Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with increasing incidence, ranking sixth amongst all cancers in incidence and fourth for cancer-related mortality worldwide . Liver transplantation is potentially curative by removing the cancer and diseased liver. For decades, restricting HCC patients from liver transplantation with Milan criteria for recipient selection was used to ensure low recurrence posttransplantation and maintaining an acceptable postliver transplantation survival. In contrast to deceased donor liver transplantation (DDLT), recipient selection for living donor liver transplantation (LDLT) is not limited by organ allocation systems. Subsequently, many centers have developed center-specific expanded criteria with acceptable results, including University of California San Francisco criteria, Extended Toronto criteria, amongst others [2–4].
Many patients with HCC listed for transplantation die from cancer progression while waiting for a deceased organ because of limited organ supply. This varies among jurisdictions but can be as high as 40% [5–7]. LDLT is, therefore, an attractive option to decrease waitlist times and theoretically limiting HCC progression. With advances in liver surgery and improvements in surgical technique, results after liver transplantation have progressively improved with excellent 1-year survival despite relatively high incidence of morbidity . However, not all HCC patients should be transplanted, even with the availability of a living donor. The treatment decision depends on factors related to the patient and the tumour. The goal is to define transplant eligibility beyond the simple criteria of size and number of lesions, understand the biologic behaviour of the tumour, and identify patients with less aggressive tumours (irrespective of tumour burden) that will benefit most from LDLT.
Benefits of living donor liver transplantation
Outcomes after LDLT versus DDLT have been extensively studied, with publications showing the absence of difference between treatments [5,9]. LDLT results are comparable with DDLT for both donation after circulatory death (DCD) and donation after brain death (DBD), as published by Kollmann et al. that demonstrated similar 5-year overall patient survival of 71.6% for DCD, 83% for DBD, 88.8% for LDLT, and graft survival of 69.2% for DCD, 79.9% for DBD, and 84.7% for LDLT among 1054 patients from a single center (P = 0.14).
Specifically for HCC, the results of LDLT and DDLT have been compared in several studies as shown in Table 1[6,11,13]. Initially some of these studies showed higher recurrence in patients transplanted with living donor and investigators hypothesized that liver regeneration could be the reason for this finding [17,18]. However, these studies evaluated the outcomes after transplantation without an intention-to-treat (ITT) analysis (i.e. from the time of listing). In a recent meta-analysis by Zhu et al. of 29 studies with 5376 patients, they suggested that LDLT was not inferior to DDLT for perioperative and survival outcomes. However, in terms of 5-year ITT overall survival (OS), LDLT was a possibly better choice for HCC patients than DDLT [relative risk = 1.11, 95% confidence interval (CI) = 1.01–1.22, P = 0.04] . Azoulay et al. analyzed 861 patients listed for liver transplantation for HCC (79 LDLT and 782 DDLT) and found no difference in 5-year ITT-OS (73.2% for LDLT versus 66.7% for DDLT, P = 0.06) and no difference in recurrence rates (10.9% for LDLT versus 11.2% for DDLT, P = 0.75). Additionally, Bhangui et al. found comparable recurrence and OS for DDLT and LDLT in an ITT analysis among a cohort of 183 HCC patients after liver transplantation. However, the mean wait list time was significantly less for the LDLT group (2.6 versus 7.9 months, P = 0.001).
Goldaracena et al.[14▪▪] published the benefit in terms of OS and disease-free survival for patients who had a potential donor for LDLT in an ITT analysis with a 5-year OS of 68% for LDLT versus 57% for DDLT (P = 0.02), reflecting a reduction in the dropout rate from 27.5% for DDLT versus 14.6% for LDLT (P < 0.001). Similarly, Wong et al.[16▪▪] described a survival benefit for LDLT in an ITT and propensity score matching analysis of 375 patients with 5-year OS of 81.4% for LDLT versus 40.8% for DDLT (P < 0.001). Table 2 summarizes different criteria utilized to select patients with HCC beyond Milan criteria for LDLT.
Results of recipients beyond Milan criteria and how far we can go
In the last 2 years, centers have published their center-specific data in LDLT for HCC. In December 2017, Kyushu University published results of a prospective study using center-specific criteria, the Kyushu University criteria, largest tumour less than 5 cm or des-γ-carboxy prothrombin (DCP) level less than 300 mAU/ml without gross vascular invasion or extrahepatic metastasis on imaging studies, irrespective of the number of tumours . Uchiyama et al. published no significant difference in 5-year recurrence-free survival probabilities and 5-year overall patient survival of patients within-Milan and beyond-Milan patients meeting Kyushu criteria.
Shimamura et al. performed a retrospective analysis of LDLT for HCC in Japan from 1998 to 2009 and based on their outcomes proposed a selection criteria for transplantation that achieved a 5-year survival rate over 70% and 5-year recurrence rate of less than 10%. They proposed the 5-5-500 rule: largest nodule size 5 cm or less in diameter, nodule number 5 or less, and alpha-fetoprotein (AFP) value 500 ng/ml or less as a new expanded criteria for LDLT for HCC and combined with Milan criteria (patients meeting either criteria) would increase patients with HCC eligible for transplantation by 19% .
In 2018, Pavel et al. published Barcelona's outcomes comparing recipients within Milan criteria and recipients fulfilling the Barcelona Clinic Liver Cancer (BCLC) Group expanded criteria, which is a single lesion 7 cm or less, up to three nodules 5 cm or less, or five nodules 3 cm or less [31,32]. Although small number of patients in each group (16 recipients within the Milan criteria and 26 in the BCLC expanded criteria) all received LDLT. There was no significant difference in 5-year and 10- year overall and disease-free survival between patients within Milan and those beyond Milan but within the BCLC expanded criteria . Due to deceased organ donation scarcity in Asia, most centers perform mainly LDLT for HCC patients using varying criteria, but most beyond Milan. Yoon and Lee [33▪] recently reported the experience with LDLT for HCC in Asia demonstrating a 5-year overall survival ranging from 80 to 85.2%.
LDLT in patients with macrovascular invasion has gained interest. In a cohort of 282 patients, Lee et al. analyzed the outcomes of 11 patients with macrovascular invasion. The overall 5-year survival was 63.6% and 5-year disease-free survival was 45.5%. In the univariate survival analysis, the level of portal vein tumor thrombosis (PVTT) extending to the main portal vein was a significant factor for recurrence (P < 0.01). Although a very small number, the results challenge the current paradigm of macrovascular invasion being a contraindication to transplantation and the authors suggest that PVTT not extending into the main portal vein would be considered for curative intent treatment with LDLT . This concept needs to be further explored in clinical trials.
Although some authors argue LDLT decreases HCC progression by decreasing wait time, others have shown that LDLT may increase recurrence rates and decrease cancer outcomes related to aggressive HCC that potentially would drop out waiting for a deceased organ. Some patients will have an unfavourable outcome regardless of the treatment received because of the individual characteristics of the tumour. In this case, liver transplantation would not be an effective treatment option and potentially preventing another patient from receiving a deceased organ or potentially undue harm to a living donor.
Tumour characteristics and evaluating tumour biology for predicting survival and posttransplant tumour recurrence in selecting patients who would benefit from transplant is not well known. Zhao et al. showed a significant effect of tumour grade of differentiation on long-term prognosis of HCC after liver transplantation in a multivariable analysis of 802 Chinese patients with a hazard ratio of death of 2.62 for poorly differentiated tumours. These results justify the exclusion of such patients from liver transplantation, as used in the Extended Toronto criteria . On the other hand, there is significant heterogeneity within a single HCC lesion with tumour structural variation within the same sample from a single needle biopsy, which suggests that preliver transplantation tumour histologic assessment may play a limited role in predicting tumour behaviour as the biopsy may not capture more aggressive tumour cells .
Efforts are focused on the identification of surrogates of tumour biology to define ways to predict results after liver transplantation for HCC. Among these strategies, response to bridging/downstaging therapies proved to be a potential predictor. As recently published by DiNorcia et al.[38▪], among 3439 HCC patients post liver transplantation, 802 patients with complete pathological response (cPR) after bridging therapies had a 5-year recurrence rate of only 5.2%, as compared with patients who do not achieve cPR (16.4%, P < 0.001). However, this study was based from the United States Multicenter HCC Transplant Consortium database and did not have granular data to assess stratification of the impact the specific percentage of tumour necrosis on outcomes, but only assessed the dichotomous cPR variable. Additionally, Doyle et al. observed that outcomes of potentially transplantable patients undergoing ablation may vary significantly according to tumour size with patients with HCC larger than 2 cm and higher serum AFP being at greater risk of recurrence beyond transplant criteria. Also, liver transplantation was proven to be equally effective as salvage therapy for patients following ablation or surgery as primary treatment, expanding the indication of liver transplantation for HCC . Conversely, response to locoregional therapy as a predictor of outcomes may be supplemented by response of serum AFP. Halazun et al.[41▪] found that among 1450 patients from three United States centers, the serum AFP response to treatment during the wait-list could predict posttransplantation outcomes and should be incorporated into HCC selection criteria to allow its expansion.
In a retrospective cohort of 455 patients listed for liver transplantation for HCC based on total tumour volume (TTV) 115 cm3 or less and AFP 400 ng/ml or less criteria, Toso et al. found that among patients downstaged to Milan, those originally beyond TTV115/AFP400 (n = 27) had similar outcomes as those originally beyond Milan but within TTV115/AFP400 (n = 53). However, the likelihood of being within Milan at transplant was lower for patients with more advanced initial HCC (P < 0.0001) . Overall, despite an expected increase in posttransplant HCC recurrence, similar survivals could be achieved with and without downstaging even when including patients with advanced initial HCC, which reinforces the importance of treatment response as surrogate of tumour biology.
Recent studies have identified new strategies of predicting tumour behaviour using a noninvasive technique. Radiomics is the process of converting medical images into high-dimensional, mineable data via high-throughput extraction of quantitative features, followed by subsequent data analysis. These radiomic features may be correlated with pathologic and genomics features, time to HCC recurrence, and survival by preliver transplantation image assessment. Zhou et al. published the use of radiomics signature to predict early recurrence of HCC among 215 patients with a predictive area under the curve of 0.83 when combined with a clinical model. MacParland et al. found an intrahepatic cellular immunologic heterogeneity using single-cell RNA that may point to understanding different tumour behaviour among patients. Finally, circulating tumour cells and cell-free DNA, also known as liquid biopsy, may be the key to understanding HCC tumour behaviour puzzle over the next few years [45,46]. Graf et al. demonstrated with a national survey that pediatric transplant programs are already including genetic assessment of patients when evaluating for liver transplantation. All these advancements will likely play a role in selecting patients with HCC for LDLT beyond size and number of tumours.
Considering systemic therapies, sorafenib was the first drug approved for the treatment of HCC and is the standard of care when other treatments are not possible. Many agents tested in phase 3 trials failed to improve or even parallel the efficacy of sorafenib. Insufficient antitumoural activity, toxicity in the context of cirrhosis, and inadequate patient selection has been attributed to these failures. Sorafenib remained the sole systemic therapy until lenvatinib showed antitumoural activity in a noninferiority trial . There is a positive trend in trials over recent years with an increasing optimism towards systemic treatment improvements for HCC. Induction therapy with these new drugs may be an alternative to test tumour responsiveness to treatment prior to LDLT. However, this needs to be investigated in prospective trials.
Multiple studies have demonstrated the benefit of having a live donor for recipients with HCC with decreased waitlist times, decreased dropout rates, and improved overall survival for recipients with liver cancer [14▪▪,16▪▪,20]. The proportion of liver transplantation performed for HCC is increasing. For example, in Asia, the proportion of adult LDLT recipients with HCC has recently increased to 30–40%, and 90% of these transplants are LDLT [33▪]. Careful consideration is required whenever evaluating a patient for liver donation, given the potential harm and no physical benefit to the donor. LDLT is a well tolerated procedure for donors. Lee et al. analyzed the Korean Organ Transplant Registry of 832 LDLT donors over a period of 2 years and found an incidence of overall, biliary, and major complications of 9.3, 1.7 and 1.9%, respectively, and no deaths. Biliary complications were the most common types of major morbidity [49▪]. Gorgen et al. presented a postoperative mortality rate of 0% over 589 patients after donor right hepatectomy in a single center. After stratifying patients over time by eras based on the year in which the surgery was performed, the only predictor of postoperative complications was volume of donor hepatectomies in the previous 12 months, associating volume as a predictor of success [50▪].
Due to better results in surgical techniques and reconstructions, the risks to recipients has less of an impact on the decision to proceed with LDLT. But even after two decades of experience in complex laparoscopic hepatobiliary procedures, data on purely laparoscopic approach for donor hepatectomy in adult LDLT are limited. Shehta et al. published in early 2019 of an expert consensus statement that laparoscopic adult living donor hepatectomy is considered in the development phase and not recommended for wide introduction at that time but shows promise application in the future.
Ethics surrounding LDLT for both the donor and recipient must be addressed balancing risk to the donor to recipient benefit. There are concerns regarding the validity of informed consent given by the donor. Organ trading is strictly prohibited, yet transplant tourism has flourished in some countries in spite of the existence of strict laws . Although donations to nonrelative patients may initially seem to be altruistic, it is important to apply careful scrutiny.
Traditionally for DDLT based on Milan criteria, outcomes of 5-year OS greater than 70% and recurrence rate less than 10% are gold standards but these rates may not be attainable when transplanting patients with more advanced HCC. Given no data available, what is an acceptable 5-year OS and 5-year recurrence rate for HCC patients undergoing LDLT beyond Milan?
Additionally, ethical dilemmas arise when patients transplanted for HCC outside standard criteria who develop early graft loss or late graft complications after LDLT require re-transplantation. Re-transplanting with a deceased organ may prevent a patient meeting standard criteria from receiving a graft. Should patients with tumours outside standard criteria undergoing LDLT be prevented from receiving a deceased organ from the donor pool if they need re-transplantation emergently early postoperatively?
Over the last 2 years, studies support a greater indication of LDLT for HCC beyond the standard Milan criteria with the development of new technologies that aid in predicting the long-term oncological outcomes with cautiously balancing the risks of harm to otherwise healthy donors. Expanding the indication for LDLT for HCC will provide a potential curable procedure to patients who otherwise have limited treatment options.
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Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
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