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31.
32.
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Bhangui P, Vibert E, Majno P, et al. Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation. Hepatology 2011; 53: 1570. Liang W, Wu L, Ling X, et al. Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl 2012; 18: 1226. Grant RC, Sandhu L, Dixon PR, et al. Living vs. deceased donor liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. Clin Transplant 2013; 27: 140. Yang LY, Fang F, Ou DP, et al. Solitary large hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma with good outcome after hepatic resection. Ann Surg 2009; 249: 118. Chu KK, Chan SC, Fan ST, et al. Radiological prognosticators of hepatocellular carcinoma treated by hepatectomy. Hepatobiliary Pancreat Dis Int 2012; 11: 612. Lu DS, Siripongsakun S, Lee JK, et al. Complete tumor encapsulation on MRI: a potentially useful imaging biomarker for better survival in solitary large hepatocellular carcinoma. Liver Transpl 2013; 19: 283. DuBay D, Sandroussi C, Sandhu L, et al. Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann Surg 2011; 253: 166. Kornberg A, Freesmeyer M, Barthel E, et al. 18F-FDG-uptake of hepatocellular carcinoma on PET predicts microvascular tumor invasion in liver transplant patients. Am J Transplant 2009; 9: 592. Lee JW, Paeng JC, Kang KW, et al. Prediction of tumor recurrence by 18F-FDG PET in liver transplantation for hepatocellular carcinoma. J Nucl Med 2009; 50: 682. Taketomi A, Sanefuji K, Soejima Y, et al. Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation. Transplantation 2009; 87: 531. Choi GH, Park JY, Hwang HK, et al. Predictive factors for longterm survival in patients with clinically significant portal hypertension following resection of hepatocellular carcinoma. Liver Int 2011; 31: 485. Chan SC, Fan ST, Chok KS, et al. Survival advantage of primary liver transplantation for hepatocellular carcinoma within the upto-7 criteria with microvascular invasion. Hepatol Int 2011 Oct 21. [Epub ahead of print].
SECTION 3. CURRENT STATUS OF DOWNSTAGING OF HEPATOCELLULAR CARCINOMA BEFORE LIVER TRANSPLANTATION
William Wei Sharr,1,2 See Ching Chan,1 and Chung-Mau Lo1 Abstract. Liver transplantation (LT) is a well-established option of cure for hepatocellular carcinoma (HCC). Milan criteria is recognized as standard for selection of patients and set the baseline of survival to be achieved. It has been shown that tumor biology including differentiation, vascular invasion, and serum >-fetoprotein (AFP) predict posttransplant recurrence and survival better than morphology. Downstaging by locoregional therapies of HCC before LT, with the response to treatments and progression within observation period, serves as a selection tool rather than modulation of tumor biology. It selects those patients outside standard criteria at presentation but good tumor biology and high chance of The authors declare no funding or conflicts of interest. 1 Department of Surgery, The University of Hong Kong, Hong Kong, SAR, China. 2 Address correspondence to: Dr. William Wei Sharr, Department of Surgery, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, SAR, China. E-mail: [email protected]
Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9708-00 DOI: 10.1097/TP.0000000000000060
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good outcome to receive transplantation. The definition of downstaging should be differentiated from neo-adjuvant therapy, and the objectives in surgical and pretransplant candidates also differ. Published studies in this area showed variation in inclusion criteria, downstaging protocol and assessment of successful downstaging. Tumor biology predownstaging and postdownstaging was not incorporated. Posttransplant outcome were not clearly stated with regard to intention-to-treat survival, disease-free survival, and comparison against those originally within criteria. Meta-analysis of these results was impossible. Nevertheless, majority had reasonable protocol and were able to select patients whom likely to have good outcome. At present, there is no evidence that downstaged patients have a poorer prognosis than those presenting within the Milan criteria. Patients with tumors outside Milan criteria should be offered downstaging therapies. Those who are successfully downstaged to within Milan criteria should be eligible to liver transplant as same as those initially fit the criteria. In the last decade, various extended criteria of HCC for LT have been proposed and reported satisfactory survival. That makes downstaging technically unnecessary. To refine and validate the role of downstaging, it needs collaborative and prospective study with significant sample size, adequate preoperative staging, standardized protocol of selection of patients, and approaches to downstaging. Selection criteria should include histopathological data on tumor biology and serum AFP. There should be standardized definition of successful downstaging. Posttransplant disease-free survival should be reported in detail and compared with those who fit the standard criteria initially. A consistent immunosuppressant protocol is important to avoid bias. Keywords: Liver transplantation, Milan criteria, Hepatocellular carcinoma, Downstaging, Neo-adjuvant, Locoregional therapy, Extended criteria.
epatocellular carcinoma (HCC) is the fifth most common malignancy worldwide (1) and the third most common cause of cancer death, accounting for about one million deaths per year (2). After initial success of liver transplantation (LT) for HCC demonstrating comparable survival to curative resection by Mazzaferro et al (3), orthotropic LT has been recommended as a primary treatment for unresectable HCC within standard criteria. Since 1996, the Milan criteria became the gold standard for selecting patients for LT. However, the disease usually presents in advanced stage and curative surgical treatments including resection and LT can only be attempted in 10%Y20% of patients with HCC (4Y6). In HCC patients treated by locoregional therapies, the 5-year survival was around 30% (7). For unresectable HCC without treatment, the median survival was 6 months, and 1-year survival was 8% (8). To extend the benefit of LT for treatment of unresectable HCC, downstaging with locoregional therapies have been offered to selected patients presented with HCC initially beyond Milan criteria. Successful downstaging can select those patients with favorable tumor biology to receive LT with survival benefit. However, there is no consensus for the definition of downstaging, standardized protocol, and assessment of response. Reported post-transplant outcomes of downstaged patients have been variable. This article clarifies the definition and objective of downstaging therapies in the management of HCC. It reviews options of locoregional therapies for downstaging and new modalities, current evidence of efficacy and posttransplant outcome of downstaged patients. It also discusses the role of
H
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downstaging in the presence of expanding criteria of HCC for LT. It concludes what have been achieved by downstaging and hopefully provides direction for development in the future.
DEFINITION OF DOWNSTAGING AND NEOADJUVANT TREATMENTS OF HCC ‘‘Downstaging’’ applies to any treatment aiming to decrease tumor load (in size and/or number) and alter the stage before definitive surgery. Its concept may overlap to some extent with that of ‘‘neoadjuvant treatment,’’ and practically both may employ the same modality. Downstaging intends to facilitate or make possible a surgical procedure that would otherwise be too risky or unfeasible. Neoadjuvant treatment aims to improve the long-term results, to minimize the complications, or to limit disease progression while waiting for the definitive surgery to be done. In HCC patients, they both apply to locoregional therapies while waiting for surgery or LT. Before resection, downstaging is performed to render nonoperable patients operable or to simplify the surgery for technical reasons, whereas neoadjuvant treatment can be given to improve the result of surgery or longterm survival. For LT candidates with HCC, the objectives of downstaging and neoadjuvant treatments are different. Neoadjuvant treatments before transplantation are given to listed patients to decrease the risk of dropout from the transplant waiting list and to lower the risks of recurrence in the long-term. On the other hand, downstaging before transplantation is offered to selected patients who presented with disease beyond standard criteria. It is used as a selection tool to identify patients with lower risk of posttransplant recurrence among those that would be excluded according to standard criteria (9).
OBJECTIVES OF TREATMENTS OF HCC BEFORE TRANSPLANTATION In the setting of transplantation, local HCC treatments will be considered differently whether a patient is within transplant criteria at presentation (neoadjuvant vs. downstaging). Currently, one third to one half of all HCC patients on the waiting list undergo local HCC treatments before transplantation (10, 11). The type of treatment varies from center to center, but transarterial chemoembolization (TACE) is the most frequently used, followed by radiofrequency ablation (RFA) (10Y13). Neoadjuvant treatments (in contrast to downstaging) are primarily used to decrease the risk of dropout from the waiting list (12, 14Y19). They may improve posttransplant patient survival, as shown by a large UNOS-based study (78% with treatment vs. 75% with surveillance alone at two years, risk ratio=0.785, P=0.014) (13). Patients with full HCC necrosis after TACE have better posttransplant survivals than those with partial response (20, 21). Without delaying LT, the use of neoadjuvant HCC treatments with limited side effects can lower dropout and improve survival. Moreover, the neoadjuvant treatments may be the best palliative option for patients who dropout, without delay while being on the waiting list. For patients with unresectable HCC beyond the accepted standard criteria (Milan, or the University of California San
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Francisco UCSF [UCSF]), successful downstaging and subsequent LT may be the only hope of potential cure. In a recent consensus conference (22), it recommended LT to be considered after successful downstaging and expected a 5-year survival comparable to that of HCC patients who meet the criteria for LT not requiring downstaging. Locoregional therapies may result in decreased tumor size and number to meet the criteria. The goal of downstaging, in addition to meet the morphological criteria, is to select patients with favorable tumor biology reflected by response to treatments and absence of progression upon observation. The posttransplant outcome of these selected patients may be superior to that suggested by morphological criteria alone. This strategy was initially suggested by the group in Hospital Paul Brousse, Paris, who retrospectively observed higher rates of survival after resection or LT in TACE responders than in nonresponders in an analysis of patients with more than 3 nodules or nodules 93 cm (20).
PROBLEMS WITH DOWNSTAGING PROTOCOLS The role of downstaging HCC before transplantation has been the topic of recent debate (23). Downstaging was not widely recognized and adopted because of inconsistent definition, lack of selection criteria, absence of long-term outcome data, and inability to construct prospective studies. The UCSF group initially reported on downstaging with only 16 months of median follow-up, which was too short to assess the risk of HCC recurrence (24). Subsequent report from the same group has proved the excellent survival of transplanted patient after successful downstaging (27). More recent reports have demonstrated successful downstaging in 24%Y90% of patients (Table 1). This wide range of success rates is primarily related to the use of different criteria to include patients in downstaging protocols and different criteria to subsequently decide on listing for transplantation. Some groups consider patients for listing as soon as HCC have decreased in size by 30% or 50%, whereas others will require full necrosis (absence of any uptake on imaging) before doing so (18, 26Y28). In addition, some centers adopt Milan criteria, whereas others use expanded ones (18, 26Y29). Despite these limitations, recent prospective studies have demonstrated that downstaging is a valid strategy before transplant (27, 28, 30). In patients with advanced HCC, not just beyond Milan criteria, but beyond UCSF criteria in some series (5, 31), after successful downstaging, posttransplant disease-free survivals have been reported to be more than 70% at 3 years and intention-to-treat post-HCC treatment survivals between 60% and 70% at 3 years (18, 27, 28, 30). Even with advanced disease, the outcomes are comparable, or even better than the generally accepted minimal long-term posttransplant survival of 50% at 5 years, an unrefined and arbitrary target that holds consensus (32, 33). For these reasons, it sounds reasonable to offer downstaging treatments in any patient beyond transplant criteria and without distant metastasis, even as palliative ones for those who fail to respond. However, the enhanced competition for donor livers after too liberal access to downstaging and subsequent LT raises the necessity to define reasonable selection criteria. Although any patient with HCC beyond transplant criteria may benefit from locoregional treatments, either as downstaging (responder) or palliation (nonresponder), it is
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TABLE 1.
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Selected publications of downstaging HCC before LT
Author
Year Inclusion criteria
Barakat et al. (67) Jang et al. (37) De Luna et al. * (36) Lewandowski et al. (30)
2010 2010 2009 2009
No upper limit No upper limit No upper limit T3
Ravaioli et al. (28)
2008
Chapman et al. (29) Yao et al. (27)
2008 2008
Cillo et al.* (66) Otto et al. (18)
2007 2006
1 e6 cm 2 e5 cm 3Y5 e4 cm Total e12 cm No upper limit 1 e8 cm 2Y3 e5 cm 4Y5 e3 cm Total e8 cm No upper limit No upper limit
Graziadei et al. (26)
2003
No upper limit
TACE
Criteria for DS
Tx Various TACE TACE TARE TACE Various
UNOS T2 Milan Milan UNOS T2
TACE Various
Various TACE
Success
No. LT
OS (%)
DFS (%)
47 (2 25 (5 84 (3 59 (3 19 (3 62 (3
75 (2 yr) 55 (5 yr) 79 (3 yr) NS NS NS
NS 66 (5 yr) NS 89 (1 yr) 73 (1 yr) 71 (3 yr)
56% 42% 63% 58% 31% 90%
14 37 15 9 11 32
ALTSG stage 2 UNOS T2 Tumor necrosis
24% 70%
17 (22%) 35 (57%)
NS 69 (4 yr)
94 (5 yr) 50 (5 yr) 92 (4 yr) 92 (4 yr)
NS RECIST (partial response) R50% reduction in tumor size
NS 55%
31 (78%) 27 (44%)
73 (5 yr) NS
79 (5 yr) NS NS 75 (5 yr)
42%
10 (28%)
31 (5 yr)
41 (4 yr)
Milan
(44%) (10%) (56%) (21%) (26%) (67%)
ITTS (%) yr) yr) yr) yr) yr) yr)
NS
* Listed patients for liver transplantation before downstaging. Tx, Treatment; DS, Downstaging; LT, Liver transplantation; NS, Not stated.; ITTS, Intention-to-treat survival; OS, Overall survival; DFS, Disease free survival; TACE, Transarterial chemoembolization; TARE, Transarterial radioembolization; UNOS, United Network for Organ Sharing; ALTSG, American Liver Tumor Study Group; RECIST, Response Evaluation Criteria In Solid Tumors.
necessary to have a strict and widely accepted selection criteria based on evidence. Besides to generate robust data for research, more importantly, it is to treat all patients (those with HCC within criteria or benign disease) on waiting list equitably. The individual’s perspective has to be balanced with the societal demand, for the responsible use of a scarce resource (9). To establish a reliable selection policy, three areas have to be clearly defined (9): (1) Entry criteria - size/number or total tumor volume of HCC - biological/pathological and molecular markers (2) End-points of successful downstaging - radiological (degree of necrosis, decrease in size) - biological (AFP) (3) Time between downstaging and listing for transplant Entry Criteria The criteria to enter a downstaging program should be able to select patients who have acceptable chances of good outcomes after transplantation if the downstaging is successful. This would limit the expansion of transplant candidate but maintain reasonable outcomes. There is currently no well-defined upper limit for size and number of lesions as eligibility criteria for downstaging, although the presence of vascular invasion and extrahepatic disease are generally considered absolute contraindications. Various scoring systems have been assessed, such as UNOS T3 (one nodule 95 cm or up to 3 nodules with one 93 cm) or combinations of size
and number with up to 5 nodules and a total tumor diameter of 8 or 12 cm (27, 28, 30). Studies reported posttransplant disease-free survival rates over 70% at 3 years (27, 28, 30). According to UNOS T3, patients with more than 3 lesions (even of small size) cannot be considered for downstaging, which maybe too restrictive. In a recent national conference in US (25), the working group proposed inclusion criteria including a single tumor o8 cm or 2 to 3 tumors, each o5 cm, with a total tumor diameter o8 cm. Patients with more than 3 tumors should be considered individually. Studies on total tumor volume (TTV) (10, 11) have shown better radiological accuracy than standard criterion. TTV does not include any number restriction. TTV e250 cm3 has been proposed as selection criteria for downstaging. It corresponds to a single HCC of 7.8 cm in diameter or three HCCs of 5.4 cm, but any size and number combination can be considered as long as the cumulated tumor volume remains within the limit. Downstaging results are still pending. Biological markers such as alpha-fetoprotein (AFP) or PIVKA-II add additional predictive accuracy if used in addition to morphological characteristics (11, 28, 34, 35). They may provide a good assessment of tumor biology, including microvascular invasion, grade and tumor aggressiveness in general. In a Scientific Registry for Transplant Recipients (SRTR)-based study, tumor volume and AFP are independent predictors of post-transplant survival, and that morphological criteria alone will miss many patients with expected poor outcomes (11). Even within Milan criteria, AFP values 9400 ng/ml has been shown to be associated with higher risk of tumor recurrence.
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End-points of Successful Downstaging Transplant criteria after successful downstaging remain to be defined more precisely. It is clear that patients not responding to downstaging should not be considered for transplantation (18, 29). To assess successful downstaging, the most useful parameters are radiological response in terms of viability and size of the tumors and probably biological response measured as a decrease in AFP. Some investigators have accepted for transplantation patients with HCC demonstrating partial response (decrease in size of 30%Y50%). European Association for the Study of the Liver (EASL) guidelines suggest that such assessment should be exclusively based on the amount of viable tumor, as differentiated from necrosis by contrast imaging (18, 26Y28). Extinction of vascularization after treatment can be taken as a surrogate marker for a favorable biology, whereas the probabilities of a distant spread associated with a large tumor size is unlikely to be changed if a lesion is still partially viable. Lesions that are fully inactive on radiology are no longer counted as a nodule in the final score in most studies (27, 28). Most available reports have used the Milan criteria to define successful downstaging (Table 1) (27Y30, 36, 37). Results have been similar to those achieved in patients within Milan from the beginning (36). Some groups add serum AFP concentrations for assessment of downstaging; however, there is no agreement on a threshold. A persistently high AFP after treatment should raise the suspicion of distant spread or vascular invasion and may represent a useful marker of unsuccessful downstaging. It is crucial to define criteria for failure of downstaging including failure to achieve listing criteria, tumor progression with development of vascular invasion, extrahepatic spread, or tumor size and number remaining beyond inclusion criteria. Time Between Downstaging and Listing for Transplant The time interval between downstaging and transplantation can be a selection of HCC with a favorable biology. While waiting for LT, those patients with rapidly recurring lesions, vascular invasion and distant metastases will be selfselected. Some studies did not have minimal surveillance time, but this was achieved naturally by a mean waiting time of at least 6 months between listing after downstaging and the date of transplantation. The most common surveillance time in published reports was 3 months, and appears as the minimum required. Those centers that ‘‘rush’’ to transplant after downstaging may experience poor overall results (38), which shift disease progression on waiting list to posttransplant recurrence. In conclusion, the criteria for inclusion in downstaging protocols used to date (with an upper limit at 8 cm, or 250 cm3), while waiting for external validation within formal protocols, appear reasonable, and have proven to be working. As a measure of achievement of successful downstaging, Milan criteria are generally adopted and counting fully inactive nodules as nonexistent and partially inactive nodules at their original size. Furthermore, patients with AFP remaining greater than 400 ng/ml after treatment are recommended to be excluded, and a minimum observation time of 6 months between entry into the downstaging program and listing for transplantation should be considered.
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OPTIONS OF DOWNSTAGING TREATMENT To downstage, locoregional treatments including radiofrequency ablation (RFA) and trans-arterial chemo-embolization (TACE) are commonly employed. Percutaneous ethanol injection (PEI) has been replaced by RFA in most centers. Transarterial radioembolization (TARE) and high intensity focused ultrasound (HIFU) are proven to be safe and effective modalities, although their places in downstaging are yet to be confirmed. The choice of a downstaging treatment should be based both on the morphological characteristics of the HCC and on the patient condition, balancing the risks and benefits of each technique. The efficiency of some treatments (including TACE and TARE) is linked to HCC biology, with a better response in HCC with higher blood supply and uptake. Others are physicomechanical treatments, like RFA, where an HCC can be destroyed whether well differentiated. Radiofrequency Ablation Radiofrequency ablation uses radiofrequency energy for hyperthermic ablation. It can be performed by interventional radiologist or surgeons, through percutaneous, laparoscopic, or open technique. Over time, it has replaced ethanol injection in the treatment of small HCCs, with a higher rate of complete necrosis (usually more than 90%) and fewer treatment sessions (39Y43). It is most effective for the treatment of HCC o3 cm in diameter. RFA should be avoided for lesions located close to neighboring organs because of the risk thermal injury. For lesions close to pedicle, there is risk of bile duct thermal injury. Theoretically for subcapsular tumor, there is risk of rupture of the liver capsule and seeding of malignant cells in the peritoneal cavity. Another potential complication of RFA is the seeding of cancer along the needle tract, which has been estimated to occur in 1% to 2% (12). In addition, the use of RFA can be hampered by the presence of ascites, which should first be drained. In the absence of transplantation, 5-year survivals up to 30% to 40% can be expected after RFA (39, 41), limited mainly by liver failure, local recurrence and the development of new primaries. As a primary treatment, it has the advantage of repeated usage for treating recurrence. High-Intensity Focused Ultrasound Among various types of ablative treatment of HCC, HIFU is the only modality that is completely extracorporeal. It works by focusing ultrasound beams (0.8Y3.5 MHz) at a distance from the radiating transducer, to a focal region of liver (HCC). The accumulated energy causes heat and tissue necrosis, without damage to surrounding tissue or structures. Although it needs general anesthesia to control breathing and stabilize the liver during ablation, it has the advantage of ‘‘no touch’’ approach, which may minimize risk of surgery or invasive instrumentation with potential risk of tumor seeding. The technique has been developed in China and pioneer investigators showed promising results. The complete ablation rates ranged from 29%Y62% (44Y46). As a treatment for unresectable HCC, 1-yr survival ranged from 43% to 62% (44, 47). In our center, HIFU is an option for treatment of unresectable HCC and also bridging therapy to LT (48). It has been proven to be a safe procedure (49). Long-term results have not been analyzed. Its potential in downstaging treatment should be explored.
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Transarterial Embolization Transarterial embolization is currently the most popular neoadjuvant treatment option for patients with HCC (8, 18, 27, 50). Treatment is usually performed using a combination of mitomycin, adriamycin, or cisplatinum mixed with lipiodol as the drug carrier and an embolization using permanent or reabsorbable occlusive particles (gelatin). After the procedure, the patients are hospitalized for observation (usually for 24 hr). From a meta-analysis of randomized studies comparing TACE to conservative management of incurable HCC patients, TACE demonstrated a significant superiority in terms of survival (51). TACE also allows treatment of larger tumors than RFA and may simplify treatment of patients with multiple tumors. The main risks of TACE are linked to the ischemic insults of the embolization. Patients with large lesions may develop a postembolization syndrome due to tumor necrosis, with fever and abdominal pain. When a large area of liver parenchyma has been embolized, patients are also exposed to the risk of liver failure, and TACE should, as a rule, not be attempted in patients with decreased liver function (ChildYPugh C), or exceptionally with hyperselective TACE by expert hands. Finally, this procedure includes a small risk of arterial injury, estimated at 2% (52). Another limitation is linked to the poor uptake of lipiodol by hypovascular HCC, and these lesions may be better treated with RFA. TACE with drug-eluting beads (DEB) is an attractive alternative to conventional drugs. In the PRECISION V multi-centered randomized trial, use of DEB with Doxorubicin (DEBDOX) showed a significant reduction of systemic toxicity compared with conventional TACE (53). In a recent study comparing conventional and DEBDOX TACE as treatment of HCC in Asian patients (54), DEBDOX showed significantly better treatment response and delayed disease progression.
The choice of a local HCC treatment should be guided by the tumor and patient characteristics, as well as the local expertise. In consideration of the relative advantages and risks of ablative and transarterial approaches, RFA or HIFU is favored for more centrally placed tumors when o3 cm diameter and in candidates with poor liver function who may not tolerate transarterial therapies well. TACE or TARE should receive primary consideration in candidates with satisfactory liver function when tumors are above optimal size for RFA (93 cm) or technically not feasible to receive ablation, when multiple tumors are present or when tumors are in a subcapsular position or adjacent to major vessels or bile ducts. Incomplete control should lead to reevaluation and consideration of the alternative approaches.
Transarterial Radioembolization Transarterial radioembolization is a transarterial procedure, which is performed by embolizing 20- to 30-ml insoluble glass microspheres impregnated with yttrium-90 (a A emitter) (TheraSphere, MDS Nordion, Ottawa, Canada; SIR-Spheres, Sirtex Medical Limited, Australia) (55). The treatment induces a local necrosis of the tumor because of the A emission. This type of local HCC treatment has gained more interest in recent years. It represents an interesting alternative to TACE, as it appears to induce a more efficient decrease in tumor size, with a shorter time to response (4.2 vs. 10.9 months) (30). In addition, TARE can be performed in cases of portal vein thrombosis, a contraindication to TACE. TARE is well tolerated in most patients leading to a discharge within 2Y6 hr (without inpatient surveillance like TACE). The most common side effects include fatigue and flu-like symptoms (30). Several complications of TARE are similar to those of TACE, including the risk of arterial injury (56). The presence of excessive intrahepatic shunting should be excluded by 99Tc-macroaggregated albumin scanning and mesenteric angiogram to minimize the risk of nontarget embolization, especially radiation injury to the lungs (30). Although TARE has several advantages over TACE, its place in the future remains to be fully defined (together with its cost efficiency) (30).
Nowadays, majority of HCC patients at presentation are not candidates for curative resection. A significant proportion is due to underlying liver disease or anatomic consideration. LT provides the only hope of cure in this group of patients with proven survival benefit over conservative treatments, maybe even better than curative resection. Standard criteria based on morphology of tumor and supported by evidence set the baseline post-transplant survival to be achieved, with a balance between scarce donor pool or living donor risk and survival benefit to HCC patients, and an equality of other transplant candidates. With technology and evidence, biology of tumor has been proven to have more prognostic value than morphology. Potentially, patients outside the standard criteria but with good tumor biology can achieve the same outcome and should be offered transplantation. Transplant community is committed to treat the patients with best chance but limited resource, and the success depends on an efficient selection tool. Downstaging of HCC before LT employs locoregional therapies to achieve short-term result in morphology (size and numbers). However, it serves as a selection of good tumor biology rather than modulation. The strategy has been recognized and investigated. Unfortunately, review of published studies of downstaging HCC before LT showed significant heterogeneity in inclusion criteria, approaches to downstaging,
DOWNSTAGING AND EXTENDED CRITERIA Mazzaferro and colleagues achieved 4-year post-OLT actuarial and recurrence-free survival rates of 75% and 83%, respectively, for patients within the Milan criteria (3), and this has become the accepted limit for liver transplantation in many countries. However, this limit has been questioned, and other investigators have shown that extending beyond these criteria may not affect outcome adversely (57, 58). Driven by the demand due to high incidence of HCC especially in Asian population, various extended criteria of HCC for LT have been developed with proven comparable survival to those within standard criteria (Table 2). This makes downstaging with current selection criteria practically unnecessary. Currently, there is no study comparing outcome of LT for downstaged patients and those with extended criteria.
DISCUSSION
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TABLE 2.
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Overview of orthotropic liver transplantation criteria for HCC Overall survival (%)
Institution
Year
No.
Milan (3) UCSF (59)
1996 2001
48 70
UCLA (57) Tokyo (60) Kyoto (62)
2007 2007 2007
467 78 136
Navarra (19)
2007
85
Seoul (65)
2007
140
Fukuoka (64) Hangzhou (61)
2007 2008
40 195
Metroticket (63)
2009
1556
Criteria
Within criteria
Beyond criteria
One tumor e5 cm, or U3 tumors, each e3 cm One tumor e6.5 cm, or U3 tumors, each e4.5 cm Total tumor diameter e8 cm UCSF U5 tumors, each e5 cm (5-5 rule) U10 tumors, all e5 cm PIVKA-II e400 mAU/mL One tumor G6 cm e3 tumors, each e5 cm Any number, tumor diameter U5 cm AFP e400 ng/ml Any number, tumor diameter U5 cm Total tumor diameter e8 cm; or total tumor diameter 98 cm and histopathological grade I or II and preoperative AFP level e400 ng/mL Tumor size (cm)+number e7
85* 75#
50* G30#
81# 94¸ 87#
32# 50¸ 37#
-
-
87#
23#
77¸^ 71#
40¸^ 19#
71#
48#
* 4-year survival rate. # 5-year survival rate. ¸ showing 3-year survival rate. ^ Disease free survival. - Not stated. HCC, Hepatocellular carcinoma; UCSF, University of California San Francisco; UCLA, University of California Los Angeles.
and definition of successful downstaging. Preoperative staging was inadequate. Markers of tumor biology were not included. Recurrence-free survival as the most important outcome was not reported in most studies. High-grade evidence by metaanalysis was impossible. Although the quality of the research in this area needs improvement, there is no evidence at present that downstaged patients have a poorer prognosis than those presenting within the Milan criteria. Most downstaging protocols published appear reasonable. They are able to select patients with a high chance of good outcome, after successful downstaging with subsequent transplant, despite being outside standard criteria at presentation. Current evidence suggests that patients with solitary HCC up to 8 cm in diameter and with up to five tumors (all o4 cm with total tumor diameter o12 cm) can be considered for downstaging. It may be more powerful in selection in combining the TTV score (250 cm3), or with the up-to-seven criteria recently published by the Metroticket collaborative study group (63). These criteria may be further refined by adding AFP as a selection marker, and the cutoff level should be confirmed in further prospective investigations. Patients who reach traditional Milan criteria (inactive tumors counting as zero), with no contraindication to transplantation appearing during a waiting time of at least 3 months (ideally 6 months) have a more favorable biology, as shown by a low recurrence rate. They should be offered liver transplantation and treated equally as those patients within Milan criteria at presentation. Extended criteria and downstaging are not mutually exclusive. Downstaging using refined protocol with respect to extended criteria can also select patients potentially curable but outside the extended criteria. With proven response and survival, that can guide the further expansion of criteria
if possible. Ultimately, both are used to select and treat as many potentially curable patients as possible, with reasonable survival and optimized utilization of resource. More definitive, collaborative clinical study with standardized protocol of downstaging and outcome measurement is needed to validate the role of downstaging. Useful information of tumor biology would be provided by study that incorporated tumor biopsy before downstaging. Posttransplant outcome (disease-free survival) would be compared with that following transplantation for tumors initially within standard criteria. A consistent immunosuppressant protocol would avoid any possible bias caused by differential effects of immunosuppression. In Asian population of high incidence of HCC and large volume of living donor liver transplantation, a registry of data and collaboration among centers can generate robust information and provide important evidence. Transplant community should continue to make effort to extend the benefit of LT to HCC patients who are hopeless of cure at the moment. REFERENCES 1. 2. 3. 4. 5.
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Chapman WC, Majella Doyle MB, Stuart JE, et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann Surg 2008; 248: 617. Lewandowski RJ, Kulik LM, Riaz A, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant 2009; 9: 1920. Sotiropoulos GC, Druhe N, Sgourakis G, et al. Liver transplantation, liver resection, and transarterial chemoembolization for hepatocellular carcinoma in cirrhosis: which is the best oncological approach? Dig Dis Sci 2009; 54: 2264. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002; 35: 519. Majno P, Mazzaferro V. Living donor liver transplantation for hepatocellular carcinoma exceeding conventional criteria: questions, answers and demands for a common language. Liver Transpl 2006; 12: 896. Hasegawa K, Imamura H, Ijichi M, et al. Inclusion of tumor markers improves the correlation of the Milan criteria with vascular invasion and tumor cell differentiation in patients with hepatocellular carcinoma undergoing liver resection (#JGSU-D-07-00462). J Gastrointest Surg 2008; 12: 858. Kim HS, Park JW, Jang JS, et al. Prognostic values of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II in hepatitis B virus-related hepatocellular carcinoma: a prospective study. J Clin Gastroenterol 2009; 43: 482. De LW, Sze DY, Ahmed A, et al. Transarterial chemoinfusion for hepatocellular carcinoma as downstaging therapy and a bridge toward liver transplantation. Am J Transplant 2009; 9: 1158. Jang JW, You CR, Kim CW, et al. Benefit of downsizing hepatocellular carcinoma in a liver transplant population. Aliment Pharmacol Ther 2010; 31: 415. Axelrod D, Koffron A, Kulik L, et al. Living donor liver transplant for malignancy. Transplantation 2005; 79: 363. Rossi S, Di SM, Buscarini E, et al. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR Am J Roentgenol 1996; 167: 759. Livraghi T, Goldberg SN, Lazzaroni S, et al. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 1999; 210: 655. Buscarini L, Buscarini E, Di SM, et al. Percutaneous radiofrequency ablation of small hepatocellular carcinoma: long-term results. Eur Radiol 2001; 11: 914. Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003; 228: 235. Livraghi T, Meloni F, Di SM, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 2008; 47: 82. Wu F, Wang ZB, Chen WZ, et al. Extracorporeal high intensity focused ultrasound ablation in the treatment of patients with large hepatocellular carcinoma. Ann Surg Oncol 2004; 11: 1061. Li YY, Sha WH, Zhou YJ, et al. Short and long term efficacy of high intensity focused ultrasound therapy for advanced hepatocellular carcinoma. J Gastroenterol Hepatol 2007; 22: 2148. Zhang L, Zhu H, Jin C, et al. High-intensity focused ultrasound (HIFU): effective and safe therapy for hepatocellular carcinoma adjacent to major hepatic veins. Eur Radiol 2009; 19: 437. Wu F, Wang ZB, Chen WZ, et al. Advanced hepatocellular carcinoma: treatment with high-intensity focused ultrasound ablation combined with transcatheter arterial embolization. Radiology 2005; 235: 659. Ng KK, Poon TP, Chan SC, et al. High-intensity focused ultrasound for hepatocellular carcinoma. A single-center experience. Ann Surg 2011; 253: 981. Cheung TT, Chu FS, Jenkins CR, et al. Tolerance of high-intensity focused ultrasound ablation in patients with hepatocellular carcinoma. World J Surg 2012; 36: 2420. Herrero JI, Sangro B, Quiroga J, et al. Influence of tumor characteristics on the outcome of liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma. Liver Transpl 2001; 7: 631. Llovet JM, Sala M. Non-surgical therapies of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2005; 17: 505.
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Xia J, Ren Z, Ye S, et al. Study of severe and rare complications of transarterial chemoembolization (TACE) for liver cancer. Eur J Radiol 2006; 59: 407. Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V Study. Cardiovasc Intervent Radiol 2010; 33: 41. Song MJ, Chun HJ, Song DS, et al. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol 2012; 57: 1244. Salem R, Thurston KG, Carr BI, et al. Yttrium-90 microspheres: radiation therapy for unresectable liver cancer. J Vasc Interv Radiol 2002; 13: S223. Riaz A, Lewandowski RJ, Kulik LM, et al. Complications following radioembolization with yttrium-90 microspheres: a comprehensive literature review. J Vasc Interv Radiol 2009; 20: 1121. Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg 2007; 246: 502. Muscari F, Foppa B, Kamar N, et al. Liberal selection criteria for liver transplantation for hepatocellular carcinoma. Br J Surg 2009; 96: 785. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001; 33: 1394. Sugawara Y, Tamura S, Makuuchi M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig Dis 2007; 25: 310. Zheng SS, Xu X, Wu J, et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation 2008; 85: 1726. Takada Y, Ito T, Ueda M, et al. Living donor liver transplantation for patients with HCC exceeding the Milan criteria: a proposal of expanded criteria. Dig Dis 2007; 25: 299. Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009; 10: 35. Soejima Y, Taketomi A, Yoshizumi T, et al. Extended indication for living donor liver transplantation in patients with hepatocellular carcinoma. Transplantation 2007; 83: 893. Kwon CH, Kim DJ, Han YS, et al. HCC in living donor liver transplantation: can we expand the Milan criteria? Dig Dis 2007; 25: 313. Cillo U, Vitale A, Grigoletto F, et al. Intention-to-treat analysis of liver transplantation in selected, aggressively treated HCCpatients exceeding the Milan criteria. Am J Transplant 2007; 7: 972. Barakat O, Wood RP, Ozaki CF, et al. Morphological features of advanced hepatocellular carcinoma as a predictor of downstaging and liver transplantation: an intention-to-treat analysis. Liver Transplantation 2010; 16: 289.
SECTION 4. FURTHER EXPANDING THE CRITERIA FOR HCC IN LIVING DONOR LIVER TRANSPLANTATION: THE TOKYO UNIVERSITY EXPERIENCE
Sumihito Tamura,1 Yasuhiko Sugawara,1,2 and Norihiro Kokudo1 Abstract. In Asia, evidence-based guidelines for the management of hepatocellular carcinoma (HCC) have evolved, including the option of liver transplantation. Because of the continuing serious organ shortage, however, living donor liver transplantation (LDLT) remains the mainstream in Japan. Unlike deceased donor transplantation, living donor transplantation is not always limited by
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the restrictions imposed by the nationwide organ allocation system. The decision for transplantation may depend on institutional or case-by-case considerations, balancing the will of the donor, the operative risk, and the overall survival benefit. Cumulative data from the Japanese national multicenter registry analysis as well as individual center experiences suggest further expanding the criteria for LDLT for HCC from the Milan criteria is feasible with acceptable outcomes. Keywords: Hepatocellular carcinoma, Milan criteria, Tokyo criteria, Expanded criteria.
HCC and Liver Transplantation Liver transplantation is now widely accepted as an effective treatment option for hepatocellular carcinoma (HCC), especially in patients with liver cirrhosis (1Y4). The efficacy of liver transplantation is maximized under limitations regarding size and the number of HCC regions. Among the size and number criteria, the Milan criteria (5), a single tumor up to 5 cm in size or up to 3 tumors no greater than 3 cm in size as determined by preoperative imaging studies, have been the most influential and are widely adopted for deceased donor liver transplantation (DDLT). In the United States, the organ allocation system has evolved to give higher priority for transplantation to patients that fulfill these criteria (6), achieving outcomes comparable to those in patients without HCC, providing significant overall benefit (7). Evidence accumulated over the past decade, however, indicates that the Milan criteria might be too strict. Although evidence - based analysis supports the Milan criteria as the bench mark (8), considerations to extend the criteria have also become justifiable, and modified criteria have been proposed based on 1556 cases by the Metroticket Investigator Study Group, which conceived the original Milan criteria in 1996 (9). The Asian Perspective Asian countries account for at least two thirds of the roughly 650,000 cases of HCC reported globally each year (10). Asian Pacific nations, including Japan have published evidence-based guidelines for the management of HCC (11). The management of HCC in Japan has achieved remarkable results, which are attributed to a combination of quantitative and qualitative evaluations incorporated in the guideline (12Y14). As in the Western countries, liver transplantation has become an important option in the region. Supported by a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grantsin-aid for Research on HIV/AIDS and Research on Measures for Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan. The authors declare no conflicts of interest. 1 Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo and Organ Transplantation Service, the University of Tokyo Hospital. 2 Address correspondence to: Yasuhiko Sugawara, Artificial Organ and Transplantation Division, Hepato-Biliary and Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected]
Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9708-00 DOI: 10.1097/TP.0000000000000060
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
31.
32.
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Bhangui P, Vibert E, Majno P, et al. Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation. Hepatology 2011; 53: 1570. Liang W, Wu L, Ling X, et al. Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl 2012; 18: 1226. Grant RC, Sandhu L, Dixon PR, et al. Living vs. deceased donor liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. Clin Transplant 2013; 27: 140. Yang LY, Fang F, Ou DP, et al. Solitary large hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma with good outcome after hepatic resection. Ann Surg 2009; 249: 118. Chu KK, Chan SC, Fan ST, et al. Radiological prognosticators of hepatocellular carcinoma treated by hepatectomy. Hepatobiliary Pancreat Dis Int 2012; 11: 612. Lu DS, Siripongsakun S, Lee JK, et al. Complete tumor encapsulation on MRI: a potentially useful imaging biomarker for better survival in solitary large hepatocellular carcinoma. Liver Transpl 2013; 19: 283. DuBay D, Sandroussi C, Sandhu L, et al. Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann Surg 2011; 253: 166. Kornberg A, Freesmeyer M, Barthel E, et al. 18F-FDG-uptake of hepatocellular carcinoma on PET predicts microvascular tumor invasion in liver transplant patients. Am J Transplant 2009; 9: 592. Lee JW, Paeng JC, Kang KW, et al. Prediction of tumor recurrence by 18F-FDG PET in liver transplantation for hepatocellular carcinoma. J Nucl Med 2009; 50: 682. Taketomi A, Sanefuji K, Soejima Y, et al. Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation. Transplantation 2009; 87: 531. Choi GH, Park JY, Hwang HK, et al. Predictive factors for longterm survival in patients with clinically significant portal hypertension following resection of hepatocellular carcinoma. Liver Int 2011; 31: 485. Chan SC, Fan ST, Chok KS, et al. Survival advantage of primary liver transplantation for hepatocellular carcinoma within the upto-7 criteria with microvascular invasion. Hepatol Int 2011 Oct 21. [Epub ahead of print].
SECTION 3. CURRENT STATUS OF DOWNSTAGING OF HEPATOCELLULAR CARCINOMA BEFORE LIVER TRANSPLANTATION
William Wei Sharr,1,2 See Ching Chan,1 and Chung-Mau Lo1 Abstract. Liver transplantation (LT) is a well-established option of cure for hepatocellular carcinoma (HCC). Milan criteria is recognized as standard for selection of patients and set the baseline of survival to be achieved. It has been shown that tumor biology including differentiation, vascular invasion, and serum >-fetoprotein (AFP) predict posttransplant recurrence and survival better than morphology. Downstaging by locoregional therapies of HCC before LT, with the response to treatments and progression within observation period, serves as a selection tool rather than modulation of tumor biology. It selects those patients outside standard criteria at presentation but good tumor biology and high chance of The authors declare no funding or conflicts of interest. 1 Department of Surgery, The University of Hong Kong, Hong Kong, SAR, China. 2 Address correspondence to: Dr. William Wei Sharr, Department of Surgery, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, SAR, China. E-mail: [email protected]
Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9708-00 DOI: 10.1097/TP.0000000000000060
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good outcome to receive transplantation. The definition of downstaging should be differentiated from neo-adjuvant therapy, and the objectives in surgical and pretransplant candidates also differ. Published studies in this area showed variation in inclusion criteria, downstaging protocol and assessment of successful downstaging. Tumor biology predownstaging and postdownstaging was not incorporated. Posttransplant outcome were not clearly stated with regard to intention-to-treat survival, disease-free survival, and comparison against those originally within criteria. Meta-analysis of these results was impossible. Nevertheless, majority had reasonable protocol and were able to select patients whom likely to have good outcome. At present, there is no evidence that downstaged patients have a poorer prognosis than those presenting within the Milan criteria. Patients with tumors outside Milan criteria should be offered downstaging therapies. Those who are successfully downstaged to within Milan criteria should be eligible to liver transplant as same as those initially fit the criteria. In the last decade, various extended criteria of HCC for LT have been proposed and reported satisfactory survival. That makes downstaging technically unnecessary. To refine and validate the role of downstaging, it needs collaborative and prospective study with significant sample size, adequate preoperative staging, standardized protocol of selection of patients, and approaches to downstaging. Selection criteria should include histopathological data on tumor biology and serum AFP. There should be standardized definition of successful downstaging. Posttransplant disease-free survival should be reported in detail and compared with those who fit the standard criteria initially. A consistent immunosuppressant protocol is important to avoid bias. Keywords: Liver transplantation, Milan criteria, Hepatocellular carcinoma, Downstaging, Neo-adjuvant, Locoregional therapy, Extended criteria.
epatocellular carcinoma (HCC) is the fifth most common malignancy worldwide (1) and the third most common cause of cancer death, accounting for about one million deaths per year (2). After initial success of liver transplantation (LT) for HCC demonstrating comparable survival to curative resection by Mazzaferro et al (3), orthotropic LT has been recommended as a primary treatment for unresectable HCC within standard criteria. Since 1996, the Milan criteria became the gold standard for selecting patients for LT. However, the disease usually presents in advanced stage and curative surgical treatments including resection and LT can only be attempted in 10%Y20% of patients with HCC (4Y6). In HCC patients treated by locoregional therapies, the 5-year survival was around 30% (7). For unresectable HCC without treatment, the median survival was 6 months, and 1-year survival was 8% (8). To extend the benefit of LT for treatment of unresectable HCC, downstaging with locoregional therapies have been offered to selected patients presented with HCC initially beyond Milan criteria. Successful downstaging can select those patients with favorable tumor biology to receive LT with survival benefit. However, there is no consensus for the definition of downstaging, standardized protocol, and assessment of response. Reported post-transplant outcomes of downstaged patients have been variable. This article clarifies the definition and objective of downstaging therapies in the management of HCC. It reviews options of locoregional therapies for downstaging and new modalities, current evidence of efficacy and posttransplant outcome of downstaged patients. It also discusses the role of
H
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downstaging in the presence of expanding criteria of HCC for LT. It concludes what have been achieved by downstaging and hopefully provides direction for development in the future.
DEFINITION OF DOWNSTAGING AND NEOADJUVANT TREATMENTS OF HCC ‘‘Downstaging’’ applies to any treatment aiming to decrease tumor load (in size and/or number) and alter the stage before definitive surgery. Its concept may overlap to some extent with that of ‘‘neoadjuvant treatment,’’ and practically both may employ the same modality. Downstaging intends to facilitate or make possible a surgical procedure that would otherwise be too risky or unfeasible. Neoadjuvant treatment aims to improve the long-term results, to minimize the complications, or to limit disease progression while waiting for the definitive surgery to be done. In HCC patients, they both apply to locoregional therapies while waiting for surgery or LT. Before resection, downstaging is performed to render nonoperable patients operable or to simplify the surgery for technical reasons, whereas neoadjuvant treatment can be given to improve the result of surgery or longterm survival. For LT candidates with HCC, the objectives of downstaging and neoadjuvant treatments are different. Neoadjuvant treatments before transplantation are given to listed patients to decrease the risk of dropout from the transplant waiting list and to lower the risks of recurrence in the long-term. On the other hand, downstaging before transplantation is offered to selected patients who presented with disease beyond standard criteria. It is used as a selection tool to identify patients with lower risk of posttransplant recurrence among those that would be excluded according to standard criteria (9).
OBJECTIVES OF TREATMENTS OF HCC BEFORE TRANSPLANTATION In the setting of transplantation, local HCC treatments will be considered differently whether a patient is within transplant criteria at presentation (neoadjuvant vs. downstaging). Currently, one third to one half of all HCC patients on the waiting list undergo local HCC treatments before transplantation (10, 11). The type of treatment varies from center to center, but transarterial chemoembolization (TACE) is the most frequently used, followed by radiofrequency ablation (RFA) (10Y13). Neoadjuvant treatments (in contrast to downstaging) are primarily used to decrease the risk of dropout from the waiting list (12, 14Y19). They may improve posttransplant patient survival, as shown by a large UNOS-based study (78% with treatment vs. 75% with surveillance alone at two years, risk ratio=0.785, P=0.014) (13). Patients with full HCC necrosis after TACE have better posttransplant survivals than those with partial response (20, 21). Without delaying LT, the use of neoadjuvant HCC treatments with limited side effects can lower dropout and improve survival. Moreover, the neoadjuvant treatments may be the best palliative option for patients who dropout, without delay while being on the waiting list. For patients with unresectable HCC beyond the accepted standard criteria (Milan, or the University of California San
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Francisco UCSF [UCSF]), successful downstaging and subsequent LT may be the only hope of potential cure. In a recent consensus conference (22), it recommended LT to be considered after successful downstaging and expected a 5-year survival comparable to that of HCC patients who meet the criteria for LT not requiring downstaging. Locoregional therapies may result in decreased tumor size and number to meet the criteria. The goal of downstaging, in addition to meet the morphological criteria, is to select patients with favorable tumor biology reflected by response to treatments and absence of progression upon observation. The posttransplant outcome of these selected patients may be superior to that suggested by morphological criteria alone. This strategy was initially suggested by the group in Hospital Paul Brousse, Paris, who retrospectively observed higher rates of survival after resection or LT in TACE responders than in nonresponders in an analysis of patients with more than 3 nodules or nodules 93 cm (20).
PROBLEMS WITH DOWNSTAGING PROTOCOLS The role of downstaging HCC before transplantation has been the topic of recent debate (23). Downstaging was not widely recognized and adopted because of inconsistent definition, lack of selection criteria, absence of long-term outcome data, and inability to construct prospective studies. The UCSF group initially reported on downstaging with only 16 months of median follow-up, which was too short to assess the risk of HCC recurrence (24). Subsequent report from the same group has proved the excellent survival of transplanted patient after successful downstaging (27). More recent reports have demonstrated successful downstaging in 24%Y90% of patients (Table 1). This wide range of success rates is primarily related to the use of different criteria to include patients in downstaging protocols and different criteria to subsequently decide on listing for transplantation. Some groups consider patients for listing as soon as HCC have decreased in size by 30% or 50%, whereas others will require full necrosis (absence of any uptake on imaging) before doing so (18, 26Y28). In addition, some centers adopt Milan criteria, whereas others use expanded ones (18, 26Y29). Despite these limitations, recent prospective studies have demonstrated that downstaging is a valid strategy before transplant (27, 28, 30). In patients with advanced HCC, not just beyond Milan criteria, but beyond UCSF criteria in some series (5, 31), after successful downstaging, posttransplant disease-free survivals have been reported to be more than 70% at 3 years and intention-to-treat post-HCC treatment survivals between 60% and 70% at 3 years (18, 27, 28, 30). Even with advanced disease, the outcomes are comparable, or even better than the generally accepted minimal long-term posttransplant survival of 50% at 5 years, an unrefined and arbitrary target that holds consensus (32, 33). For these reasons, it sounds reasonable to offer downstaging treatments in any patient beyond transplant criteria and without distant metastasis, even as palliative ones for those who fail to respond. However, the enhanced competition for donor livers after too liberal access to downstaging and subsequent LT raises the necessity to define reasonable selection criteria. Although any patient with HCC beyond transplant criteria may benefit from locoregional treatments, either as downstaging (responder) or palliation (nonresponder), it is
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TABLE 1.
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Selected publications of downstaging HCC before LT
Author
Year Inclusion criteria
Barakat et al. (67) Jang et al. (37) De Luna et al. * (36) Lewandowski et al. (30)
2010 2010 2009 2009
No upper limit No upper limit No upper limit T3
Ravaioli et al. (28)
2008
Chapman et al. (29) Yao et al. (27)
2008 2008
Cillo et al.* (66) Otto et al. (18)
2007 2006
1 e6 cm 2 e5 cm 3Y5 e4 cm Total e12 cm No upper limit 1 e8 cm 2Y3 e5 cm 4Y5 e3 cm Total e8 cm No upper limit No upper limit
Graziadei et al. (26)
2003
No upper limit
TACE
Criteria for DS
Tx Various TACE TACE TARE TACE Various
UNOS T2 Milan Milan UNOS T2
TACE Various
Various TACE
Success
No. LT
OS (%)
DFS (%)
47 (2 25 (5 84 (3 59 (3 19 (3 62 (3
75 (2 yr) 55 (5 yr) 79 (3 yr) NS NS NS
NS 66 (5 yr) NS 89 (1 yr) 73 (1 yr) 71 (3 yr)
56% 42% 63% 58% 31% 90%
14 37 15 9 11 32
ALTSG stage 2 UNOS T2 Tumor necrosis
24% 70%
17 (22%) 35 (57%)
NS 69 (4 yr)
94 (5 yr) 50 (5 yr) 92 (4 yr) 92 (4 yr)
NS RECIST (partial response) R50% reduction in tumor size
NS 55%
31 (78%) 27 (44%)
73 (5 yr) NS
79 (5 yr) NS NS 75 (5 yr)
42%
10 (28%)
31 (5 yr)
41 (4 yr)
Milan
(44%) (10%) (56%) (21%) (26%) (67%)
ITTS (%) yr) yr) yr) yr) yr) yr)
NS
* Listed patients for liver transplantation before downstaging. Tx, Treatment; DS, Downstaging; LT, Liver transplantation; NS, Not stated.; ITTS, Intention-to-treat survival; OS, Overall survival; DFS, Disease free survival; TACE, Transarterial chemoembolization; TARE, Transarterial radioembolization; UNOS, United Network for Organ Sharing; ALTSG, American Liver Tumor Study Group; RECIST, Response Evaluation Criteria In Solid Tumors.
necessary to have a strict and widely accepted selection criteria based on evidence. Besides to generate robust data for research, more importantly, it is to treat all patients (those with HCC within criteria or benign disease) on waiting list equitably. The individual’s perspective has to be balanced with the societal demand, for the responsible use of a scarce resource (9). To establish a reliable selection policy, three areas have to be clearly defined (9): (1) Entry criteria - size/number or total tumor volume of HCC - biological/pathological and molecular markers (2) End-points of successful downstaging - radiological (degree of necrosis, decrease in size) - biological (AFP) (3) Time between downstaging and listing for transplant Entry Criteria The criteria to enter a downstaging program should be able to select patients who have acceptable chances of good outcomes after transplantation if the downstaging is successful. This would limit the expansion of transplant candidate but maintain reasonable outcomes. There is currently no well-defined upper limit for size and number of lesions as eligibility criteria for downstaging, although the presence of vascular invasion and extrahepatic disease are generally considered absolute contraindications. Various scoring systems have been assessed, such as UNOS T3 (one nodule 95 cm or up to 3 nodules with one 93 cm) or combinations of size
and number with up to 5 nodules and a total tumor diameter of 8 or 12 cm (27, 28, 30). Studies reported posttransplant disease-free survival rates over 70% at 3 years (27, 28, 30). According to UNOS T3, patients with more than 3 lesions (even of small size) cannot be considered for downstaging, which maybe too restrictive. In a recent national conference in US (25), the working group proposed inclusion criteria including a single tumor o8 cm or 2 to 3 tumors, each o5 cm, with a total tumor diameter o8 cm. Patients with more than 3 tumors should be considered individually. Studies on total tumor volume (TTV) (10, 11) have shown better radiological accuracy than standard criterion. TTV does not include any number restriction. TTV e250 cm3 has been proposed as selection criteria for downstaging. It corresponds to a single HCC of 7.8 cm in diameter or three HCCs of 5.4 cm, but any size and number combination can be considered as long as the cumulated tumor volume remains within the limit. Downstaging results are still pending. Biological markers such as alpha-fetoprotein (AFP) or PIVKA-II add additional predictive accuracy if used in addition to morphological characteristics (11, 28, 34, 35). They may provide a good assessment of tumor biology, including microvascular invasion, grade and tumor aggressiveness in general. In a Scientific Registry for Transplant Recipients (SRTR)-based study, tumor volume and AFP are independent predictors of post-transplant survival, and that morphological criteria alone will miss many patients with expected poor outcomes (11). Even within Milan criteria, AFP values 9400 ng/ml has been shown to be associated with higher risk of tumor recurrence.
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End-points of Successful Downstaging Transplant criteria after successful downstaging remain to be defined more precisely. It is clear that patients not responding to downstaging should not be considered for transplantation (18, 29). To assess successful downstaging, the most useful parameters are radiological response in terms of viability and size of the tumors and probably biological response measured as a decrease in AFP. Some investigators have accepted for transplantation patients with HCC demonstrating partial response (decrease in size of 30%Y50%). European Association for the Study of the Liver (EASL) guidelines suggest that such assessment should be exclusively based on the amount of viable tumor, as differentiated from necrosis by contrast imaging (18, 26Y28). Extinction of vascularization after treatment can be taken as a surrogate marker for a favorable biology, whereas the probabilities of a distant spread associated with a large tumor size is unlikely to be changed if a lesion is still partially viable. Lesions that are fully inactive on radiology are no longer counted as a nodule in the final score in most studies (27, 28). Most available reports have used the Milan criteria to define successful downstaging (Table 1) (27Y30, 36, 37). Results have been similar to those achieved in patients within Milan from the beginning (36). Some groups add serum AFP concentrations for assessment of downstaging; however, there is no agreement on a threshold. A persistently high AFP after treatment should raise the suspicion of distant spread or vascular invasion and may represent a useful marker of unsuccessful downstaging. It is crucial to define criteria for failure of downstaging including failure to achieve listing criteria, tumor progression with development of vascular invasion, extrahepatic spread, or tumor size and number remaining beyond inclusion criteria. Time Between Downstaging and Listing for Transplant The time interval between downstaging and transplantation can be a selection of HCC with a favorable biology. While waiting for LT, those patients with rapidly recurring lesions, vascular invasion and distant metastases will be selfselected. Some studies did not have minimal surveillance time, but this was achieved naturally by a mean waiting time of at least 6 months between listing after downstaging and the date of transplantation. The most common surveillance time in published reports was 3 months, and appears as the minimum required. Those centers that ‘‘rush’’ to transplant after downstaging may experience poor overall results (38), which shift disease progression on waiting list to posttransplant recurrence. In conclusion, the criteria for inclusion in downstaging protocols used to date (with an upper limit at 8 cm, or 250 cm3), while waiting for external validation within formal protocols, appear reasonable, and have proven to be working. As a measure of achievement of successful downstaging, Milan criteria are generally adopted and counting fully inactive nodules as nonexistent and partially inactive nodules at their original size. Furthermore, patients with AFP remaining greater than 400 ng/ml after treatment are recommended to be excluded, and a minimum observation time of 6 months between entry into the downstaging program and listing for transplantation should be considered.
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OPTIONS OF DOWNSTAGING TREATMENT To downstage, locoregional treatments including radiofrequency ablation (RFA) and trans-arterial chemo-embolization (TACE) are commonly employed. Percutaneous ethanol injection (PEI) has been replaced by RFA in most centers. Transarterial radioembolization (TARE) and high intensity focused ultrasound (HIFU) are proven to be safe and effective modalities, although their places in downstaging are yet to be confirmed. The choice of a downstaging treatment should be based both on the morphological characteristics of the HCC and on the patient condition, balancing the risks and benefits of each technique. The efficiency of some treatments (including TACE and TARE) is linked to HCC biology, with a better response in HCC with higher blood supply and uptake. Others are physicomechanical treatments, like RFA, where an HCC can be destroyed whether well differentiated. Radiofrequency Ablation Radiofrequency ablation uses radiofrequency energy for hyperthermic ablation. It can be performed by interventional radiologist or surgeons, through percutaneous, laparoscopic, or open technique. Over time, it has replaced ethanol injection in the treatment of small HCCs, with a higher rate of complete necrosis (usually more than 90%) and fewer treatment sessions (39Y43). It is most effective for the treatment of HCC o3 cm in diameter. RFA should be avoided for lesions located close to neighboring organs because of the risk thermal injury. For lesions close to pedicle, there is risk of bile duct thermal injury. Theoretically for subcapsular tumor, there is risk of rupture of the liver capsule and seeding of malignant cells in the peritoneal cavity. Another potential complication of RFA is the seeding of cancer along the needle tract, which has been estimated to occur in 1% to 2% (12). In addition, the use of RFA can be hampered by the presence of ascites, which should first be drained. In the absence of transplantation, 5-year survivals up to 30% to 40% can be expected after RFA (39, 41), limited mainly by liver failure, local recurrence and the development of new primaries. As a primary treatment, it has the advantage of repeated usage for treating recurrence. High-Intensity Focused Ultrasound Among various types of ablative treatment of HCC, HIFU is the only modality that is completely extracorporeal. It works by focusing ultrasound beams (0.8Y3.5 MHz) at a distance from the radiating transducer, to a focal region of liver (HCC). The accumulated energy causes heat and tissue necrosis, without damage to surrounding tissue or structures. Although it needs general anesthesia to control breathing and stabilize the liver during ablation, it has the advantage of ‘‘no touch’’ approach, which may minimize risk of surgery or invasive instrumentation with potential risk of tumor seeding. The technique has been developed in China and pioneer investigators showed promising results. The complete ablation rates ranged from 29%Y62% (44Y46). As a treatment for unresectable HCC, 1-yr survival ranged from 43% to 62% (44, 47). In our center, HIFU is an option for treatment of unresectable HCC and also bridging therapy to LT (48). It has been proven to be a safe procedure (49). Long-term results have not been analyzed. Its potential in downstaging treatment should be explored.
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Transarterial Embolization Transarterial embolization is currently the most popular neoadjuvant treatment option for patients with HCC (8, 18, 27, 50). Treatment is usually performed using a combination of mitomycin, adriamycin, or cisplatinum mixed with lipiodol as the drug carrier and an embolization using permanent or reabsorbable occlusive particles (gelatin). After the procedure, the patients are hospitalized for observation (usually for 24 hr). From a meta-analysis of randomized studies comparing TACE to conservative management of incurable HCC patients, TACE demonstrated a significant superiority in terms of survival (51). TACE also allows treatment of larger tumors than RFA and may simplify treatment of patients with multiple tumors. The main risks of TACE are linked to the ischemic insults of the embolization. Patients with large lesions may develop a postembolization syndrome due to tumor necrosis, with fever and abdominal pain. When a large area of liver parenchyma has been embolized, patients are also exposed to the risk of liver failure, and TACE should, as a rule, not be attempted in patients with decreased liver function (ChildYPugh C), or exceptionally with hyperselective TACE by expert hands. Finally, this procedure includes a small risk of arterial injury, estimated at 2% (52). Another limitation is linked to the poor uptake of lipiodol by hypovascular HCC, and these lesions may be better treated with RFA. TACE with drug-eluting beads (DEB) is an attractive alternative to conventional drugs. In the PRECISION V multi-centered randomized trial, use of DEB with Doxorubicin (DEBDOX) showed a significant reduction of systemic toxicity compared with conventional TACE (53). In a recent study comparing conventional and DEBDOX TACE as treatment of HCC in Asian patients (54), DEBDOX showed significantly better treatment response and delayed disease progression.
The choice of a local HCC treatment should be guided by the tumor and patient characteristics, as well as the local expertise. In consideration of the relative advantages and risks of ablative and transarterial approaches, RFA or HIFU is favored for more centrally placed tumors when o3 cm diameter and in candidates with poor liver function who may not tolerate transarterial therapies well. TACE or TARE should receive primary consideration in candidates with satisfactory liver function when tumors are above optimal size for RFA (93 cm) or technically not feasible to receive ablation, when multiple tumors are present or when tumors are in a subcapsular position or adjacent to major vessels or bile ducts. Incomplete control should lead to reevaluation and consideration of the alternative approaches.
Transarterial Radioembolization Transarterial radioembolization is a transarterial procedure, which is performed by embolizing 20- to 30-ml insoluble glass microspheres impregnated with yttrium-90 (a A emitter) (TheraSphere, MDS Nordion, Ottawa, Canada; SIR-Spheres, Sirtex Medical Limited, Australia) (55). The treatment induces a local necrosis of the tumor because of the A emission. This type of local HCC treatment has gained more interest in recent years. It represents an interesting alternative to TACE, as it appears to induce a more efficient decrease in tumor size, with a shorter time to response (4.2 vs. 10.9 months) (30). In addition, TARE can be performed in cases of portal vein thrombosis, a contraindication to TACE. TARE is well tolerated in most patients leading to a discharge within 2Y6 hr (without inpatient surveillance like TACE). The most common side effects include fatigue and flu-like symptoms (30). Several complications of TARE are similar to those of TACE, including the risk of arterial injury (56). The presence of excessive intrahepatic shunting should be excluded by 99Tc-macroaggregated albumin scanning and mesenteric angiogram to minimize the risk of nontarget embolization, especially radiation injury to the lungs (30). Although TARE has several advantages over TACE, its place in the future remains to be fully defined (together with its cost efficiency) (30).
Nowadays, majority of HCC patients at presentation are not candidates for curative resection. A significant proportion is due to underlying liver disease or anatomic consideration. LT provides the only hope of cure in this group of patients with proven survival benefit over conservative treatments, maybe even better than curative resection. Standard criteria based on morphology of tumor and supported by evidence set the baseline post-transplant survival to be achieved, with a balance between scarce donor pool or living donor risk and survival benefit to HCC patients, and an equality of other transplant candidates. With technology and evidence, biology of tumor has been proven to have more prognostic value than morphology. Potentially, patients outside the standard criteria but with good tumor biology can achieve the same outcome and should be offered transplantation. Transplant community is committed to treat the patients with best chance but limited resource, and the success depends on an efficient selection tool. Downstaging of HCC before LT employs locoregional therapies to achieve short-term result in morphology (size and numbers). However, it serves as a selection of good tumor biology rather than modulation. The strategy has been recognized and investigated. Unfortunately, review of published studies of downstaging HCC before LT showed significant heterogeneity in inclusion criteria, approaches to downstaging,
DOWNSTAGING AND EXTENDED CRITERIA Mazzaferro and colleagues achieved 4-year post-OLT actuarial and recurrence-free survival rates of 75% and 83%, respectively, for patients within the Milan criteria (3), and this has become the accepted limit for liver transplantation in many countries. However, this limit has been questioned, and other investigators have shown that extending beyond these criteria may not affect outcome adversely (57, 58). Driven by the demand due to high incidence of HCC especially in Asian population, various extended criteria of HCC for LT have been developed with proven comparable survival to those within standard criteria (Table 2). This makes downstaging with current selection criteria practically unnecessary. Currently, there is no study comparing outcome of LT for downstaged patients and those with extended criteria.
DISCUSSION
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TABLE 2.
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* 2014 Lippincott Williams & Wilkins
Overview of orthotropic liver transplantation criteria for HCC Overall survival (%)
Institution
Year
No.
Milan (3) UCSF (59)
1996 2001
48 70
UCLA (57) Tokyo (60) Kyoto (62)
2007 2007 2007
467 78 136
Navarra (19)
2007
85
Seoul (65)
2007
140
Fukuoka (64) Hangzhou (61)
2007 2008
40 195
Metroticket (63)
2009
1556
Criteria
Within criteria
Beyond criteria
One tumor e5 cm, or U3 tumors, each e3 cm One tumor e6.5 cm, or U3 tumors, each e4.5 cm Total tumor diameter e8 cm UCSF U5 tumors, each e5 cm (5-5 rule) U10 tumors, all e5 cm PIVKA-II e400 mAU/mL One tumor G6 cm e3 tumors, each e5 cm Any number, tumor diameter U5 cm AFP e400 ng/ml Any number, tumor diameter U5 cm Total tumor diameter e8 cm; or total tumor diameter 98 cm and histopathological grade I or II and preoperative AFP level e400 ng/mL Tumor size (cm)+number e7
85* 75#
50* G30#
81# 94¸ 87#
32# 50¸ 37#
-
-
87#
23#
77¸^ 71#
40¸^ 19#
71#
48#
* 4-year survival rate. # 5-year survival rate. ¸ showing 3-year survival rate. ^ Disease free survival. - Not stated. HCC, Hepatocellular carcinoma; UCSF, University of California San Francisco; UCLA, University of California Los Angeles.
and definition of successful downstaging. Preoperative staging was inadequate. Markers of tumor biology were not included. Recurrence-free survival as the most important outcome was not reported in most studies. High-grade evidence by metaanalysis was impossible. Although the quality of the research in this area needs improvement, there is no evidence at present that downstaged patients have a poorer prognosis than those presenting within the Milan criteria. Most downstaging protocols published appear reasonable. They are able to select patients with a high chance of good outcome, after successful downstaging with subsequent transplant, despite being outside standard criteria at presentation. Current evidence suggests that patients with solitary HCC up to 8 cm in diameter and with up to five tumors (all o4 cm with total tumor diameter o12 cm) can be considered for downstaging. It may be more powerful in selection in combining the TTV score (250 cm3), or with the up-to-seven criteria recently published by the Metroticket collaborative study group (63). These criteria may be further refined by adding AFP as a selection marker, and the cutoff level should be confirmed in further prospective investigations. Patients who reach traditional Milan criteria (inactive tumors counting as zero), with no contraindication to transplantation appearing during a waiting time of at least 3 months (ideally 6 months) have a more favorable biology, as shown by a low recurrence rate. They should be offered liver transplantation and treated equally as those patients within Milan criteria at presentation. Extended criteria and downstaging are not mutually exclusive. Downstaging using refined protocol with respect to extended criteria can also select patients potentially curable but outside the extended criteria. With proven response and survival, that can guide the further expansion of criteria
if possible. Ultimately, both are used to select and treat as many potentially curable patients as possible, with reasonable survival and optimized utilization of resource. More definitive, collaborative clinical study with standardized protocol of downstaging and outcome measurement is needed to validate the role of downstaging. Useful information of tumor biology would be provided by study that incorporated tumor biopsy before downstaging. Posttransplant outcome (disease-free survival) would be compared with that following transplantation for tumors initially within standard criteria. A consistent immunosuppressant protocol would avoid any possible bias caused by differential effects of immunosuppression. In Asian population of high incidence of HCC and large volume of living donor liver transplantation, a registry of data and collaboration among centers can generate robust information and provide important evidence. Transplant community should continue to make effort to extend the benefit of LT to HCC patients who are hopeless of cure at the moment. REFERENCES 1. 2. 3. 4. 5.
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Chapman WC, Majella Doyle MB, Stuart JE, et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann Surg 2008; 248: 617. Lewandowski RJ, Kulik LM, Riaz A, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant 2009; 9: 1920. Sotiropoulos GC, Druhe N, Sgourakis G, et al. Liver transplantation, liver resection, and transarterial chemoembolization for hepatocellular carcinoma in cirrhosis: which is the best oncological approach? Dig Dis Sci 2009; 54: 2264. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002; 35: 519. Majno P, Mazzaferro V. Living donor liver transplantation for hepatocellular carcinoma exceeding conventional criteria: questions, answers and demands for a common language. Liver Transpl 2006; 12: 896. Hasegawa K, Imamura H, Ijichi M, et al. Inclusion of tumor markers improves the correlation of the Milan criteria with vascular invasion and tumor cell differentiation in patients with hepatocellular carcinoma undergoing liver resection (#JGSU-D-07-00462). J Gastrointest Surg 2008; 12: 858. Kim HS, Park JW, Jang JS, et al. Prognostic values of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II in hepatitis B virus-related hepatocellular carcinoma: a prospective study. J Clin Gastroenterol 2009; 43: 482. De LW, Sze DY, Ahmed A, et al. Transarterial chemoinfusion for hepatocellular carcinoma as downstaging therapy and a bridge toward liver transplantation. Am J Transplant 2009; 9: 1158. Jang JW, You CR, Kim CW, et al. Benefit of downsizing hepatocellular carcinoma in a liver transplant population. Aliment Pharmacol Ther 2010; 31: 415. Axelrod D, Koffron A, Kulik L, et al. Living donor liver transplant for malignancy. Transplantation 2005; 79: 363. Rossi S, Di SM, Buscarini E, et al. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR Am J Roentgenol 1996; 167: 759. Livraghi T, Goldberg SN, Lazzaroni S, et al. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 1999; 210: 655. Buscarini L, Buscarini E, Di SM, et al. Percutaneous radiofrequency ablation of small hepatocellular carcinoma: long-term results. Eur Radiol 2001; 11: 914. Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003; 228: 235. Livraghi T, Meloni F, Di SM, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 2008; 47: 82. Wu F, Wang ZB, Chen WZ, et al. Extracorporeal high intensity focused ultrasound ablation in the treatment of patients with large hepatocellular carcinoma. Ann Surg Oncol 2004; 11: 1061. Li YY, Sha WH, Zhou YJ, et al. Short and long term efficacy of high intensity focused ultrasound therapy for advanced hepatocellular carcinoma. J Gastroenterol Hepatol 2007; 22: 2148. Zhang L, Zhu H, Jin C, et al. High-intensity focused ultrasound (HIFU): effective and safe therapy for hepatocellular carcinoma adjacent to major hepatic veins. Eur Radiol 2009; 19: 437. Wu F, Wang ZB, Chen WZ, et al. Advanced hepatocellular carcinoma: treatment with high-intensity focused ultrasound ablation combined with transcatheter arterial embolization. Radiology 2005; 235: 659. Ng KK, Poon TP, Chan SC, et al. High-intensity focused ultrasound for hepatocellular carcinoma. A single-center experience. Ann Surg 2011; 253: 981. Cheung TT, Chu FS, Jenkins CR, et al. Tolerance of high-intensity focused ultrasound ablation in patients with hepatocellular carcinoma. World J Surg 2012; 36: 2420. Herrero JI, Sangro B, Quiroga J, et al. Influence of tumor characteristics on the outcome of liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma. Liver Transpl 2001; 7: 631. Llovet JM, Sala M. Non-surgical therapies of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2005; 17: 505.
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SECTION 4. FURTHER EXPANDING THE CRITERIA FOR HCC IN LIVING DONOR LIVER TRANSPLANTATION: THE TOKYO UNIVERSITY EXPERIENCE
Sumihito Tamura,1 Yasuhiko Sugawara,1,2 and Norihiro Kokudo1 Abstract. In Asia, evidence-based guidelines for the management of hepatocellular carcinoma (HCC) have evolved, including the option of liver transplantation. Because of the continuing serious organ shortage, however, living donor liver transplantation (LDLT) remains the mainstream in Japan. Unlike deceased donor transplantation, living donor transplantation is not always limited by
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the restrictions imposed by the nationwide organ allocation system. The decision for transplantation may depend on institutional or case-by-case considerations, balancing the will of the donor, the operative risk, and the overall survival benefit. Cumulative data from the Japanese national multicenter registry analysis as well as individual center experiences suggest further expanding the criteria for LDLT for HCC from the Milan criteria is feasible with acceptable outcomes. Keywords: Hepatocellular carcinoma, Milan criteria, Tokyo criteria, Expanded criteria.
HCC and Liver Transplantation Liver transplantation is now widely accepted as an effective treatment option for hepatocellular carcinoma (HCC), especially in patients with liver cirrhosis (1Y4). The efficacy of liver transplantation is maximized under limitations regarding size and the number of HCC regions. Among the size and number criteria, the Milan criteria (5), a single tumor up to 5 cm in size or up to 3 tumors no greater than 3 cm in size as determined by preoperative imaging studies, have been the most influential and are widely adopted for deceased donor liver transplantation (DDLT). In the United States, the organ allocation system has evolved to give higher priority for transplantation to patients that fulfill these criteria (6), achieving outcomes comparable to those in patients without HCC, providing significant overall benefit (7). Evidence accumulated over the past decade, however, indicates that the Milan criteria might be too strict. Although evidence - based analysis supports the Milan criteria as the bench mark (8), considerations to extend the criteria have also become justifiable, and modified criteria have been proposed based on 1556 cases by the Metroticket Investigator Study Group, which conceived the original Milan criteria in 1996 (9). The Asian Perspective Asian countries account for at least two thirds of the roughly 650,000 cases of HCC reported globally each year (10). Asian Pacific nations, including Japan have published evidence-based guidelines for the management of HCC (11). The management of HCC in Japan has achieved remarkable results, which are attributed to a combination of quantitative and qualitative evaluations incorporated in the guideline (12Y14). As in the Western countries, liver transplantation has become an important option in the region. Supported by a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grantsin-aid for Research on HIV/AIDS and Research on Measures for Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan. The authors declare no conflicts of interest. 1 Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo and Organ Transplantation Service, the University of Tokyo Hospital. 2 Address correspondence to: Yasuhiko Sugawara, Artificial Organ and Transplantation Division, Hepato-Biliary and Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected]
Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9708-00 DOI: 10.1097/TP.0000000000000060
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
