INTRODUCTION

Liver transplantation for nonresectable colorectal liver metastases (CRLMs) has for long been considered a contraindication for transplantation due to poor outcomes. During the last decade, there has been a renewed interest in this field of transplant oncology due to a series of studies suggesting that liver transplantation for CRLM may have a role in clinical practice for highly selected patients. This review will give an overview of the recent literature. 

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BACKGROUND

Colorectal cancer (CRC) is the second most frequent cause of cancer related mortality [1] in the western world and the incidence of CRC has been rising in the last two decades, particularly in the younger age groups [2]. Metastatic disease is seen in about 50% of the patients, either at the time of diagnosis (synchronous) or later during the course of the disease (metachronous). Common metastatic routes are hematogenous and or by lymphatic pathways and the most frequent manifestation of dissemination is liver metastases [3]. The only established potential curative treatment option for CRLM is liver resection but local ablation by radiofrequency or microwave may be added as an adjunct to the therapeutic repertoire given that the number of lesions to treat is low, and the maximum diameter does not exceed about 30 mm [4,5].

Chemotherapy plays an important role also in curative intent resection, and has improved the recurrence free and overall survival (OS) after liver resection [6], and response to chemotherapy is considered an important prognostic sign.

Several surgical and interventional radiology techniques have contributed to increased resection rates in CRLM including two-stage hepatectomy, combined surgery and interventional radiology, portal vein embolization (PVE), associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and liver venous deprivation [7–10]. Modern chemotherapy is also an integral part of downsizing strategies to convert initially unresectable disease [11–13]. Taken together, advances in oncological and surgical therapy during the last two decades have increased the resectability rates by about 10–15%. Nevertheless, 75–80% of CRLM patients are left with palliative chemotherapy as the only realistic option where the reported 5-year survival rate is around 10%. Thus, there is a large need for potential curative treatment options in this large cohort of patients.

TRANSPLANTATION FOR COLORECTAL LIVER METASTASIS

The concept of total hepatectomy and liver transplantation in patients with nonresectable CRLM was conceived in the early liver transplantation era, but hampered by poor outcomes [14,15], and CRLM was therefore later considered a contraindication. These early experiences were however accompanied by high perioperative morbidity and mortality not related to the malignant disease. In 2013, the results of a prospective pilot study (SECA-I trial) showed that an estimated 5-year survival of 60% could be obtained in a heterogeneous group of patients with CRLM, thereby sparking renewed interest within this particular field of ‘transplant oncology’ [16].

Patient selection and transplant criteria

There has been a steadily growing international interest in the use of liver transplantation for CRLM, and recently the International Hepato-Pancreato-Biliary association commissioned a multidisciplinary working group to define management principles with respect to patient selection, evaluation of biological behavior, graft selection, recipient considerations and outcomes [17▪]. In general, the premise of liver transplantation in CRLM relies on the ability to select patients where the liver is the sole metastatic location and that the disease displays a favorable ‘tumor biological phenotype’. The latter is undeniably an ill-defined term that for a lack of specific reliable parameters has to be described by an array of clinical and pathological surrogate markers. The goal of the selection process is to try to identify patients with a predictive 5-year survival probability above 60–70% to justify transplantation and avoid the futile use of liver grafts.

Pretransplant imaging to ascertain liver only disease should include computed tomography (CT) scans alone and combined with fluorine-18 fluorodeoxyglucose PET/CT with the possible addition of MRI. Nevertheless, some patients will be false negative with respect to lymph node involvement, thus frozen section of lymph nodes in the hepatoduodenal ligament at the time of intended transplant should be mandatory [18]. PET–CT is a valuable tool in excluding extrahepatic metastases. Furthermore, radiomic analysis of data from the PET–CT has also proven to be useful in assessing the biological ‘aggressiveness’ of the disease by quantifying the enhancement volume in the liver lesions. This is done by estimating the so-called metabolic tumor volume (MTV) which is defined as the enhancement volume that is equal or greater than 40% of the standardized maximal uptake volume [19]. A MTV of all CRLMs per patient below 70 cm3 clearly stratify between patients with superior and inferior long-term survival [20].

Certain disease characteristics are inherently linked to inferior outcome in CRC treatment in general and are best avoided. Right sided primary tumor, undifferentiated primary or signet ring cell differentiation as well as BRAF mutation are all features associated with inferior outcome [21,22]. Similarly, progression on chemotherapy should usually prohibit transplantation as long-term survival is not realistic although the patients may display substantial treatment benefit as compared with palliative chemotherapy [23,24]. Transplant candidates need to have excellent performance status (ECOG 0–1) and general symptoms like fatigue and loss of appetite have been shown to be linked to inferior survival probability [25]. Lymph node status N2 of the primary increases the likelihood of systemic disease, and if accepted, warrants longer pretransplant observation time to ensure liver only disease [22].

Recently, advances in immunotherapy have had a major impact on treatment outcome in a range of cancer types. In patients with microsatellite instability (MSI) and deficient DNA mismatch repair immunotherapy has been approved with good overall response rate [26], and further possibilities are under investigation [27]. Until recently there have been concerns about combining immunotherapy and organ transplantation, although the reported outcomes in terms of rejection have been variable [28,29]. The international consensus document has thus so far not considered patients with MSI-high status as transplant candidates, but the rapid development in this particular field is likely to change how immunotherapy is approached in transplant recipients.

After these relatively clear negative factors as outlined above have been ruled out and liver only disease confirmed, the prognostic suitability of a candidate can be assessed by scoring systems. As the true biological nature of the disease is difficult to assess and treatment response needs to be evaluated longitudinally, a minimal observation period from time of diagnosis to transplant listing of at least 12 months is recommended to ensure disease stability. Three different scoring systems may be applied to predict long-term outcome:

(1) The Oslo score is based on four parameters, each assigned a value of 0 or 1; maximal tumor diameter in the liver more than 5.5 cm, carcinoembryonic antigen (CEA) value more than 80 μg/l, progression on chemotherapy and time interval from diagnosis to transplant less than 24 months [16]. Oslo score of 0–2 is associated with good prognosis after transplantation [30]. (2) MTV on PET–CT within 90 days of transplantation below 70 cm3 is associated with excellent long-term prognosis after transplantation [30]. (3) The Fong Clinical Risk Score (FCRS) was originally developed for predicting recurrence after liver resection for CRLM [31], but additionally a low score (0–2) has been shown to be associated with excellent long-term survival outcomes after liver transplantation for CRLM [30].

All these three scores are intercorrelated, that is, patients with low Oslo scores will predominantly have low MTV and FCRS, and Oslo score 0–2 is the least strict criterion of the three mentioned above.

An overview over recommended management and patient selection algorithm from the International Hepato-Pancreato-Biliary Association is given in Fig. 1.

FIGURE 1: Proposed management algorithm for patients with nonresectable colorectal liver metastasis considered for liver transplantation. NRCRLM, nonresectable colorectal liver metastasis. ∗No BRAF V600E mutation, microsatellite stable and mismatch repair proficient. Adapted with permission from [17▪].Survival outcomes and recurrence

The effect of more stringent selection was demonstrated in the SECA-2 trial. This was a sequel study to the original SECA-1 study where a minimal interval from diagnosis to transplant of 12 months and a response to chemotherapy of at least 10% according to the RECIST criteria was required. The hepatic tumor load was clearly lower than in the first trial, and no patient had a maximal tumor diameter exceeding 47 mm. After a median follow up of 36 months, the overall estimated 5-year survival was 83%, clearly indicating that stringent selection improves OS probability [32▪]. A disease-free survival (DFS) of 35% at 3 years was a clear improvement compared with the SECA-1 study, where essentially all patients recurred within 2 years. The high rate of recurrence has however sparked discussion and controversy: Is liver transplantation only a palliative measure given the short DFS? DFS is commonly used as a surrogate endpoint for OS in cancer trials, since there is a close relationship between the two. This relationship seems to be more complex in liver transplantation for CRLM. The pattern of recurrence after liver transplantation for CRLM is distinctly different from that seen after liver resection with lung metastasis being the predominant manifestation in up to 70% of cases [33,34]. In the majority of patients, these lesions grow slowly and interestingly, the growth rate is not adversely affected by the immunosuppression when compared with similar nonimmunosuppressed CRC patients [35]. Therefore, the majority of patients with pulmonary metastases can be offered lung resection with curative intent, and this translates into long-term OS, despite short DFS [36]. Although the high recurrence rate is a serious concern, it above all reflects the lacking ability to detect minimal metastatic disease outside in the lungs. On the other hand, since a large proportion of the patients have long-term survival after surgery for lung recurrence, DFS has limited value as a parameter of treatment efficacy in liver transplantation for CRLM. The lack of correlation between DFS and OS is illustrated in Fig. 2.

FIGURE 2:

Relationship between overall and disease-free survival time in months for patients transplanted for colorectal liver metastasis at Oslo University Hospital (n = 54). Patient status is stratified as currently alive (magenta) or deceased (orange) after transplant. Pearson's correlation coefficients are r = −0.11 (P = 0.59) and r = 0.27 (P = 0.18) for patients alive and deceased respectively. Sixteen of the patients with recurrence (31.3%) have an observed survival of more than 5 years.

Future development

Although the current knowledge of liver transplantation for CRLM is based on a limited number of performed transplantations, it seems reasonable to assume that this disease may become a valid indication for liver transplantation in highly selected cases of unresectable disease. This naturally begs the question; where are we going to get the extra number of liver grafts needed to avoid negative impact on the waiting lists for patients with conventional indications for liver transplantation? There is no simple standard answer to this question, since there is a substantial disparity between regions and countries in waiting times, waitlist mortality, pattern of disease burden as well as living donor transplant rate. Accordingly, strategies will most likely be variable depending on the epidemiological situation. Important to realize is that CRLM patients do usually not have liver failure nor portal hypertension. Consequently, it is highly likely that they will tolerate transplantation utilizing extended criteria donor grafts better than patients with high Model For End-Stage Liver Disease (MELD)-score due to chronic liver failure. Split liver transplantation is a well documented way to increase availability of liver grafts. About 10–15% of liver grafts may be suitable for splitting, and reported series indicate that this is an option that can provide good outcomes despite somewhat increased rate of biliary and vascular complications [37–39]. Another, still novel way to expand the donor pool is the RAPID procedure (Resection And Partial liver auxiliary transplantation with Delayed completion hepatectomy) where small for size liver grafts (usually segment 2 + 3) are transplanted in an auxiliary fashion with redirection of portal flow under pressure guidance to the graft to induce fast liver regeneration. This is then followed by a second stage-stage hepatectomy of the native liver 2–3 weeks after the transplantation [40–42]. The number of splittable livers not allocated for pediatric recipients is however limited. Applying the RAPID concept by utilizing living donors could be a favorable strategy to offer transplant to patients that otherwise does not get this option and simultaneously keeping the risk to the donor at a very low level [41]. Experience from living donor liver transplantation in Asia indicate that small grafts with a graft weight to body weight ratio of as low as 0.5 can be successfully used in cases without portal hypertension. Finally, eligibility and thereby the demand for liver transplantation in CRLM must be regulated by transplant criteria that are consistent with survival outcomes that are on level with regular transplant indications. Among the various criteria, centers may opt for the strictest versions [30].

The current experience with liver transplantation for CRLM is solely based on patients with unresectable disease, where the potential treatment benefit versus palliative chemotherapy is substantial and clearly clinically significant. The conventional approach to patients with CRLM is to determine if the disease is technically resectable or can be bridged to resectability by downstaging therapy combined with liver augmentation techniques like PVE or ALPPS if needed. Complex parenchymal sparing resections have also been reported, achieving tumor resectability, but leading to questionable radicality along vascular pedicles (R1 vascular) [43]. The outcomes after resection are highly variable, ranging from about 25 to 60% 5-year survival, and dependent on a large range of clinicopathological factors. Individual prognostic assessment in addition to technical resectability is however not common in regular clinical practice. This is somewhat logical given that the 5-year survival on palliative chemotherapy is around 10% combined with the assumption that liver resection is the only potentially curative therapeutic option. If liver transplantation were to be included as a potential therapeutic option for a small subgroup of technically resectable patients, the situation would become more complex. In such a scenario, individual prognostic evaluation similarly to what is routinely performed in transplant oncology would be needed. In this context is it is relevant to note that none of the prognostic factors for liver transplantation in CRLM has anything to do with resectability. It therefore defies logic to assume that the selection criteria identified for liver transplantation in unresectable CRLM are not valid in resectable disease. A scientifically and clinically relevant question is therefore whether there is a subgroup of patients where the clinicopathological features indicate that liver resection yields low 5-year survival probability, but where transplant would be expected to provide higher survival rates.

High hepatic tumor burden is consistently associated with substantially lower survival and high recurrence rates [44–46], whereas number of lesions appear to be a less significant factor in liver transplantation. Significantly, MTV on PET/CT has prognostic implications both in palliative chemotherapy for CRLM [47], liver resection [48], as well as transplantation [20]. The threshold value for MTV stratifying between favorable and inferior outcome appears to be about ten times higher in liver transplantation, indicating a far greater level of ‘tolerable hepatic tumor load’. In a recent published study, two similar groups of patients resected or transplanted for CRLM were compared [49▪]. Median MTV at preoperative PET–CT was 21–23 cm3 in both groups. Median number of metastases was 1.5 (1–6) and 5 (1–25) in the resection and transplant group respectively, thus the tumor load was significantly higher in liver transplanted patients. Despite the modest tumor load in the resected group, overall and disease-free as well as survival after recurrence was significantly longer in the transplanted patients (Fig. 3). This suggests that PET MTV might be useful in individual prognostic assessment of patients with CRLM, regardless of surgical treatment modality. Furthermore, one might hypothesize, that a small subgroup of well selected CRLM patients with resectable disease, but high number of hepatic lesions could gain a clinically relevant survival benefit by liver transplantation rather than standard of care liver resection. This has been further elucidated in a recently published article that has compared liver resected and transplanted patients with a focus on tumor load and the Oslo score [50]. In patients that had a tumor burden score at least 9 and an Oslo score of 2 or less, the outcome was far better after liver transplantation than liver resection (Fig. 4). The level of maintenance immunosuppression may have an important role in cancer recurrence and thereby survival outcomes. Steps to minimize the long-term immunosuppression should therefore be undertaken and experiences from Europe indicate that this is a feasible strategy in a high proportion of patients if conducted at late timepoints after transplantation [51–53].

FIGURE 3: Disease-free survival (a), overall survival (b) and survival after recurrence (c) for patients treated by liver transplantation (blue line) or liver resection (red line) for colorectal metastases. In the liver transplantation group, 7/12 patients had a relapse, five patients with lung metastases underwent lung resection with curative intent. In the liver resection group, 12/18 had a relapse, six in the liver only six multisite. Five patients had repeat resection. Adapted with permission from [49▪].FIGURE 4: Comparison of (a) overall survival, (b) disease-free survival and (c) survival after recurrence in patients treated by liver resection (green line) or liver transplantation (blue line) and that had a tumor burden score at least 9 and Oslo score of 2 or less. (d - f) overall, disease-free and survival after recurrence in the same population but with maximal tumor burden score of 16.2. Adapted with permission from [50].CONCLUSION

Liver transplantation for CRLM is gradually moving toward validation as an indication for liver transplantation in well selected patients. International consensus on selection criteria as well as collaborative common registries is needed in the process toward full, clinical validation.

Acknowledgements

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Conflicts of interest

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

REFERENCES 1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136:E359–E386. 2. Vuik FE, Nieuwenburg SA, Bardou M, et al. Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years. Gut 2019; 68:1820–1826. 3. Quan D, Gallinger S, Nhan C, et al. The role of liver resection for colorectal cancer metastases in an era of multimodality treatment: a systematic review. Surgery 2012; 151:860–870. 4. Kanas GP, Taylor A, Primrose JN, et al. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol 2012; 4:283–301. 5. Kron P, Linecker M, Jones RP, et al. Ablation or resection for colorectal liver metastases? A systematic review of the literature. Front Oncol 2019; 9:1052. 6. Ciliberto D, Prati U, Roveda L, et al. Role of systemic chemotherapy in the management of resected or resectable colorectal liver metastases: a systematic review and meta-analysis of randomized controlled trials. Oncol Rep 2012; 27:1849–1856. 7. Schadde E, Ardiles V, Robles-Campos R, et al. Early survival and safety of ALPPS. Ann Surg 2014; 260:829–838. 8. Sandstrom P, Røsok BI, Sparrelid E, et al. ALPPS improves resectability compared with conventional two-stage hepatectomy in patients with advanced colorectal liver metastasis: results from a scandinavian multicenter randomized controlled trial (LIGRO trial). Ann Surg 2018; 267:833–840. 9. Lam VWT, Laurence JM, Johnston E, et al. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB 2013; 15:483–491. 10. Chebaro A, Buc E, Durin T, et al. Liver venous deprivation or associating liver partition and portal vein ligation for staged hepatectomy? Ann Surg 2021; 274:874–880. 11. Adam R, Kitano Y. Multidisciplinary approach of liver metastases from colorectal cancer. Ann Gastroenterol Surg 2019; 3:50–56. 12. Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010; 11:38–47. 13. Jones RP, Hamann S, Malik HZ, et al. Defined criteria for resectability improves rates of secondary resection after systemic therapy for liver limited metastatic colorectal cancer. Eur J Cancer 2014; 50:1590–1601. 14. Starzl TE. The saga of liver replacement, with particular reference to the reciprocal influence of liver and kidney transplantation (1955–1967). J Am Col Surg 2002; 195:587–610. 15. Mühlbacher F, Huk I, Steininger R, et al. Is orthotopic liver transplantation a feasible treatment for secondary cancer of the liver? Transplant Proc 1991; 23 (1 Pt 2):1567–1568. 16. Hagness M, Foss A, Line P-D, et al. Liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg 2013; 257:800–806. 17▪. Bonney GK, Chew CA, Lodge P, et al. Liver transplantation for nonresectable colorectal liver metastases: the International Hepato-Pancreato-Biliary Association consensus guidelines. Lancet Gastroenterol Hepatol 2021; 6:933–946. 18. Grut H, Revheim ME, Line P-D, Dueland S. Importance of 18F-FDG PET/CT to select patients with nonresectable colorectal liver metastases for liver transplantation. Nucl Med Commun 2018; 39:1–627. 19. Bai B, Bading J, Conti PS. Tumor quantification in clinical positron emission tomography. Theranostics 2013; 3:787–801. 20. Grut H, Dueland S, Line P-D, Revheim ME. The prognostic value of (18)F-FDG PET/CT prior to liver transplantation for nonresectable colorectal liver metastases. Eur J Nucl Med Mol Imaging 2017; 4: (Suppl 1): 283. 21. Missiaglia E, Jacobs B, D’Ario G, et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol 2014; 25:1995–2001. 22. Smedman TM, Line P-D, Hagness M, et al. Liver transplantation for unresectable colorectal liver metastases in patients and donors with extended criteria (SECA-II arm D study). BJS Open 2020; 4:467–477. 23. Dueland S, Guren TK, Hagness M, et al. Chemotherapy or liver transplantation for nonresectable liver metastases from colorectal cancer? Ann Surg 2014; 261:956–960. 24. Dueland S, Hagness M, Line P-D, et al. Is liver transplantation an option in colorectal cancer patients with nonresectable liver metastases and progression on all lines of standard chemotherapy? Ann Surg Oncol 2014; 22:1–6. 25. Dueland S, Line PD, Hagness M, et al. Long-term quality of life after liver transplantation for nonresectable colorectal metastases confined to the liver. BJS Open 2018; 3:180–185. 26. Casak SJ, Marcus L, Fashoyin-Aje L, et al. FDA approval summary: pembrolizumab for the first-line treatment of patients with MSI-H/dMMR advanced unresectable or metastatic colorectal carcinoma. Clin Cancer Res 2021; 27:4680–4684. 27. Dai Y, Zhao W, Yue L, et al. Perspectives on immunotherapy of metastatic colorectal cancer. Front Oncol 2021; 11:659964. 28. Kumar V, Shinagare AB, Rennke HG, et al. The safety and efficacy of checkpoint inhibitors in transplant recipients: a case series and systematic review of literature. Oncologist 2020; 25:505–514. 29. Abdel-Wahab N, Safa H, Abudayyeh A, et al. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J Immunother Cancer 2019; 7:106. 30. Dueland S, Grut H, Syversveen T, et al. Selection criteria related to long-term survival following liver transplantation for colorectal liver metastasis. Am J Transplant 2019; 20:530–537. 31. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309–318. discussion 318–321. 32▪. Dueland S, Syversveen T, Solheim JM, et al. Survival following liver transplantation for patients with nonresectable liver-only colorectal metastases. Ann Surg 2020; 271:212–218. 33. Hagness M, Foss A, Egge TS, Dueland S. Patterns of recurrence after liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg Oncol 2014; 21:1323–1329. 34. Line P-D, Ruffolo LI, Toso C, et al. Liver transplantation for colorectal liver metastases: what do we need to know? Int J Surg Lond Engl 2020; 82S:87–92. 35. Grut H, Solberg S, Seierstad T, et al. Growth rates of pulmonary metastases after liver transplantation for unresectable colorectal liver metastases. Br J Surg 2018; 105:295–301. 36. Dueland S, Smedman TM, Røsok B, et al. Treatment of relapse and survival outcomes after liver transplantation in patients with colorectal liver metastases. Transplant Int 2021; 34:2205–2213. 37. Bowring MG, Massie AB, Schwarz KB, et al. Survival benefit of split liver transplantation for pediatric and adult candidates. Liver Transplant 2021. 38. Sneiders D, Dijk ARM, Polak WG, et al. Full-left-full-right split liver transplantation for adult recipients: a systematic review and meta-analysis. Transplant Int 2021; 34:2534–2546. 39. Broering DC, Wilms C, Lenk C, et al. Technical refinements and results in full-right full-left splitting of the deceased donor liver. Ann Surg 2005; 242:802–813. 40. Line P-D, Hagness M, Berstad AE, et al. A novel concept for partial liver transplantation in nonresectable colorectal liver metastases: the RAPID concept. Ann Surg 2015; 262:e5–e9. 41. Nadalin S, Königsrainer A, Capobianco I, et al. Auxiliary living donor liver transplantation combined with two-stage hepatectomy for unresectable colorectal liver metastases. Curr Opin Organ Transplant 2019; 24:651–658. 42. Nadalin S, Settmacher U, Rauchfuß F, et al. RAPID procedure for colorectal cancer liver metastasis. Int J Surg 2020; 82S:93–96. 43. Donadon M, Cescon M, Cucchetti A, et al. Parenchymal-sparing surgery for the surgical treatment of multiple colorectal liver metastases is a safer approach than major hepatectomy not impairing patients’ prognosis: a bi-institutional propensity score-matched analysis. Digest Surg 2017; 35:342–349. 44. Allard MA, Adam R, Giuliante F, et al. Long-term outcomes of patients with 10 or more colorectal liver metastases. Br J Cancer 2017; 117:604–611. 45. Sasaki K, Margonis GA, Andreatos N, et al. The prognostic utility of the ‘Tumor Burden Score’ based on preoperative radiographic features of colorectal liver metastases. J Surg Oncol 2017; 116:515–523. 46. Sasaki K, Morioka D, Conci S, et al. The tumor burden score: a new ‘metro-ticket’ prognostic tool for colorectal liver metastases based on tumor size and number of tumors. Ann Surg 2018; 267:132–141. 47. Tam HH, Cook GJ, Chau I, et al. The role of routine clinical pretreatment 18F-FDG PET/CT in predicting outcome of colorectal liver metastasis. Clin Nucl Med 2015; 40:e259–e264. 48. Grut H, Stern NM, Dueland S, et al. Preoperative 18F-FDG PET/computed tomography predicts survival following resection for colorectal liver metastases. Nucl Med Commun 2020; 41:916–923. 49▪. Grut H, Line P-D, Labori KJ, et al. Survival after liver resection and liver transplantation for colorectal liver metastases: a comparative analysis stratified by metabolic tumor volume assessed by 18F-FDG PET/CT. HPB 2021. 50. Lanari J, Hagness M, Sartori A, et al. Liver transplantation versus liver resection for colorectal liver metastasis: a survival benefit analysis in patients stratified according to tumor burden score. Transplant Int 2021; 34:1722–1732. 51. Benítez C, Londoño M-C, Miquel R, et al. Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology 2013; 58:1824–1835. 52. Lerut JP, Pinheiro RS, Lai Q, et al. Is minimal, [almost] steroid-free immunosuppression a safe approach in adult liver transplantation? Long-term outcome of a prospective, double blind, placebo-controlled, randomized, investigator-driven study. Ann Surg 2014; 260:886–892. 53. Manzia T-M, Angelico R, Toti L, et al. Long-term survival and cost-effectiveness of immunosuppression withdrawal after liver transplantation. Liver Transplant 2018; 24:1199–1208.