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Keywords:

  • liver transplantation;
  • locoregional therapy;
  • neo-adjuvant therapy

Abstract

  1. Top of page
  2. Abstract
  3. Neo-adjuvant locoregional therapy for hepatocellular carcinoma
  4. Transarterial therapies
  5. Which neo-adjuvant strategy should be used?
  6. Downstaging for hepatocellular carcinoma beyond the Milan criteria
  7. Endpoints of successful downstaging before liver transplantation
  8. Response of the tumour markers to locoregional therapy
  9. Should we treat patients within Milan criteria hepatocellular carcinoma?
  10. Conclusion
  11. References

Because of its increasing incidence of hepatocellular carcinoma, it is now recognized as a worldwide health problem affecting mostly patients with chronic liver disease. Liver transplantation is the optimal therapy and achieves its best results in patients with small tumour burden. In an effort to prevent tumour progression and patient dropout from the transplant wait list, the concept and utilization of neo-adjuvant locoregional therapies have gained relevance in the past few years. Moreover, good and maintained response to therapy is now considered a surrogate of favourable tumour biology, therefore aiding the patient transplant selection process. Herein, we review the current role of neo-adjuvant therapies and revise concepts of tumour ‘downstaging’ or ‘bridging therapy’ in the setting of liver transplantation. In addition, we explore the debate of implementing locoregional therapy for patients with small tumours and short waiting times to liver transplantation.

Abbreviations
DEB,

drug-eluting beads;

PEI,

percutaneous ethanol injection;

RFA,

radiofrequency ablation;

TACE,

transarterial chemo-embolization;

TACI,

transarterial chemo-infusion;

TARE,

transarterial radio-embolization;

UCSF,

University of California at San Francisco.

Hepatocellular carcinoma (HCC) constitutes the third most common cause of cancer death worldwide. Cirrhosis induced by hepatitis C and hepatitis B carries the higher risk for HCC in western and Asian countries respectively (1–3). The global complexity of the patient with chronic liver disease and the heterogeneity of HCCs continue to challenge the development of effective treatments. However, various therapies for HCC have evolved during the past two decades. These include surgical, locoregional and drug-based therapies. Liver transplantation and surgical resection are potentially curative, while locoregional therapies are meant to downstage or ‘bridge’ tumours to transplantation or to treat tumours not amenable to surgical intervention. Compared with surgical resection, liver transplantation is associated with better overall and disease-free survival in well-selected patients (5 year-DFS>75 vs. 50%) (4–6). Not long ago, liver transplantation was considered to be a contra-indication for HCC because of unacceptable post-transplant recurrent rates (7, 8). It was Bismuth who initially reported good outcomes with liver transplantation for small HCC (9), and subsequently, Mazzaferro introduced the Milan or T2 criteria (one lesion≤5 cm, or two to three lesions≤3 cm) reporting liver transplantation for HCC with equivalent outcomes to non-HCC patients (4 year-DFS >80%) (10). At present, the Milan Criteria are adopted as a guideline to liver transplantation for HCC. In North America as well as in many other world regions, patients within Milan criteria HCC are given priority to liver transplantation to prevent disease progression and wait list dropout (11–13).

Pretransplant locoregional therapy has been adopted by the liver transplant community worldwide. The rationale of implementing pretransplant locoregional therapy is two-fold. Locoreginal therapy for HCC beyond the Milan criteria has been performed with the purpose of downstaging HCC into the Milan criteria. This enables substantially the expansion of liver transplantation candidates with potential good outcomes after transplantation. Although no survival benefit has been proven with the implementation of pretransplant locoregional therapy, response to neo-adjuvant locoregional therapy has been considered a surrogate of favourable tumour biology (14–17). In line with this, more recently, the concept of ‘ablate and wait’ strategy has gained popularity among transplant centres (18). This concept points out the need to address tumour stability over a period of time (wait) after neo-adjuvant treatment (ablate) as a way to predict post-transplant outcomes.

Another aim of pretransplant locoregional therapy is to prevent tumour progression and wait list dropout in patients within Milan criteria HCC. This concept, known as ‘bridging therapy’, finds no general consensus among transplant centres regarding when it should be implemented. Some transplant specialists suggest that there is no proven benefit for this group of patients to undergo neo-adjuvant bridging therapy unless the waiting time to transplant is longer than 6 months (19, 20). On the other hand, other investigators propose locoregional therapy when the expected waiting time to liver transplantation is 3–6 months if patients have a higher risk of wait list dropout due to tumour progression (11).

Although associated with good results, around 10% of within Milan criteria HCC patients will exhibit post-transplant recurrence (21–23) and in an effort to recognize these patients and therefore optimize the utilization of the donor organ pool, the ‘ablate and wait’ strategy has been suggested for within Milan criteria HCC patients as well (18).

Locoreginal therapy is continuously evolving and gaining importance in the treatment of HCCs. The most popular techniques include transarterial chemo-embolization (TACE), transarterial drug-eluting beads (DEB), transarterial radio-embolization (TARE) and radiofrequency ablation (RFA).

Herein, we review the rationale behind each strategy and the studies on neo-adjuvant treatments for HCC before liver transplantation.

Neo-adjuvant locoregional therapy for hepatocellular carcinoma

  1. Top of page
  2. Abstract
  3. Neo-adjuvant locoregional therapy for hepatocellular carcinoma
  4. Transarterial therapies
  5. Which neo-adjuvant strategy should be used?
  6. Downstaging for hepatocellular carcinoma beyond the Milan criteria
  7. Endpoints of successful downstaging before liver transplantation
  8. Response of the tumour markers to locoregional therapy
  9. Should we treat patients within Milan criteria hepatocellular carcinoma?
  10. Conclusion
  11. References

Neo-adjuvant therapy is defined as presurgical treatment for HCC. Although occasionally implemented in large tumours to allow subsequent resection, preresection neo-adjuvant therapy is not a standard practice. On the other hand, owing to its efficacy in inducing endurance of patient transplant eligibility or transforming non-transplant candidates into candidates, neo-adjuvant locoregional therapy plays a pivotal role before liver transplantation.

‘Bridge’ therapy is meant to limit tumour progression and dropout rate while patients are on the transplant wait list. It is indicated for patients who meet HCC transplant criteria.

‘Downstaging’ therapy is meant to reduce the tumour burden so patients are transplant-eligible.

Transarterial therapies

  1. Top of page
  2. Abstract
  3. Neo-adjuvant locoregional therapy for hepatocellular carcinoma
  4. Transarterial therapies
  5. Which neo-adjuvant strategy should be used?
  6. Downstaging for hepatocellular carcinoma beyond the Milan criteria
  7. Endpoints of successful downstaging before liver transplantation
  8. Response of the tumour markers to locoregional therapy
  9. Should we treat patients within Milan criteria hepatocellular carcinoma?
  10. Conclusion
  11. References

Transarterial chemo-embolization

In non-transplant settings, TACE has been associated with survival benefit revealed by a meta-analysis of randomized-controlled trials (24). By current guidelines, TACE is the standard of care for intermediate stage HCC, that is, unresectable, multifocal disease confined to the liver in the absence of portal vein thrombosis and in asymptomatic patients (25).

The technique of the procedure entails selective cathetherization of the artery feeding the tumour with a subsequent infusion of chemotherapy agents (doxorubicin, mitomycin, adriamycin or cisplatinum) mixed with ethiodized oil, followed by embolization of the artery. The dual effect of ischaemia and chemotherapy induces tumour necrosis (26, 27).

In case of a poor liver reserve (billirubin≥2 mg/dl) or portal vein thrombosis, chemotherapy agents are avoided (bland embolization) or a superselective approach to spare non-tumour parenchyma is attempted (28).

In the transplant setting, TACE is currently the most popular neo-adjuvant treatment (14, 29). It is indicated in Child–Pugh A or B cirrhotic patients to downstage tumours into the Milan criteria or to prevent tumour progression.

Majno and colleagues first reported the concept of locoregional therapy using TACE before resection or liver transplantation. The study showed that locoregional therapy improved the resectability of tumours, with successful rates of downstaging of 62%. In transplant candidates, downstaging of tumours >3 cm [19 of 35 patients (54%)] was associated with better disease-free survival than either incomplete response to TACE or no TACE (71 vs. 29 and 49% at 5 years, P=0.01 and 0.09) (15).

Since this initial report, the world literature regarding pretransplant TACE has elicited mixed results (16, 30–32). There are no robust data supporting survival benefit associated with preliver transplantation TACE; however, TACE is considered a well-established approach to prevent tumour stage progression and to reduce tumour burden so that transplant criteria are met. Successful downstaging rates with TACE have been reported to range from 31 to 61% (16, 30, 33, 34).

Drug-eluting beads

Beads loaded with chemotherapy agents are delivered into the tumour through the feeding artery. Chemotherapy agents are released gradually, so systemic side effects are reduced and tumour drug delivery is enhanced. The PRECISION study compared conventional TACE with DEB for the treatment of 212 patients with Child–Pugh A or B cirrhosis and unresectable HCC (35). Subpopulation analysis revealed that patients with Child–Pugh B cirrhosis or bilobar tumour disease showed a better response to DEB. In addition, the overall DEB was better tolerated than conventional TACE.

In the transplant setting, a recent small retrospective study from Milan compared tumour response in explanted livers after treatment with DEB (n=8) vs. bland embolization (n=8) (36). Chemo-embolization with DEB achieved complete necrosis in 77% of lesions, whereas bland embolization achieved complete necrosis in 27.2% of lesions. No significant complications were observed.

While it appears that DEB might be better tolerated than conventional TACE, more extensive data are needed to address extension of tumour necrosis induced by DEB vs. TACE in explanted livers.

Transarterial radio-embolization

Radio-embolization is a form of liver-directed brachytherapy that consists of insoluble glass microspheres containing Y90 (37, 38). TARE has been used as a primary therapy for unresectable HCC. A large cohort study of 108 patients showed good safety and efficacy associated with TARE (28). A study reporting a correlation between radiological and pathological findings in patients with HCC treated with TARE before transplantation showed that 23 of 38 (61%) had completed pathological necrosis (39). This novel modality with lower post-embolization syndrome (40), no hospitalization and equivalent response rates seems promising for downstaging or bridging therapy before transplantation especially in marginal candidates for TACE because of portal vein thrombosis. Lewandowski and colleagues compared the downstaging efficacy of TACE vs. TARE in patients with T3 stage HCC to T2 to make patients transplant candidates. Partial response and downstaging to the T2 stage were significantly better in the TARE group (61 vs. 37%, 58 vs. 31% respectively) (34). Furthermore, time to progression favoured TARE vs. TACE (33.3 vs. 18.2 months). Although promising, larger RCTs comparing TARE vs. TACE are needed to better define the role of TARE.

Radiofrequency ablation

Radiofrequency ablation is the second most popular locoregional therapy before liver transplantation after TACE (41). A needle that deploys spikes is inserted into the tumour as a generator delivers rapidly alternating current (radiofrequency energy) inducing heat and therefore tumour necrosis.

Radiofrequency ablation appears to be equivalent to surgical resection inducing total tumour necrosis in 80–90% of tumours ≤3 cm (42–44). For HCCs >3 cm, the efficacy of RFA is suboptimal. Incomplete tumour necrosis has been reported to be as high as 40–70% in explanted livers from patients who underwent liver transplantation (45, 46).

In transplant candidates, RFA has been used mainly as a bridge therapy rather than for downstaging before transplantation because of its limited efficacy for large tumours. A large single-centre prospective study from Milan included 50 patients (40 patients within the Milan criteria) treated with a single ablation session (45). RFA was safely performed in patients with a mean Child score of 7.4. Four patients (8%) had major post-treatment problems requiring hospitalization. There was no wait list dropout, with a mean waiting time of 9.5 months. Recurrences after transplant were observed in only two patients, with a median follow-up of 22 months. Both had tumours >5 cm. This was in line with the pathological findings showing that tumours >3 cm had higher viability rates after treatment compared with those <3 cm (71 vs. 37%).

Another study from the University of California at Los Angeles group reported 52 patients (43 patients within the Milan criteria) treated mainly RFA (46) as a bridge to liver transplantation. There were only three patients (5.8%) who dropped out from the wait list because of tumour progression, with a mean waiting time of 12.7 months. Only three patients had significant therapy-related complications. No recurrence after transplant was observed with a mean follow-up of 15 months.

Systemic therapies

Generally speaking, HCC is a chemotherapy-resistant tumour secondary to drug resistance gene expression and therefore this therapeutic modality has not been used as a bridging therapy before liver transplantation. However, for the first time in the treatment of HCC, a targeted therapy has shown to be associated with a survival benefit in patients with advanced-stage disease. Sorafenib, an oral multikinase inhibitor with anti-angiogenic activity, induced 3 months longer survival in patients with advanced-stage unresectable HCC in a large RCT, becoming the standard of care for this group of patients (47, 48). In the neo-adjuvant setting, few pilot studies are attempting to address the safety and efficacy of sorafenib before liver transplantation. In the near future, the combination of this and other molecular targeted and locoregional therapy might take the pretransplant neo-adjuvant approach to the next level.

Which neo-adjuvant strategy should be used?

  1. Top of page
  2. Abstract
  3. Neo-adjuvant locoregional therapy for hepatocellular carcinoma
  4. Transarterial therapies
  5. Which neo-adjuvant strategy should be used?
  6. Downstaging for hepatocellular carcinoma beyond the Milan criteria
  7. Endpoints of successful downstaging before liver transplantation
  8. Response of the tumour markers to locoregional therapy
  9. Should we treat patients within Milan criteria hepatocellular carcinoma?
  10. Conclusion
  11. References

Patient-individualized treatment strategy should be based on the performance status, hepatic reserve, tumour burden and tumour vascularity pattern.

Single or repetitive sessions of therapy should be implemented as needed to achieve tumour response. Regardless of the type of locoregional therapy implemented, a successful response to treatment is considered when a lack of residual tumour arterial enhancement is noticed in cross-sectional imaging studies.

For single HCC <3 cm in a favourable anatomic location, RFA may be appropriate. For larger or multifocal HCC, TACE would be indicated. In cases of thrombosis of the main or large branches of the portal vein, TARE appears to be better tolerated because of its less embolic nature. These therapies might be implemented alone or via a combined approach. In addition, the benefit of the thoughtful concept of combining locoregional therapy with systemic therapies such as sorafenib has to be proven. However, due to the lack of prospective data, the most appropriate treatment protocol has not yet been defined (49).

Downstaging for hepatocellular carcinoma beyond the Milan criteria

  1. Top of page
  2. Abstract
  3. Neo-adjuvant locoregional therapy for hepatocellular carcinoma
  4. Transarterial therapies
  5. Which neo-adjuvant strategy should be used?
  6. Downstaging for hepatocellular carcinoma beyond the Milan criteria
  7. Endpoints of successful downstaging before liver transplantation
  8. Response of the tumour markers to locoregional therapy
  9. Should we treat patients within Milan criteria hepatocellular carcinoma?
  10. Conclusion
  11. References

In most regions of the world, particularly where cadaveric donation enables the largest source of transplants, patients with HCC beyond the Milan criteria need to be downstaged before undergoing liver transplantation (15, 50). This attempts to minimize the risk of post-transplant tumour recurrence by reducing tumour burden. This approach has been implemented after observing that patients with tumours successfully downstaged had good post-transplant HCC-free survival (14, 16, 29, 51). Response to treatment and tumour stability over a period of time (ablate and wait strategy) are deemed to be associated with favourable tumour biology (14, 16), which plays a pivotal role in selecting patients for liver transplantation (16, 18) (Table 1).

Table 1.  Selected studies on downstaging before transplant
AuthorYearPatientsTreatmentInclusion criteriaNumber of treatmentSuccessful downstage
Roayaie200280TACETumour >5 cm1.53 ± 0.92 
Graziadei200336TACEBeyond MC5.1 ± 2.750% decrease in size
Otto200662TACEBeyond MC3 (2–11)30% decrease in the diameter of lesions
Chapman200876TACEBeyond MC2 (1–5)MC
Yao200861TACE, RFA and/or resection(1) One lesion, 5–8 cm1.25UCSF
   (2) Two to three lesions, 3–5 cm, total diameter ≤8 cm  
   (3) Four to five lesions, ≤3 cm, total diameter ≤8 cm  
Ravaioli200848TACE, RFA, PEI and/or resection(1) One lesion, 5–8 cmNAMC and AFP ≤400 ng/ml
   (2) Two lesions 3–5 cm, total diameter ≤8 cm  
   (3) Three to five lesions, ≤4 cm, total diameter ≤12 cm  
Lewandowski200986TACE (43)UNOS T32 (1–2)MC
  TARE (43)UNOS T31 (1–2)MC
De Luna200927TACIBeyond MC2.8 ± 1.3MC
Downstaging rateIntention-to-treat survivalTransplanted patientsWaiting time to LT (months)Patient survival after LTRecurrence-free survival after LT
  1. AFP, α-fetoprotein; LT, liver transplantation; MC, Milan criteria; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transarterial chemo-embolization; TACI, transarterial chemo-infusion; TARE, transarterial radio-embolization; UCSF, University of California at San Francisco; UNOS, United Network for Organ Sharing.

43/80, 54%NA434.7 ± 5.6 (0.3–23.2)44% at 5 years40% at 5 years
11/36, 31%31% at 5 years108.5 ± 4.8 (3.7–17.6)41% at 4 yearsThree patients recurrence
34/62, 55%NA275.9 (1.9–19.3)73.2% at 5 years68% at 5 years
18/76, 24% (Stage III 34%, Stage IV 11%)NA175.8 ± 3.593.8% at 5 years100% at 3 years, 50% at 5 years
43/61, 71%69% at 4 years358.2 (3–25)92% at 2 years92% at 2 years
32/48, 67%62% at 3 years326 (minimum 3)NA78%, 71% at 1, 3 years
11/35, 31%19% at 3 years11N/ANA73% at 1 year
25/43, 58%59% at 3 years9NANA89% at 1 year
17/27, 63%84% at 3 years1510.9 (0.7–114.1)78.8% at 3 yearsNA

The concept of tumour response to locoregional therapy to undergo liver transplantation was introduced in part by Otto et al. (16). The study reported that repetitive TACE treatments achieving successful downstaging were able to select biologically less aggressive tumours in patients undergoing liver transplantation. The study included 34 patients within the Milan criteria and 62 patients beyond the Milan criteria. Of the 62 patients exceeding the Milan criteria, 34 (55%) patients responded to TACE and 27 patients underwent liver transplantation after median TACE treatments of three and a median waiting time of 6 months. Of the total of 50 patients who finally received liver transplantation (23 patients within the Milan criteria and 27 beyond the Milan criteria), 39 who responded to treatment or exhibited no tumour progression had a significantly better 5-year recurrent-free survival than the 11 patients with tumour progression before liver transplantation (94.5 vs. 35.4%, P=0.0017).

In line with this, a recent study reported that 18 of 76 (23.7%) patients beyond the Milan criteria were downstaged to the Milan criteria with a mean of 2 (1–5) TACE interventions and had a mean waiting time to liver transplantation of 6 months (29). Recurrence after liver transplantation was found in only 1 of 18 patients, with a median follow-up of 19.6 months.

Another study from University of California at San Francisco (UCSF) limited the inclusion criteria for downstaging as follows: (i) one lesion of 5–8 cm; (ii) two to three lesions with at least one lesion of 3–5 cm, with a total tumour diameter up to 8 cm; or (iii) four to five lesions with none >3 cm, with a total tumour diameter up to 8 cm (14). Among the 62 patients who were enrolled in the study, 43 patients (70.5%) were successfully downstaged into the UCSF criteria (solitary tumour up to 6.5 cm or up to three nodules, with the largest being up to 4.5 cm and a total tumour diameter up to 8 cm) and 35 patients received liver transplantation with excellent post-transplant outcome. Recurrence-free survival at 2 years was 92%. Interestingly, explant histopathological examination revealed that none of the 35 patients who received liver transplantation had poorly differentiated grade tumours, and only one had vascular invasion. These more favourable histopathological tumour features were likely to contribute to the better post-transplant outcomes of successfully downstaged patients.

Endpoints of successful downstaging before liver transplantation

  1. Top of page
  2. Abstract
  3. Neo-adjuvant locoregional therapy for hepatocellular carcinoma
  4. Transarterial therapies
  5. Which neo-adjuvant strategy should be used?
  6. Downstaging for hepatocellular carcinoma beyond the Milan criteria
  7. Endpoints of successful downstaging before liver transplantation
  8. Response of the tumour markers to locoregional therapy
  9. Should we treat patients within Milan criteria hepatocellular carcinoma?
  10. Conclusion
  11. References

There is a need to define the end-points of successful downstaging before liver transplantation. Most of the published studies used the Milan criteria as the criteria for liver transplantation after downstaging (29, 33, 34, 52). As described above, the response to the treatments has been well associated with good outcomes after liver transplantation. Otto and colleagues considered successful downstaging when at least a 30% decrease in the largest diameter of arterial enhancement of targeted lesions was achieved. Patients who fulfilled this criterion underwent liver transplantation regardless of the Milan criteria. Yao and colleagues used the UCSF criteria to define transplant eligibility after downstaging and performed tumour surveillance for at least 3 months before liver transplantation. The maximum diameter of residual tumour enhancement on CT or MRI was used to evaluate staging in these studies. Both studies showed good outcomes (post-transplant patient survival; 73.2% at 5 years, 92% at 2 years respectively).

Thus, transplant criteria after downstaging may not necessarily be the Milan criteria as long as tumours respond well to locoregional therapy and remain stable for a period of time before transplant. Based on reported experiences, although a consensus has not been established, it appears that successfully downstaged patients should be observed for at least 3 months before undergoing liver transplantation (14, 19, 50, 52).

Response of the tumour markers to locoregional therapy

  1. Top of page
  2. Abstract
  3. Neo-adjuvant locoregional therapy for hepatocellular carcinoma
  4. Transarterial therapies
  5. Which neo-adjuvant strategy should be used?
  6. Downstaging for hepatocellular carcinoma beyond the Milan criteria
  7. Endpoints of successful downstaging before liver transplantation
  8. Response of the tumour markers to locoregional therapy
  9. Should we treat patients within Milan criteria hepatocellular carcinoma?
  10. Conclusion
  11. References

Biomarkers such as α-fetoprotein (AFP) or des-γ-carboxy prothrombin (DCP), also known as protein induced by vitamin K absence or antagonist-II (PIVKA-II), have received the attention as predictors of recurrence after transplant. Increased AFP and DCP levels can be related to unfavourable pathological features of HCC such as microvascular invasion or poor differentiation, which may have a negative impact in post-transplant outcomes (22, 52–54).

Regarding transplantation criteria after downstaging, Ravaioli et al. (52) selected the patients downstaged to the Milan criteria whose AFP had been ≤400 ng/ml during the waiting time. These groups of patients exhibited a 3-year disease-free survival equivalent to patients who underwent liver transplantation with original HCCs within the Milan criteria (71 vs. 71%).

Several studies have shown a pre-operative AFP level >1000 ng/ml to be a strong independent predictor of tumour recurrence after liver transplantation (54–56). In line with this, some investigators recommend that for patients with AFP >1000 ng/ml, successful downstaging should include a decrease in the AFP levels <500 ng/ml before liver transplantation (11).

Should we treat patients within Milan criteria hepatocellular carcinoma?

  1. Top of page
  2. Abstract
  3. Neo-adjuvant locoregional therapy for hepatocellular carcinoma
  4. Transarterial therapies
  5. Which neo-adjuvant strategy should be used?
  6. Downstaging for hepatocellular carcinoma beyond the Milan criteria
  7. Endpoints of successful downstaging before liver transplantation
  8. Response of the tumour markers to locoregional therapy
  9. Should we treat patients within Milan criteria hepatocellular carcinoma?
  10. Conclusion
  11. References

The benefit vs. the risk of bridging therapy for patients within Milan criteria hepatocellular carcinoma

The rationale of treating patients meeting the Milan criteria is to impede tumour progression and to prevent wait list dropout.

The most popular locoregional therapy for bridging is TACE, followed by RFA (Table 2). Graziadei et al. (31) first reported successful pretransplant TACE treatments as a bridging therapy for patients within the Milan criteria waiting for liver transplantation. No dropout was observed during a mean waiting time of 6 months. Five-year intention-to-treat survival was as high as 94%. On the other hand, Yao et al. (57) used a multimodality approach for bridging therapies in patients within the Milan criteria whose mean waiting time was 6 months with acceptable tumour progression and dropout rate (26 and 29% respectively).

Table 2.  Selected studies on bridge therapy before transplant
AuthorYearTreatmentPatientsTumour stageNumber of treatmentsExclusion for LTTotal dropoutTumour progression rate
Graziadei2003TACE48Within MC2.5 (1–8)MC0 (0%)0 (0%)
Yao2003TACE, RFA, PEI, resection70Within MC3.1 (1–8)UCSF20 (29%)18 (26%)
Hayashi2004TACE20Within MCNAMC6 (35%)4 (20%)
Mazzaferro2004RFA5040 within MC, 10 beyond MC1.0MC0 (0%)0 (0%)
Lu2005RFA5242 within MC, 10 beyond MC1.5MC6 (12%)3 (6%)
Millonig2007TACE68Within MC2.7 ± 1.7UCSF2 (3%)2 (3%)
De Luna2009TACI95Within MC1.8 ± 1.1MC17 (18%)6 (6%)
Intention-to-treat survivalTransplanted patientsWaiting time to LT (months)Patient survival after LTPatients with recurrence after LT
  1. LT, liver transplantation; MC, Milan criteria; PEI percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transarterial chemo-embolization; TACI, transarterial chemo-infusion; UCSF, University of California at San Francisco.

94% at 5 years41 (85%)6.0 (0.9–15)94% at 5 years1
57% at 3 years38 (54%)6.1NANA
61% at 5 years12 (60%)11.4 ± 9.8100% at 4 years0
NA50 (100%)9.5 (2–47)83% at 3 years2
74% at 3 years41 (79%)12.776% at 3 years0
70% at 5 years66 (97%)9.0 (1.2–34)NA5
85% at 3 years68 (72%)11.4 (0.92–132.9)82.4% at 3 yearsNA

It is important to know the wait list dropout rate and bridging therapy-associated complication rate, because the benefit of preventing wait list dropout should outweigh the risk of bridging therapy.

Under the current US organ allocation system, patients who meet the Milan criteria receive MELD exception points and incremental points every 3 months to receive priority for liver transplantation (58). In 2003, the rate of wait list dropout for patients meeting the Milan criteria was reported to be 10 and 25% in the first 6 and 12 months respectively (57, 59). In 2006, Freeman and colleagues analysed the dropout rate of 2052 HCC liver transplant candidates, with the majority of those meeting the Milan criteria. Unadjusted dropout rates showed to be slightly increased: 8.7, 16.9 and 31.8% at 3, 6 and 12 months respectively (60). This trend of increasing wait list dropout rate raises more demand for bridging therapy.

Regarding the risk of locoregional therapy, the rate of significant complications such as TACE-induced hepatic decompensation should be taken into account for the indication of bridging therapy. Early studies suggest a moderate risk of TACE-related liver decompensation (2.5–15%) (30, 31, 57). However, recent series show that it is now a rare complication (0–5%) (17, 29, 61). In addition, there are now more choices of locoregional therapies with higher tolerability than TACE such as TARE, DEB, bland embolization or ablative therapies for patients with marginal liver function.

Recent studies of bridging therapy for patients within the Milan criteria with waiting times between 9 and 12 months reported excellent outcomes with low rates of dropout because of tumour progression varying from 0 to 18% (17, 33, 45, 46). Extremely low rates of exclusion from the waiting list because of locoregional therapy-induced complications (0–5%) in these studies justify the aggressive use of bridging therapy certainly for patients with a moderate risk of dropout (expected dropout rate>15% or expected waiting time>6 months) or even for patients with minimal risk (expected dropout rate 5–15% or expected waiting time 3–6 months).

Dropout rates are also associated with tumour characteristics. Among them, patients with single tumours >3 cm or three lesions have a higher risk of wait list dropout because of tumour progression (11, 57). The indication of bridging therapy for these patients can be considered more aggressively. Some investigators encourage locoregional therapy in this group of patients if the expected waiting times are longer than 3–6 months (11).

Potential benefit of locoregional therapy for within Milan criteria patients in post-transplant outcomes

Although associated with good results, around 10% of within Milan criteria HCC patients will exhibit post-transplant recurrence. Another potential rationale for pretransplant locoregional therapy for these patients is to reduce further post-transplant recurrence rates.

A recent cohort study from Austria has shown that the response to neo-adjuvant therapies is associated with better intention-to-treat survival and survival after liver transplantation in HCC patients within the Milan criteria. The study included 68 patients within the Milan criteria treated by TACE (17). A median waiting time was 9 months. Patients with complete and partial response during the waiting time had better intention-to-treat 2-year survival and 1-year survival after transplant than those with unmodified or progressive disease (2-year intention-to-treat survival; 94.7, 91.3, 40%, 1-year survival after liver transplantation; 89.2, 94.4, 37.5% respectively). The result of the study advocates a period of tumour surveillance after locoregional therapy for patients within the Milan criteria as well as those beyond the Milan criteria before liver transplantation.

Some transplant specialists claim that quick transplantation after locoregional therapy in HCC within the Milan criteria may be accompanied by higher recurrence rates because of insufficient time for the tumour biology to be unveiled (19). Under the current US allocation system, HCC patients within the Milan criteria receive 22 MELD exception points (58), allowing transplantation within 3 months after listing in more than half of the UNOS regions. In these areas, whether a fast track to transplant may impede unveiling tumour biology is a question that has to be scrutinized.

However, a retrospective case–control study from Pennsylvania (31 treated vs. 33 untreated) failed to prove this theory. Seven completely responded patients (23%) were identified in the treated group. Paradoxically, mortality after transplantation was the highest among complete responders, while survival for incompletely responded patients was similar to the untreated group (completely responded: 54%, incompletely responded: 92% vs. untreated; 94%, P=0.04) (62).

In conclusion, in terms of preventing dropout from wait list, there is the benefit of bridging therapy for patients within the Milan criteria with a moderate risk of wait list dropout (expected dropout rate >15%). Further experience is needed to define the benefit of locoregional therapy with regard to unveiling tumour biology for patients within the Milan criteria.

Conclusion

  1. Top of page
  2. Abstract
  3. Neo-adjuvant locoregional therapy for hepatocellular carcinoma
  4. Transarterial therapies
  5. Which neo-adjuvant strategy should be used?
  6. Downstaging for hepatocellular carcinoma beyond the Milan criteria
  7. Endpoints of successful downstaging before liver transplantation
  8. Response of the tumour markers to locoregional therapy
  9. Should we treat patients within Milan criteria hepatocellular carcinoma?
  10. Conclusion
  11. References

The minimal risk associated with pretransplant locoregional therapy and its benefit in preventing disease progression and wait list dropout along with the potential role in unveiling tumour biology advocate for its implementation. At this point in time, we could consider pretransplant locoregional therapy a ‘necessity’ for patients beyond the Milan criteria and those within the Milan criteria who have a moderate risk of wait list dropout such as those with an expected waiting time more than 6 months or those with high-risk characteristics of HCC. Pretransplant locoregional therapy may be an ‘option’ for patients within the Milan criteria who have a low risk of wait list dropout. Forthcoming larger clinical experiences should shed light on this important issue in an era of increasing HCC incidence and severe organ shortage. The search for accurate biomarkers predicting disease recurrence after transplant is pivotal because it will take the therapy patient selection process to the next level.

References

  1. Top of page
  2. Abstract
  3. Neo-adjuvant locoregional therapy for hepatocellular carcinoma
  4. Transarterial therapies
  5. Which neo-adjuvant strategy should be used?
  6. Downstaging for hepatocellular carcinoma beyond the Milan criteria
  7. Endpoints of successful downstaging before liver transplantation
  8. Response of the tumour markers to locoregional therapy
  9. Should we treat patients within Milan criteria hepatocellular carcinoma?
  10. Conclusion
  11. References
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