HCC Despite the increasing interest in LDLT for selected patients with HCC, many questions regarding both the role of the procedure and the risk to the donor remain unanswered. The observed national decrease in the number of LDLT performed in 2002 and 2003 (compared with prior years) has been hypothesized to be a result of 2 separate developments (Figure 1). First, the highly publicized death of a living donor on January 13, 2002, heightened public concern for donor safety and questioned the viability of living donor procedures. Second, the implementation of MELD on February 27, 2002, diminished the necessity for LDLT in patients with HCC given their upgraded status. At our institu-
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Figure 1. Adult liver transplant characteristics, 1993–2002. (Source: OPTN/SRTR as of April 1, 2004.)
tion, the latter explanation is supported by the fact that there was a significant decrease in the number of LDLTs performed for HCC during the first MELD era (02/27/02 to 02/26/03); the total number performed reached a growth plateau when compared with the pre-MELD era (02/27/01 to 02/26/02). There was an overall increase in the percentage of patients with HCC who were transplanted with organs from deceased donors during the first MELD era (38% vs. 18% in the pre-MELD era). This increase can be directly attributed to the implementation of MELD, specifically, the assigned MELD scores for patients with HCC. This institutional trend parallels observed national trends (Table 2). In addition to the use of LDLT for patients with HCC and to decrease the drop out rate due to tumor progression, Yao and coworkers12 have proposed that there be an expansion of the tumor size limits (the University of California, San Francisco [UCSF] criteria). Their criteria consist of a solitary tumor ⱕ6.5 cm or 3 or fewer nodules with the largest ⱕ4.5 cm and a total tumor diameter ⱕ8 cm, without gross vascular invasion. These authors have demonstrated preservation of the 1- and 5-year survival rates of 90% and 75%, respectively, despite an expansion of the anatomical staging of HCC beyond the Milan criteria. Other centers have reported similar encouraging survival and recurrence-free survival rates via retrospective analysis of explants using the USCF criteria.13 At Northwestern, there have been a total of 10 recurrences out of 74 transplants (15 incidental HCC) performed
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with a minimum of 9 months follow-up. Table 3 shows that 75% of the recurrences occurred in patients within UCSF criteria on the basis of pretransplant radiographic examination and 50% occurred in patients who met UCSF criteria in the explant. There are limited data regarding LDLT for HCC and even a greater paucity of data exists comparing the efficacy of LDLT versus DDLT in the clinical setting of HCC. The National Institutes of Health recognized the need to accrue outcomes of a large, diverse population of donors and recipients undergoing LDLT, and in June 2002, announced that 9 of the leading transplant centers in the United States, who perform LDLT, would participate in the “Adult-to-Adult Living Donor Liver Transplantation Cohort Study” (A2ALL).14 The study will span a period of over 7 years. The 2 major aims of the study are (1) to compare DDLT with LDLT and (2) to assess the overall risk to the donor. Within the A2ALL study, subgroups, such as patients with HCC, will be investigated and compared with those who receive a DDLT. The goal is to collect sufficient data from an adequately powered study to generate meaningful guidelines for the use of LDLT, including HCC as the indication for transplantation. Preliminary data collected from the 9 A2ALL centers indicate that 17 of 63 patients with HCC (27%) who received a LDLT (incidental HCC excluded) have had recurrence of the tumor. Radiographically, 56% met Milan criteria pretransplantation. However, 88% of the explants showed at least T3 disease. These findings are consistent with the Northwestern data and suggest that (1) there is significant understaging (radiologic) of HCC pretransplant and (2) the recurrence rate of HCC after a LDLT may be higher than what has traditionally been reported with DDLT. A few single centers have reported their experience with LDLT in the setting of HCC. Gongolesi and coworkers15 recently published the results of 36 LDLTs performed for patients with HCC at Mt. Sinai Hospital. In their cohort, 53% of patients exceeded the UNOS/ Milan criteria. They compared their results with the
Table 2. Increase in Proportion of Decreased Donor Liver Transplants (DDLTs) Done for HCC Paralleled the Decrease in the Numbers of Living Donor Liver Transplants (LDLTs) for HCC, Analyzed According to Pre-MELD or MELD Era All Indications
1 year Pre-MELD (02/27/01-02/26/02) 1 year MELD 1 (02/27/02-02/26/03) 1 year MELD 2 (02/27/03-02/26/04)
HCC
DDLT
LDLT
DDLT
LDLT
TOTAL
36/45 (80%) 48/61 (79%) 16/85 (86%)
9/45 (20%) 13/61 (21%) 12/85 (14%)
4/36 (11%) 20/48 (42%) 16/68 (24%)
4/9 (44%) 3/13 (23%) 2/12 (17%)
8/45 (18%) 23/61 (38%) 18/85 (21%)
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Table 3. Recurrence Rates of HCC After Liver Transplantation in Patients (n ⫽ 10) Who Fulfilled Either the Milan or UCSF Criteria Using Either Radiographic and Explant Staging
Within Milan criteria Radiographic Explant Within UCSF criteria Radiographic Explant
Pre-MELD DDLT
Post-MELD DDLT
LDLT
Others (Splits/Domino)
0/1 0/1
2/2 1/2
1/4 1/4
3/3 3/3
1/1 0/1
2/2 1/2
3/4 2/4
3/3 3/3
outcomes of 165 patients who underwent DDLT for HCC, which showed no significant differences in survival or recurrence rate in both the overall group, as well as in a subset of patients with a tumor size greater than 5 cm. Another report by Lo et al.16 describes a cohort of 51 patients with HCC who met listing criteria (Milan and UCSF criteria). The cohort was divided into 2 groups: those with (group 1, n ⫽ 25) and those without an available living donor (group 2, n ⫽ 26). Patients in the second group were listed for a DDLT without any prioritization specific for HCC. Twenty-one patients in group 1 underwent a LDLT with a mean waiting time of 24 days. The remaining 4 patients in group 1 were subsequently listed for a DDLT. At the time of their publication, only 6 of the 30 patients awaiting transplant received a DDLT after a median waiting time of 344 days. Nineteen of the 30 patients died while awaiting transplant and 2 were removed from the waiting list because of tumor progression, accounting for a 70% drop out rate. There was no significant difference in tumor characteristics found on explant between those who received a LDLT versus a DDLT. Two patients who received a LDLT died from recurrent HCC at 19 and 22 months posttransplant. In the patients who underwent DDLT, 2 died because of recurrent hepatitis B virus infection, with no mention of recurrent HCC. The intention to treat survival at 1, 2, 3, and 4 years was statistically different between group 1 (88%, 76%, 66%, and 66%) and group 2 (72%, 46%, 38%, and 31%). Although the survival advantage of LDLT compared with DDLT is clearly seen in the intention-to-treat analysis, one must be cautious to not be overly optimistic with regard to LDLT for HCC. Despite no significant difference in tumor characteristics, both preoperatively and at explant, other than waiting time, between LDLT and DDLT recipients, there was a higher recurrence rate, accounting for 2 of the 3 deaths in the LDLT group. At Northwestern, we have noted an increase in the recurrence of HCC stage for stage in patients who have undergone “fast tracking” to transplantation, defined as LDLT, partial liver transplants (splits), domino liver
transplant, or MELD upgrade for HCC (unpublished data). Among 315 patients who underwent liver transplantation between 1994 and 2003, 74 had HCC (15 incidental). All patients have had a minimum of 9 months of follow-up. Patients were divided for analysis into 2 eras. Era 1 consisted of only full-sized cadaveric liver transplants. Era 2 began in February 1998 with the performance of the first split liver transplantation. This era also included LDLT, domino transplant, and full-size DDLT. Patients who underwent LDLT, split, domino, or were given a MELD score advantage were considered to be “fast tracked.” We hypothesized that a subset of “fast tracked” patients with a more biologically aggressive tumor, who normally would drop out from the waiting list because of tumor progression, might not be allowed adequate time for the tumor to progress before LDLT. Transplantation of these more aggressive tumors would presumably translate into a higher recurrence rate. Our data shows a 15% recurrence rate (5 of 32) observed in patients with a T1 or T2 stage in the “fast track” group that contrasts sharply with a 0% (0 of 5) in a cohort of patients with T3 or T4 tumors on explant in the “nonfast track” group. When comparing “fast-track” (era 2) versus “non–fast-track” (eras 1 and 2), there was a significant difference in HCC recurrence (P ⫽ 0.044). Although these numbers are small, the data suggest a possible association between recurrence and an accelerated path to transplantation (Table 4).
Factors Affecting Recurrence of HCC After LDLT One intriguing theory for a potentially high recurrence rate in patients with HCC undergoing LDLT is a tumor-enhancing effect of the cytokines, growth factors, and transcription factors that are activated as a result of hepatic regeneration. Indeed, the role of such factors is an ongoing debate with regard to recurrent HCV after LDLT. This theory would require the presence of microscopic extrahepatic tumor at the time of transplantation. Because the surgical techniques in
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Table 4. Recurrence of HCC in Patients Undergoing Liver Transplantation According to Tumor Stage, Era, and Whether the Transplant Was “Accelerated” “Non–Fast-Track”
“Fast-Track”
Stage
Era 1
Era 2
Total
Era 2
P value
T1/T2 T3/T4 Total
0/10 1/3 1/13
0/15 0/5 0/20
0/25 1/8 1/33
5/32 4/9 9/41
0.044
NOTE. During era 1 (09/94 – 02/98), only full-sized deceased donor livers were used. During Era 2 (02/98 – 06/03) “fast-track” recipients included patients who received liver donor, split, or domino livers or MELD advantage. “Non–fast-track” patients included recipients of deceased donor liver transplantation with no MELD advantage.
LDLT are not grossly different from those used in DDLT, especially when the “piggy-back” technique is used, it is unlikely that there is a difference in the presence of residual microscopic HCC in LDLT compared with DDLT. An alternative theory is that patients with HCC undergoing LDLT may be transplanted so quickly that the biologic behavior of the HCC may not have declared itself. In contrast, a patient with an aggressive HCC required to wait for DDLT would “drop out” because of tumor progression. The biologic behavior of HCC appears to be unpredictable, as evidenced by the highly variable doubling times of HCC, which range from 6 to 19 months.17 Traditionally, tumor size has been used as a surrogate marker of biological behavior. However, this approach has been challenged because of its inaccuracy in predicting the degree of the tumor’s aggressive nature.12,18 –21 Several studies have found the presence of microscopic vascular invasion to correlate with the risk of recurrence posttransplant.18,22–26 Unfortunately, this variable can only be determined during the examination of the explant. Preoperative markers of biological behavior, that are able to reasonably predict the risk of recurrence, are clearly needed. Cillo et al.27 suggest that tumor grade may be a helpful tool. In this study, one of the exclusion criteria was poorly differentiated HCC on a fine-needle tumor aspirate. A subsequent cohort of 33 patients with moderately or well-differentiated HCC were prospectively followed for a median follow-up of 44 months post OLT. Thirty-nine percent of the patients were outside the range of the Milan criteria. The majority of the patients (94%) received therapy, transarterial chemoembolization and/or radiofrequency ablation, or percutaneous ethanol injection while awaiting OLT. There have been 3 recurrences, all of which met the Milan criteria pretransplant. The 1-, 3-, and 5-year actuarial survival rates were 94%, 79%, and 75%, respectively. This and other studies suggest that tumor grade may provide invaluable diagnostic information in selecting appropriate transplant candidates. Interestingly, tumor size and
invasion do not appear to correlate with risk of recurrence in patients with well-differentiated tumors.19,21 Marsh et al.28 have also published some intriguing work in the area of predictive markers of biological behavior. Using a combination of artificial neural network with genotyping of the tumor for tumor suppressor gene markers of allelic loss, the authors were able to accurately predict the clinical outcome in 91 of 103 patients transplanted with HCC. If this tool is validated, it could become invaluable in a physician’s decision-making process of which patients with HCC would maximally benefit from liver transplantation, especially in the realm of LDLT. The role of adjuvant therapy for patients awaiting OLT has been used by many centers in an attempt to control tumor growth and ultimately decrease the drop out rate. Although this approach seems quite reasonable, especially with dropout rates ranging from 20% to 50%, randomized control trials to support this treatment are lacking.29,30 The effect of adjuvant therapy on the biological behavior of HCC, if any, is unknown.
Conclusions There is no stated consensus on the use of LDLT for patients with HCC. Under the current MELD allocation system, patients with T2 lesions can be listed for transplant with an assigned MELD score of 24, barring evidence of extrahepatic spread and/or gross vascular invasion. Patients who exceed these criteria may be listed for deceased donor liver transplantation (DDLT); however, they are not assigned the HCC MELD points, making it highly unlikely (although variable depending on the UNOS region) that they will receive a transplant before progression of HCC and their ultimate demise. Therefore, it would appear that LDLT should be reserved for patients with HCC who are unlikely to receive DDLT. The lack of consensus regarding the role of LDLT for patients with HCC is a direct consequence of the lack of adequate data. Thus, large prospective studies such as A2ALL will be instrumental in defining the role of LDLT
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in HCC. The risk of recurrence after LDLT needs to be balanced against the risk of drop out because of tumor progression while awaiting DDLT. The possibility that LDLT may be associated with an increase in the recurrence rate needs to be carefully examined. Although some reports have analyzed the impact of waiting times on recurrence rates after DDLT,15,16 it is clear that the role of LDLT in patients with HCC will only be defined by a direct analysis of both recurrence and dropout rates in comparable patient cohorts with HCC undergoing either DDLT or LDLT.
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16. 17.
18.
19.
20.
References 1. El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: An update. Ann Intern Med 2003;139:817– 823. 2. United Network for Organ Sharing. 3. Yokoyama I, Todo S, Iwatsuki S, Starzl TE. Liver transplantation in the treatment of primary liver cancer. Hepatogastroenterology 1990;37:188 –193. 4. Penn I. Hepatic transplantation for primary and metastatic cancers of the liver. Surgery 1991;110:726 –734; discussion 734 – 735. 5. Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 1993;218:145–155. 6. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693– 699. 7. American Liver Tumor Study Group. A randomized prospective multi-institutional trial of orthotopic liver transplantation or partial hepatic resection with or without adjuvant chemotherapy for hepatocellular carcinoma. Investigator Booklet and Protocol 1998. 8. Cheng SJ, Pratt DS, Freeman RB Jr, Kaplan MM, Wong JB. Livingdonor versus cadaveric liver transplantation for non-resectable small hepatocellular carcinoma and compensated cirrhosis: a decision analysis. Transplantation 2001;72:861– 868. 9. Sarasin FP, Majno PE, Llovet JM, Bruix J, Mentha G, Hadengue A. Living donor liver transplantation for early hepatocellular carcinoma: a life-expectancy and cost-effectiveness perspective. Hepatology 2001;33:1073–1079. 10. Freeman RB Jr, Wiesner RH, Edwards E, Harper A, Merion R, Wolfe R, United Network for Organ Sharing, Organ Procurement and Transplantation Network, Liver and Transplant Committee. Results of the first year of the new liver allocation plan. Liver Transplant 2004;10:7–15. 11. Adam R, Azoulay D, Castaing D, Eshkanazy R, Pascal C, Hashizume R, Samuel D, Bismuth H. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg 2003;238:508 –518; discussion 518 –519. 12. Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394 –1403. 13. Marsh JW, Dvorchik I. Liver organ allocation for hepatocellular carcinoma: are we sure? Liver Transplant 2003;9:693– 696. 14. A2ALL. Available at: www.nih-a2all.orgf. Accessed 15. Gondolesi GE, Roayaie S, Munoz L, Kim-Schluger L, Schiano T, Fishbein TM, Emre S, Miller CM, Schwartz ME. Adult living donor
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liver transplantation for patients with hepatocellular carcinoma: extending UNOS priority criteria. Ann Surg 2004;239:142–149. Lo CM, Fan ST. Liver transplantation for hepatocellular carcinoma. Br J Surg 2004;91:131–133. Ryder SD, British Society of Gastroenterology. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut 2003;52(Suppl 3):iii1– 8. Jonas S, Bechstein WO, Steinmuller T, Herrmann M, Radke C, Berg T, Settmacher U, Neuhaus P. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001; 33:1080 –1086. Klintmalm GB. Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg 1998;228:479 – 490. Hemming AW, Cattral MS, Reed AI, Van Der Werf WJ, Greig PD, Howard RJ. Liver transplantation for hepatocellular carcinoma. Ann Surg 2001;233:652– 659. Tamura S, Kato T, Berho M, Misiakos EP, O’Brien C, Reddy KR, Nery JR, Burke GW, Schiff ER, Miller J, Tzakis AGl. Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch Surg 2001;136:25–30. Schlitt HJ, Neipp M, Weimann A, Oldhafer KJ, Schmoll E, Boeker K, Nashan B, Kubicka S, Maschek H, Tusch G, Raab R, Ringe B, Manns MP, Pilchmayr R. Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation. J Clin Oncol 1999;17:324 –331. Lauwers GY, Terris B, Balis UJ, Batts KP, Regimbeau JM, Chang Y, Graeme-cook F, Yamabe H, Ikai I, Cleary KR, Fujita S, Flejou JF, Zukerberg LR, Nagorney DM, Belghiti J, Yamaoka K, Vauthey JN, International Cooperative Study Group on Hepatocellular Carcinoma. Prognostic histologic indicators of curatively resected hepatocellular carcinomas: a multi-institutional analysis of 425 patients with definition of a histologic prognostic index. Am J Surg Pathol 2002;26:25–34. Vauthey JN, Lauwers GY, Esnaola NF, Do KA, Belghiti J, Mirza N, Curley SA, Ellis LM, Regimbeau JM, Rashid A, Cleary KR, Nagorney DM. Simplified staging for hepatocellular carcinoma. J Clin Oncol 2002;20:1527–1536. Margarit C, Charco R, Hidalgo E, Allende H, Castells L, Bilbao I. Liver transplantation for malignant diseases: selection and pattern of recurrence. World J Surg 2002;26:257–263. Marsh JW, Casavilla A, Iwatsuki S, Dvorchik I, Subotin M, Balan V, Rakela J, Subbotin V, Popechitelev EP. Predicting the risk of tumor recurrence following transplantation for hepatocellular carcinoma. Hepatology 1997;26:1689 –1691. Cillo U, Vitale A, Bassanello M, Boccagni P, Brolese A, Zanus G, Burra P, Fagiuoli S, Farinati F, Rugge M, D’Amico DF. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg 2004;239:150 –159. Marsh JW, Finkelstein SD, Demetris AJ, Swalsky PA, Sasatomi E, Bandos A, Subotin M, Dvorchik I. Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival. Liver Transplant 2003;9: 664 – 671. Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects. J Hepatol 2003;38(Suppl 1):S136 – 149. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519 –524.
Address requests for reprints to: Michael Abecassis, M.D., M.B.A., Division of Organ Transplantation, Feinberg School of Medicine, Northwestern University, Galter Pavilion, Suite 17-200, 675 North St. Clair Street, Chicago, Illinois 60611. e-mail: [email protected]; fax: (312) 695-9194.
Living Donor Liver Transplantation for Hepatocellular Carcinoma LAURA KULIK* and MICHAEL ABECASSIS† *Departments of Medicine, Division of Hepatology, and †Surgery, Division of Transplantation Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
The incidence of hepatocellular carcinoma (HCC) is increasing at an alarming rate in the United States, such that HCC has become an important indication for liver transplantation. The role of liver transplantation in patients with HCC has evolved over the past 2 decades, and transplantation has become one of the few curative treatment modalities for patients with HCC, especially in selected patients with favorable tumors. The advent of living donor liver transplantation for adult recipients provides another therapeutic venue, in particular for patients with HCC who are disadvantaged by current allocation algorithms for grafts from deceased donors. Living donor transplantation may limit the waiting time and, as a result, may decrease the progression of disease so that intuitively the recurrence rate should be lower than for recipients who wait for an organ from a deceased donor. There are limited data on the efficacy of living donor liver transplantation in the setting of HCC. Based on a limited cohort of patients undergoing transplantation for HCC at Northwestern University Medical Center, a higher recurrence rate, stage for stage, was found in recipients whose transplants were accelerated (“fasttracked”) by performing a living donor transplant, especially in the era in which patients with HCC were disadvantaged by the allocation algorithm. Clearly, the role of living donor liver transplantation in management of patients with HCC requires prospective direct analysis of both recurrence and dropout rates in comparable patient cohorts with HCC undergoing either deceased or living donor liver transplantation.
he incidence of HCC continues to increase at an alarming rate. It is predicted that the burden of HCC will continue to rise in the next 2 decades,1 potentially overwhelming the current number of 18,000 patients listed for orthotopic liver transplant (OLT) in the United States.2 In an effort to bridge the gap between the organ supply and demand, living donor liver transplantation (LDLT) has become an acceptable, alternative treatment option for patients with HCC.
T
Role of Liver Transplantation The role of liver transplantation in patients with HCC has evolved over the last 2 decades as both the medical community and governmental agencies have struggled with the issues of equity and justice versus utility of an increasingly scarce resource (shortage of organs from deceased donors). National allocation policies for these organs have changed significantly because of changing views on the effectiveness of OLT for patients with HCC. Accordingly, in April 2001, the Center for Medicare and Medicaid Services approved a National Coverage Decision expanding the list of covered indications to include HCC. This coverage decision reinforced a recent allocation policy by the United Network for Organ Sharing (UNOS) to assign a relatively higher priority status for patients with HCC awaiting liver transplantation. This optimistic approach to these patients was in sharp contrast to previous pessimism based on published data reflecting a high rate of recurrence and 5-year survival rates of between 18% and 25% in patients with HCC.3,4 These discouraging results of liver transplantation in patients with HCC were because of the lack of appropriate selection of candidates. A pivotal study by Mazzafero et al.6 showed that carefully selected patients with HCC could be successfully transplanted with a survival rate equivalent to patients transplanted without HCC (75% survival at 4 years) and with less than a 10% risk of recurrence.5 This important publication confirmed a similar observation by the transplant community in the United States that led to the change in the UNOS allocation policy for patients with T1 and T2 HCC7 (Table 1). Thus, the Mazzaferro (Milan) criteria (a Abbreviations used in this paper: A2ALL, Adult-to-Adult Living Donor Liver Transplantation Cohort Study; DDLT, deceased donor liver transplantation; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation; UCSF, University of California at San Francisco. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gast.2004.09.042
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Table 1. American Liver Tumor Study Group Modified TumorNode-Metastasis (TNM) Staging Classification Classification TX, NX, MX TO, NO, MO T1 T2 T3 T4a T4b
N1 M1 Stage Stage Stage Stage Stage Stage
I II III IVA1 IVA2 IVB
Definition Not assessed Not found One nodule ⬍ 1.9 cm One nodule 2.0–5.0 cm; 2 or 3 nodules, all ⬍ 3.0 cm One nodule ⬎ 5.0 cm; 2 or 3 nodules, at least one ⬎ 3.0 cm Four or more nodules, any size T2, T3, or T4a plus gross intrahepatic portal or hepatic vein involvement as indicated by CT, MRI, or ultrasound Regional (portal hepatis) nodes involved Metastatic disease, including extrahepatic portal or hepatic vein involvement T1 T2 T3 T4a T4b Any N1, any M1
single lesion ⬍5 cm or 3 lesions ⬍3 cm, without gross vascular invasion) were consistent with the UNOS criteria for HCC. However, waiting time, rather than the patient’s underlying disease severity, remained a major determinant of the local, regional, and national allocation of organs. Therefore, when the National Coverage Decision by the Center for Medicare and Medicaid Services for unresectable HCC within Milan criteria was implemented, there were large regional variations in waiting times and, consequently, in organ availability for patients with HCC, highlighting the need for expanding the donor pool. The first successful LDLT was performed in a child in 1989. Almost a decade later the first successful adult-to-adult LDLT was performed in 1998. The advantage that LDLT offered to patients with HCC was the lack of a lengthy waiting period, which intuitively translates into a decline in the dropout rate because of disease progression. Two decision analysis studies examining the utility and cost-effectiveness of LDLT in patients with HCC published during this time period concluded that LDLT conferred a substantial survival advantage in patients with early stage HCC (3.5 cm) who would otherwise have waited over 7 months for a deceased donor liver transplant (DDLT).8,9 Thus, given that the existing allocation policy for organs from deceased donors clearly placed patients with HCC at a disadvantage, the use of LDLT for patients with HCC represented an excellent treatment option for patients with early stage HCC.
Impact of the Model for End-Stage Liver Disease on Patients With HCC The Model for End-Stage Liver Disease (MELD) adopted by the UNOS on February 27, 2002, changed the allocation of organs from deceased donors dramatically in favor of patients with HCC. A significant advantage was given to patients with T1 (assigned MELD score 24) and T2 (assigned MELD score 29) lesions, who otherwise would not have been transplanted on the basis of synthetic dysfunction alone (calculated MELD score). This assigned priority score had a profound effect on the number of transplants performed for the indication of HCC and also made LDLT less warranted in patients with HCC (within Milan criteria). The trend of a disproportionately high number of patients being transplanted with HCC (23% of DDLT in 11 months) led to a subsequent revision in the assigned priority score given to patients with HCC.10 In February 2003, the assigned MELD score was decreased from 24 and 29 MELD points to 20 and 24, respectively. Subsequently, it was decided that T1 lesions would not be assigned the MELD score advantage. This decision was based on key observations made after the MELD allocation system had been in place for 12 months. Approximately 86% of patients with T1 lesions were being transplanted within 3 months of listing, whereas ⬍10% of patients with T1 lesions were dropping off the list at 1 year because of tumor progression. The downgrading of patients with HCC may make LDLT once again a justifiable procedure as waiting times for the patients increase and as the incidence of HCC rises. There are also growing data that support the superiority of transplantation over resection in selected patients with small tumors which may also play a role in an even further increase in demand for liver transplantation in the setting of HCC.4,11
Living Donor Liver Transplantation in Patients With HCC Despite the increasing interest in LDLT for selected patients with HCC, many questions regarding both the role of the procedure and the risk to the donor remain unanswered. The observed national decrease in the number of LDLT performed in 2002 and 2003 (compared with prior years) has been hypothesized to be a result of 2 separate developments (Figure 1). First, the highly publicized death of a living donor on January 13, 2002, heightened public concern for donor safety and questioned the viability of living donor procedures. Second, the implementation of MELD on February 27, 2002, diminished the necessity for LDLT in patients with HCC given their upgraded status. At our institu-
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Figure 1. Adult liver transplant characteristics, 1993–2002. (Source: OPTN/SRTR as of April 1, 2004.)
tion, the latter explanation is supported by the fact that there was a significant decrease in the number of LDLTs performed for HCC during the first MELD era (02/27/02 to 02/26/03); the total number performed reached a growth plateau when compared with the pre-MELD era (02/27/01 to 02/26/02). There was an overall increase in the percentage of patients with HCC who were transplanted with organs from deceased donors during the first MELD era (38% vs. 18% in the pre-MELD era). This increase can be directly attributed to the implementation of MELD, specifically, the assigned MELD scores for patients with HCC. This institutional trend parallels observed national trends (Table 2). In addition to the use of LDLT for patients with HCC and to decrease the drop out rate due to tumor progression, Yao and coworkers12 have proposed that there be an expansion of the tumor size limits (the University of California, San Francisco [UCSF] criteria). Their criteria consist of a solitary tumor ⱕ6.5 cm or 3 or fewer nodules with the largest ⱕ4.5 cm and a total tumor diameter ⱕ8 cm, without gross vascular invasion. These authors have demonstrated preservation of the 1- and 5-year survival rates of 90% and 75%, respectively, despite an expansion of the anatomical staging of HCC beyond the Milan criteria. Other centers have reported similar encouraging survival and recurrence-free survival rates via retrospective analysis of explants using the USCF criteria.13 At Northwestern, there have been a total of 10 recurrences out of 74 transplants (15 incidental HCC) performed
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with a minimum of 9 months follow-up. Table 3 shows that 75% of the recurrences occurred in patients within UCSF criteria on the basis of pretransplant radiographic examination and 50% occurred in patients who met UCSF criteria in the explant. There are limited data regarding LDLT for HCC and even a greater paucity of data exists comparing the efficacy of LDLT versus DDLT in the clinical setting of HCC. The National Institutes of Health recognized the need to accrue outcomes of a large, diverse population of donors and recipients undergoing LDLT, and in June 2002, announced that 9 of the leading transplant centers in the United States, who perform LDLT, would participate in the “Adult-to-Adult Living Donor Liver Transplantation Cohort Study” (A2ALL).14 The study will span a period of over 7 years. The 2 major aims of the study are (1) to compare DDLT with LDLT and (2) to assess the overall risk to the donor. Within the A2ALL study, subgroups, such as patients with HCC, will be investigated and compared with those who receive a DDLT. The goal is to collect sufficient data from an adequately powered study to generate meaningful guidelines for the use of LDLT, including HCC as the indication for transplantation. Preliminary data collected from the 9 A2ALL centers indicate that 17 of 63 patients with HCC (27%) who received a LDLT (incidental HCC excluded) have had recurrence of the tumor. Radiographically, 56% met Milan criteria pretransplantation. However, 88% of the explants showed at least T3 disease. These findings are consistent with the Northwestern data and suggest that (1) there is significant understaging (radiologic) of HCC pretransplant and (2) the recurrence rate of HCC after a LDLT may be higher than what has traditionally been reported with DDLT. A few single centers have reported their experience with LDLT in the setting of HCC. Gongolesi and coworkers15 recently published the results of 36 LDLTs performed for patients with HCC at Mt. Sinai Hospital. In their cohort, 53% of patients exceeded the UNOS/ Milan criteria. They compared their results with the
Table 2. Increase in Proportion of Decreased Donor Liver Transplants (DDLTs) Done for HCC Paralleled the Decrease in the Numbers of Living Donor Liver Transplants (LDLTs) for HCC, Analyzed According to Pre-MELD or MELD Era All Indications
1 year Pre-MELD (02/27/01-02/26/02) 1 year MELD 1 (02/27/02-02/26/03) 1 year MELD 2 (02/27/03-02/26/04)
HCC
DDLT
LDLT
DDLT
LDLT
TOTAL
36/45 (80%) 48/61 (79%) 16/85 (86%)
9/45 (20%) 13/61 (21%) 12/85 (14%)
4/36 (11%) 20/48 (42%) 16/68 (24%)
4/9 (44%) 3/13 (23%) 2/12 (17%)
8/45 (18%) 23/61 (38%) 18/85 (21%)
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Table 3. Recurrence Rates of HCC After Liver Transplantation in Patients (n ⫽ 10) Who Fulfilled Either the Milan or UCSF Criteria Using Either Radiographic and Explant Staging
Within Milan criteria Radiographic Explant Within UCSF criteria Radiographic Explant
Pre-MELD DDLT
Post-MELD DDLT
LDLT
Others (Splits/Domino)
0/1 0/1
2/2 1/2
1/4 1/4
3/3 3/3
1/1 0/1
2/2 1/2
3/4 2/4
3/3 3/3
outcomes of 165 patients who underwent DDLT for HCC, which showed no significant differences in survival or recurrence rate in both the overall group, as well as in a subset of patients with a tumor size greater than 5 cm. Another report by Lo et al.16 describes a cohort of 51 patients with HCC who met listing criteria (Milan and UCSF criteria). The cohort was divided into 2 groups: those with (group 1, n ⫽ 25) and those without an available living donor (group 2, n ⫽ 26). Patients in the second group were listed for a DDLT without any prioritization specific for HCC. Twenty-one patients in group 1 underwent a LDLT with a mean waiting time of 24 days. The remaining 4 patients in group 1 were subsequently listed for a DDLT. At the time of their publication, only 6 of the 30 patients awaiting transplant received a DDLT after a median waiting time of 344 days. Nineteen of the 30 patients died while awaiting transplant and 2 were removed from the waiting list because of tumor progression, accounting for a 70% drop out rate. There was no significant difference in tumor characteristics found on explant between those who received a LDLT versus a DDLT. Two patients who received a LDLT died from recurrent HCC at 19 and 22 months posttransplant. In the patients who underwent DDLT, 2 died because of recurrent hepatitis B virus infection, with no mention of recurrent HCC. The intention to treat survival at 1, 2, 3, and 4 years was statistically different between group 1 (88%, 76%, 66%, and 66%) and group 2 (72%, 46%, 38%, and 31%). Although the survival advantage of LDLT compared with DDLT is clearly seen in the intention-to-treat analysis, one must be cautious to not be overly optimistic with regard to LDLT for HCC. Despite no significant difference in tumor characteristics, both preoperatively and at explant, other than waiting time, between LDLT and DDLT recipients, there was a higher recurrence rate, accounting for 2 of the 3 deaths in the LDLT group. At Northwestern, we have noted an increase in the recurrence of HCC stage for stage in patients who have undergone “fast tracking” to transplantation, defined as LDLT, partial liver transplants (splits), domino liver
transplant, or MELD upgrade for HCC (unpublished data). Among 315 patients who underwent liver transplantation between 1994 and 2003, 74 had HCC (15 incidental). All patients have had a minimum of 9 months of follow-up. Patients were divided for analysis into 2 eras. Era 1 consisted of only full-sized cadaveric liver transplants. Era 2 began in February 1998 with the performance of the first split liver transplantation. This era also included LDLT, domino transplant, and full-size DDLT. Patients who underwent LDLT, split, domino, or were given a MELD score advantage were considered to be “fast tracked.” We hypothesized that a subset of “fast tracked” patients with a more biologically aggressive tumor, who normally would drop out from the waiting list because of tumor progression, might not be allowed adequate time for the tumor to progress before LDLT. Transplantation of these more aggressive tumors would presumably translate into a higher recurrence rate. Our data shows a 15% recurrence rate (5 of 32) observed in patients with a T1 or T2 stage in the “fast track” group that contrasts sharply with a 0% (0 of 5) in a cohort of patients with T3 or T4 tumors on explant in the “nonfast track” group. When comparing “fast-track” (era 2) versus “non–fast-track” (eras 1 and 2), there was a significant difference in HCC recurrence (P ⫽ 0.044). Although these numbers are small, the data suggest a possible association between recurrence and an accelerated path to transplantation (Table 4).
Factors Affecting Recurrence of HCC After LDLT One intriguing theory for a potentially high recurrence rate in patients with HCC undergoing LDLT is a tumor-enhancing effect of the cytokines, growth factors, and transcription factors that are activated as a result of hepatic regeneration. Indeed, the role of such factors is an ongoing debate with regard to recurrent HCV after LDLT. This theory would require the presence of microscopic extrahepatic tumor at the time of transplantation. Because the surgical techniques in
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Table 4. Recurrence of HCC in Patients Undergoing Liver Transplantation According to Tumor Stage, Era, and Whether the Transplant Was “Accelerated” “Non–Fast-Track”
“Fast-Track”
Stage
Era 1
Era 2
Total
Era 2
P value
T1/T2 T3/T4 Total
0/10 1/3 1/13
0/15 0/5 0/20
0/25 1/8 1/33
5/32 4/9 9/41
0.044
NOTE. During era 1 (09/94 – 02/98), only full-sized deceased donor livers were used. During Era 2 (02/98 – 06/03) “fast-track” recipients included patients who received liver donor, split, or domino livers or MELD advantage. “Non–fast-track” patients included recipients of deceased donor liver transplantation with no MELD advantage.
LDLT are not grossly different from those used in DDLT, especially when the “piggy-back” technique is used, it is unlikely that there is a difference in the presence of residual microscopic HCC in LDLT compared with DDLT. An alternative theory is that patients with HCC undergoing LDLT may be transplanted so quickly that the biologic behavior of the HCC may not have declared itself. In contrast, a patient with an aggressive HCC required to wait for DDLT would “drop out” because of tumor progression. The biologic behavior of HCC appears to be unpredictable, as evidenced by the highly variable doubling times of HCC, which range from 6 to 19 months.17 Traditionally, tumor size has been used as a surrogate marker of biological behavior. However, this approach has been challenged because of its inaccuracy in predicting the degree of the tumor’s aggressive nature.12,18 –21 Several studies have found the presence of microscopic vascular invasion to correlate with the risk of recurrence posttransplant.18,22–26 Unfortunately, this variable can only be determined during the examination of the explant. Preoperative markers of biological behavior, that are able to reasonably predict the risk of recurrence, are clearly needed. Cillo et al.27 suggest that tumor grade may be a helpful tool. In this study, one of the exclusion criteria was poorly differentiated HCC on a fine-needle tumor aspirate. A subsequent cohort of 33 patients with moderately or well-differentiated HCC were prospectively followed for a median follow-up of 44 months post OLT. Thirty-nine percent of the patients were outside the range of the Milan criteria. The majority of the patients (94%) received therapy, transarterial chemoembolization and/or radiofrequency ablation, or percutaneous ethanol injection while awaiting OLT. There have been 3 recurrences, all of which met the Milan criteria pretransplant. The 1-, 3-, and 5-year actuarial survival rates were 94%, 79%, and 75%, respectively. This and other studies suggest that tumor grade may provide invaluable diagnostic information in selecting appropriate transplant candidates. Interestingly, tumor size and
invasion do not appear to correlate with risk of recurrence in patients with well-differentiated tumors.19,21 Marsh et al.28 have also published some intriguing work in the area of predictive markers of biological behavior. Using a combination of artificial neural network with genotyping of the tumor for tumor suppressor gene markers of allelic loss, the authors were able to accurately predict the clinical outcome in 91 of 103 patients transplanted with HCC. If this tool is validated, it could become invaluable in a physician’s decision-making process of which patients with HCC would maximally benefit from liver transplantation, especially in the realm of LDLT. The role of adjuvant therapy for patients awaiting OLT has been used by many centers in an attempt to control tumor growth and ultimately decrease the drop out rate. Although this approach seems quite reasonable, especially with dropout rates ranging from 20% to 50%, randomized control trials to support this treatment are lacking.29,30 The effect of adjuvant therapy on the biological behavior of HCC, if any, is unknown.
Conclusions There is no stated consensus on the use of LDLT for patients with HCC. Under the current MELD allocation system, patients with T2 lesions can be listed for transplant with an assigned MELD score of 24, barring evidence of extrahepatic spread and/or gross vascular invasion. Patients who exceed these criteria may be listed for deceased donor liver transplantation (DDLT); however, they are not assigned the HCC MELD points, making it highly unlikely (although variable depending on the UNOS region) that they will receive a transplant before progression of HCC and their ultimate demise. Therefore, it would appear that LDLT should be reserved for patients with HCC who are unlikely to receive DDLT. The lack of consensus regarding the role of LDLT for patients with HCC is a direct consequence of the lack of adequate data. Thus, large prospective studies such as A2ALL will be instrumental in defining the role of LDLT
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in HCC. The risk of recurrence after LDLT needs to be balanced against the risk of drop out because of tumor progression while awaiting DDLT. The possibility that LDLT may be associated with an increase in the recurrence rate needs to be carefully examined. Although some reports have analyzed the impact of waiting times on recurrence rates after DDLT,15,16 it is clear that the role of LDLT in patients with HCC will only be defined by a direct analysis of both recurrence and dropout rates in comparable patient cohorts with HCC undergoing either DDLT or LDLT.
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16. 17.
18.
19.
20.
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Address requests for reprints to: Michael Abecassis, M.D., M.B.A., Division of Organ Transplantation, Feinberg School of Medicine, Northwestern University, Galter Pavilion, Suite 17-200, 675 North St. Clair Street, Chicago, Illinois 60611. e-mail: [email protected]; fax: (312) 695-9194.