Liver Transplantation For Colorectal Liver Metastases:

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Article

Reference

LT for CRLM should be employed under investigational protocols through clinical trials

LINE, Pål-Dag, et al.

Abstract

Adenocarcinoma of the colon and rectum (CRC) is the second leading cause of cancer mortality, driven by stage IV disease [1]. While surgical resection of liver metastases has demonstrated a survival advantage, a minority of patients are candidates for resection due to anatomic involvement of disease. Recent advances in liver surgery, chemotherapy, and decision making guided by stratification at the time of presentation has better equipped us to perform aggressive metastasectomies, with resulting improved survival [2-4]. As a result, there is a resurgent interest in the concept of total hepatectomy and liver transplantation (LT) for colorectal liver metastases (CRLM). As of this writing, eight prospective clinical trials in six countries are assessing the viability of split or whole LT for CRLM. However, LT for CRLM remains controversial. Recent prospective trials have illustrated the importance of patient selection, and a disciplined respect for tumor biology. Here we present the current status of LT for CRLM, and suggest clinical decision criteria aimed at matching survival benefit comparable to other indications for LT.

LINE, Pål-Dag, et al. LT for CRLM should be employed under investigational protocols through clinical trials. International Journal of Surgery, 2020, vol. 82 Suppl, p. 87-92

DOI : 10.1016/j.ijsu.2020.03.079 PMID : 32305529

Available at:

http://archive-ouverte.unige.ch/unige:143043

Disclaimer: layout of this document may differ from the published version.

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Journal Pre-proof

LT for CRLM should be employed under investigational protocols through clinical trials

Pål-Dag Line, Luis I. Ruffolo, Christian Toso, Svein Dueland, Silvio Nadalin, Roberto Hernandez-Alejandro

PII: S1743-9191(20)30302-2

DOI: https://doi.org/10.1016/j.ijsu.2020.03.079 Reference: IJSU 5395

To appear in: International Journal of Surgery Received Date: 20 December 2019

Revised Date: 16 February 2020 Accepted Date: 31 March 2020

Please cite this article as: Line P-D, Ruffolo LI, Toso C, Dueland S, Nadalin S, Hernandez-Alejandro R, LT for CRLM should be employed under investigational protocols through clinical trials, International Journal of Surgery, https://doi.org/10.1016/j.ijsu.2020.03.079.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Liver Transplantation For Colorectal Liver Metastases:

What Do We Need To Know?

Pål-Dag Line, ^1,2Luis I. Ruffolo, ^3,4 Christian Toso, ⁵ Svein Dueland, ⁶ Silvio Nadalin, ⁷ Roberto Hernandez-Alejandro, ³

1. Department of Transplantation Medicine, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway

2. Corresponding Author

3. Department of Surgery and Division of Abdominal Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, United States of America 4. Shared First Author

5. Division of Abdominal Surgery, Department of Surgery, University of Geneva, Geneva, Switzerland

6. Experimental Transplantation and Malignancy Research Group, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway 7. Department of General and Transplant Surgery, University Hospital Tübingen, Germany

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Credit Author Statement

PL Developed the concepts and edited the manuscript, LR developed the concept, wrote the manuscript and developed the figures and tables, CT PL Developed the concepts and edited the manuscript, SV PL Developed the concepts and edited the manuscript, SN PL Developed the concepts and edited the manuscript, and RHA PL Developed the concepts, organized the effort to prepare the manuscript, and edited the manuscript. All authors approve of the final version of this manuscript.

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To the Editors and Reviewers,

Thank you for your careful and thoughtful review of our manuscript now re-titled “Liver transplantation for colorectal liver metastases: What do we need to know?” We have addressed every point from Reviewer 1 and the Editor-in-Chief. Specifically:

Reviewer #1: The authors nicely describe the current status of liver

transplantation (LT) for unresectable colorectal liver metastases (CRLM). The paper is well-presented and accompanied by nice illustrations and figures.

Following modifications and changes should be performed:

1. The editors would prefer to stick to the proposed title "Liver transplantation for colorectal liver metastases: What do we have to know?". Please change.

Thank you, we have changed the title to “Liver transplantation for colorectal liver metastases: What do we need to know?”

2. Although the transplant technique is not the main player in selecting patients with CRLM for LT, the authors should create a short paragraph on surgical transplant technique (whole organ, split, living-related, RAPID). To mention the RAPID concept at the first time in conclusions appears to late I the flow of the manuscript.

Thank you, we have incorporated a new paragraph detailing the growth of novel trials which include testing split allograft techniques for this novel indication. The paragraph follows:

With these early encouraging results, a number of institutions across Scandinavia, Europe, and North America initiated transplant protocols for patients with unresectable colorectal liver metastases. Through these trials, important questions will be tested including: 1) the role of adjuvant chemotherapy on disease-free survival 2) the feasibility of split graft techniques such as the RAPID technique, which involves a left lateral sectionectomy and section 2-3 liver transplant followed by an extended right hepatectomy in a second stage after adequate allograft hypertrophy, or a similar operative strategy to mitigate living donation risk in the LD-RAPID fashion and 3) the feasibility of utilizing living-donor and extended-criteria donor allografts (Table 2).

3. The manuscript would benefit from an additional table of the 6 ongoing prospective trials on LT for CRLM. Table columns should mirror following

information: (1) name or abbreviation of the trial, (2) country, (3) nature of the trial (prospective, multi-center … including NCI number if available), (4) primary

endpoint and other outcome measures. Therefore, we would encourage the authors to create such table and add to the manuscript.

This is a terrific idea, we have incorporated a new Table which details the new protocols listed on ClinicalTrials.gov incorporating LT for unresectable CRLM.

4. Minor (table 1): Please create footnotes, which should contain explanations (spell-out) of all abbreviations used in the table (CEA, LT), the statement of 1- point assignment to each risk factor, and the information of the primary target variable of the Oslo and Fong risk score (recurrence, survival, …).

Thank you, we have incorporated abbreviations below each table.

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Comments from Editor-in-Chief:

I have the following criticisms on this article:

(1) Please change "Key Takeaways" to "Highlights"

Thank you, we have retitled this sections

(2) Change the world "….. resurged in interested …." to "…. resurged in interest

….."

Thank you, we have edited this error

(3) Please add some data into the Abstract to support your views

Thank you, we have incorporated data and citations for the evolving landscape of treatment for CLRM:

“..Adenocarcinoma of the colon and rectum (CRC) is the second leading cause of cancer mortality, driven by stage IV disease [1]...Recent advances in liver surgery, chemotherapy, and decision making guided by stratification at the time of presentation has better equipped us to perform aggressive metastasectomies, with resulting improved survival [2–4]....”

(4) Please standardize the format of References into a single format, e.g.

reference 1, pages 114-119, reference 15, pages 309-18.

Thank you, we have formatted the citations to match the IJS standard.

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To the Editors,

Thank you for this opportunity to review Liver Transplantation for Colorectal Liver Metastases. All authors have reviewed the work and agree with the content of the manuscript. Finally, the authors have no relevant conflicts to disclose.

Sincerely,

Pål-Dag Line, MD, PhD Corresponding Author

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Liver Transplantation For Colorectal Liver Metastases:

What Do We Need To Know?

Pål-Dag Line,^1,2Luis I. Ruffolo,^3,4 Christian Toso,⁵ Svein Dueland,⁶ Silvio Nadalin,⁷ Roberto Hernandez-Alejandro,³

1. Department of Transplantation Medicine, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway

2. Corresponding Author

3. Department of Surgery and Division of Abdominal Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, United States of America 4. Shared First Author

5. Division of Abdominal Surgery, Department of Surgery, University of Geneva, Geneva, Switzerland

6. Experimental Transplantation and Malignancy Research Group, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway 7. Department of General and Transplant Surgery, University Hospital Tübingen, Germany

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Credit Author Statement

PL Developed the concepts and edited the manuscript, LR developed the concept, wrote the manuscript and developed the figures and tables, CT PL Developed the concepts and edited the manuscript, SV PL Developed the concepts and edited the manuscript, SN PL Developed the concepts and edited the manuscript, and RHA PL Developed the concepts, organized the effort to prepare the manuscript, and edited the manuscript. All authors approve of the final version of this manuscript.

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Abstract:

Adenocarcinoma of the colon and rectum (CRC) is the second leading cause of cancer mortality, driven by stage IV disease [1]. While surgical resection of liver metastases has demonstrated a survival advantage, a minority of patients are candidates for resection due to anatomic involvement of disease. Recent advances in liver surgery, chemotherapy, and decision making guided by stratification at the time of presentation has better equipped us to perform aggressive metastasectomies, with resulting improved survival [2–4]. As a result, there is a resurgent interest in the concept of total hepatectomy and liver transplantation (LT) for colorectal liver metastases (CRLM). As of this writing, eight prospective clinical trials in six countries are assessing the viability of split or whole LT for CRLM. However, LT for CRLM remains controversial. Recent prospective trials have illustrated the importance of patient selection, and a disciplined respect for tumor biology. Here we present the current status of LT for CRLM, and suggest clinical decision criteria aimed at matching survival benefit comparable to other indications for LT.

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Introduction:

Surgical resection of colorectal liver metastases (CRLM) remains the standard of care for patients’ whose disease is amenable for surgery. Robust data has buttressed the concept of aggressive curative intent metastasectomy for CRLM, including repeated resection, two stage hepatectomies to clear future liver remnant, and the use of pro-regenerative techniques as associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) for patients with insufficient future liver remnants [5–7]. However, only 10-20% of patients present with disease amenable for resection, and 5 year overall survival for patients treated with systemic therapies alone remains dismal at less than 10% [4,8,9]. Furthermore, patients who are candidates for primary resection experience recurrence in the majority of cases, often involving the remnant liver [10,11]. Thus the concept of local disease control through total hepatectomy and transplantation is an intriguing approach for local disease control for patients with unresectable primary or recurrent CRLM anatomy.

LT for CRLM is not a new concept, indeed LT for CRLM was first reported in the 1980s.

The largest series reported from this era are the outcomes from the European Liver Transplant registry. These LT for CRLM were performed prior to the implementation of multidisciplinary tumor boards, selection criteria for disease stage, or effective systemic chemotherapy. Notably, perioperative mortality approached 30%, and 40% of patients recurred within one year [12]. As a result 5 year overall survival ranged from 0-18% [12,13]. Not surprisingly, LT was abandoned for this disease, considered a futile procedure with unacceptable disease control, especially within the context of widespread liver allograft shortages for end-stage liver disease.

Since the poor outcomes of the 1980s and 90s, medical and surgical management of metastatic CRC has improved considerably. The use of VEGF and EGFR targeting antibodies, in combination with Oxaliplatin and Irinotecan chemotherapy has enhanced response and disease control dramatically, doubling median overall survival compared to a decade ago [14–

17]. Our understanding of risk factors for CRLM risk of recurrence, and drivers of CRC biology

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have also improved [2,18,19]. Lastly, perioperative mortality following LT and effective immunosuppression regimens have also vastly improved since the failed LT trials for CRLM [20]. Put simply, medical science has matured such that we can now more judiciously offer surgical therapy for CRLM, with better operative outcomes, and following more effective systemic therapies. In this review, we present available data for stratifying and selecting candidate patients for LT in the setting of liver-only CRLM. Additionally, we discuss future areas of investigation for incorporating biomarker, molecular, and advanced imaging modalities to more effectively select patients for LT, and target comparable overall survival as currently accepted indications for LT.

The Current State of LT for Unresectable CRLM:

In 2013 the Oslo group sparked a new wave of interest in LT for CRLM following a pilot, proof-of-concept prospective trial utilizing the unique surplus of organs within the Norwegian system [21]. The Secondary Cancer (SECA) I study included 21 patients with liver-only stage IV CRC, which was not amenable for primary resection. Encouragingly, the Oslo group reported 1, 3, and 5 year overall survival of 95%, 68%, and 60% respectively, which when compared to a disease and demographic matched cohort from the NORDIC VII first-line chemotherapy trial outperformed the best available systemic therapy overwhelmingly [22].

SECA I included a heterogeneous population of patients, in part due to relatively broad inclusion criteria. From this population, a number of risk factors were demonstrated to be synergistic in conferring superior survival following transplantation including tumor < 5.5cm, CEA < 80ng/L, > 2 years between resection of primary and date of transplantation, and evidence of tumor partial response or stable disease on chemotherapy [21]. The validity of the Oslo Score (See Table 1) was later supported in a retrospective cohort of patients who underwent LT for CLRM, notably finding the risk of recurrence is predicted by the interval from disease treatment to LT and the presence of a serum CEA below 80ug/L [23]. Not surprisingly, many of these variables map similarly to Fong’s Clinical Risk Score for recurrence after liver

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resection for colorectal liver metastases (FCRS) [2]. SECA I Included carefully screened patients, all with ECOG 0-1, who demonstrated no evidence of extrahepatic disease on contrasted computed tomography and 14-FDG-PET imaging. It is worth noting the utility of 14- FDG-PET to not only identify occult disease undetected by contrast computed tomography, but also the observed prognostic value of elevated metabolic tumor volume and tumor glycolysis [24]. Thus all patients in consideration for LT or CRLM should routinely undergo 14-FDG-PET in addition to conventional cross sectional imaging.

Additional key insights from the SECA I trial was the observed tumor recurrence pattern and the growth of metastases. Part of the reticence to offer LT for CRLM is the observed high rate of recurrence following partial hepatectomy, and the belief that this could be worsened by systemic immunosuppression [25,26]. Indeed while 90% of patients from SECA I developed recurrence of disease, the natural history of the disease was dissimilar from that of hepatectomies for CRLM. Of all patients demonstrating recurrence of disease, 68% developed isolated pulmonary metastases, of which 38% were able to undergo curative intent pulmonary resection [27]. This pattern appears to be repeated when evaluating data from SECA II [28]. In this more selective trial, pulmonary recurrences are the sole or primary location in 75% of patients. In comparison, contemporary series report recurrence following hepatectomy for CRLM shifted towards the remnant liver, with only 26% of patients presenting with isolated lung metastases (Figure 1) [7]. Furthermore, a subanalysis of the growth kinetics of these pulmonary metastases suggested that they grow at a similar rate in the immunosuppressed patients compared to immunocompetent patients [29]. Thus, total hepatectomy and transplantation, in the highly selected patient, may have an advantageous recurrence profile, which may in part explain the observed survival advantage in SECA I and II.

With these early encouraging results, a number of institutions across Scandinavia, Europe, and North America initiated transplant protocols for patients with unresectable

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colorectal liver metastases. Through these trials, important questions will be tested including: 1) the role of adjuvant chemotherapy on disease-free survival 2) the feasibility of split graft techniques such as the RAPID technique, which involves a left lateral sectionectomy and section 2-3 liver transplant followed by an extended right hepatectomy in a second stage after adequate allograft hypertrophy, or a similar operative strategy to mitigate living donation risk in the LD-RAPID fashion [30,31], and 3) the feasibility of utilizing living-donor and extended-criteria donor allografts (Table 2).

Proposed criteria for including patients with unresectable CRLM onto LT Protocols

In theory, a new treatment strategy must only surpass the current standard of care for it to garner adoption. Thus, all other things being equal, LT need only outperform the most effective systemic therapy to warrant consideration for adoption. However, most countries continue to experience severe liver allograft shortages and on-waitlist mortality. Thus, equitable use of allografts for a new indication should match the benefit for current indications requiring LT. 5 year OS for LT for ESLD or HCC are accepted to be 75% [32,33].

It is not unreasonable to consider that one may employ a stringent enough selection criteria to confer equivalent survival benefit for LT for patients with CRLM compared to those for other indications. In fact, an Oslo Score below 4 (0-3) has been demonstrated to afford similar overall survival to LT for HCC within Milan criteria [33]. However, which selection factors one incorporates may swing the pendulum too far, and exclude patients who may otherwise benefit similarly from LT. For example the interim analysis of the SECA II trial including 15 patients with Oslo Scores equal to or below 1 demonstrated a 5 year OS of 83% [28]. Interestingly, within this cohort, the FCRS demonstrated further ability to stratify patient’s DFS. Thus, incorporating these variables may yield an even higher expected OS, but potentially at the expense of excluding patients who would benefit sufficiently to justify LT.

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A recent analysis of SECA I and II patients, all of whom had PET-CT imaging within 90 days of transplantation, explored selection factors and compared the Oslo Score, the FCRS, metabolic tumor volume >70 cm³, and sidedness of the primary lesion [34]. Through these four criteria, the authors were able to demonstrate Kaplan Meier analyses which conferred longer and shorter overall survival. Not surprisingly, the most stringent of these metrics (the FCRS), was able to project a 100% 5 year survival when the FCRS was 0-2 (Figure 2) [34]. However, this selectivity came at the cost of excluding 70% of patients [34]. Conversely, a metabolic tumor volume of 70 cm³ served as a sensitive watermark for selecting patients with 5 year survival of 80%. It is noteworthy that right-sided primary tumors were associated with an inferior outcome after transplantation compared to left-sided tumors [34], and this is in line with other reports on the impact of the location of the primary tumor on clinical course [35]. As we strive to balance sufficient benefit with increased access for diverse populations of patients presenting with unresectable CRLM, a continuous reassessment of criteria and consensus around what constitutes the benefit/risk inflection point of this goldilocks dilemma will have to be met.

Molecular risk stratification of colorectal cancer

A number of pathways and driver oncogenes have been well characterized to fuel CRC growth and metastasis, while rendering the disease more difficult to treat. For example, mutations in BRAF and SMAD family proteins are well described to confer worse progression and overall survival [18]. Similarly, constitutive activation of RAS family proteins have been shown to limit the effectiveness of targeted EGFR therapy, and confer a higher risk of recurrence following R0 resection [14,36]. Furthermore RAS displays a synergistic effect with TP53 mutations, a common deranged tumor suppressor in CRC [19]. Notably, two of the six prospective trials exploring LT for CRLM exclude patients on the basis of mutant BRAF.

Interestingly, clinical criteria may in effect exclude more aggressive tumor biology underpinned by certain oncogene mutations. For example, SECA I which included higher Oslo and FCRS scores compared to SECA II encompassed 43% of patients with (K)RAS mutations compared to

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just 7% in SECA II [21,22,28]. More broadly, It may be prudent to exclude patients with BRAF, KRAS, or SMAD mutations, however, future trials will need to elucidate the benefit of such strategies, compared to clinical criteria of disease biology.

Perhaps equally challenging is the dilemma of what to do in patients with actionable disease mutations. For example, CRC with impaired DNA mismatch repair have been shown to respond favorably to immune checkpoint blockade [37]. Similarly, tumors with Her2 amplification, though rare, have shown response to Her2 targeted therapy [38]. In these patients, transplantation should be considered with caution, and only after having exhausted approved effective targeted or immune therapies.

Conclusions

The recent rekindling of interest for LT for CRLM is likely to grow if additional centers are able to recapitulate the promising results from SECA I and II. As with the early experience in LT for HCC, strict adherence to selection criteria will maximize benefit, while maintaining dual equipoise with other patients on waitlists for liver allografts [39]. The liver transplant community must proceed with caution into this new domain of transplant oncology. New centers should enroll patients in prospective trials to enhance transparency and maximize the acquired knowledge. Cross-institutional consortia will be required to tackle many challenges of LT for CRC such as the impact of oncogene mutations and the best management for recurrence.

The pervasive allograft shortage has stimulated the development of living donation programs and split allograft transplantation aided by regenerative techniques (See accompanying article on the RAPID Concept) [30,31]. These strategies, as well as the utilization of extended criteria allografts may serve a starting point for introducing LT for CRLM. However, the future incorporation of unresectable CRLM as an indication for LT, as is the case for HCC, hilar cholangiocarcinomas, and metastatic neuroendocrine tumors begs the consideration of how to incorporate CRLM into the LT ecosystem. Recent work by the Norwegian group has

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demonstrated that various selection criteria can be used to target a particular OS following LT.

However, to push to the extreme is to exclude patients who likely will meet OS targets.

Conceptually, LT from deceased donors for CRLM must marry patients fit enough for LT, who’s disease can be reasonably cured or the oncologic clock reset such that the gained survival is sufficient to offset the incurred morbidity and peri-operative mortality to match the benefit otherwise gained by another patient on the waitlist. Selection criteria will be central to being able to achieve this balance. Fortunately, the added volume of LT should CRLM join HCC and other indications would be less a tsunami than a drop in the bucket. However, before we open the spigot, we must calibrate the filter through which to determine eligible patients.

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Oslo Score (0-4) Fong Clinical Risk Score (0-5)

Tumor Diameter >5.5 cm Largest Tumor >5 cm

CEA >80ug/L CEA>200 ug/L

Less than 2 year interval between primary resection and LT

Synchronous Disease (Primary to Liver Recurrence <12 months)

Progressive disease at time of LT Node-Positive Primary

More than 1 Liver Metastasis

Table 1: The Oslo Score for Risk Stratification of Patients Undergoing LT for CRLM, and The Fong Clinical Risk Score For Predicting Recurrence After Hepatectomy for CRLM [2,21].

Abbreviations: LT, liver transplantation; CEA, carcinoembryonic antigen;

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Trial Protocol

Clinical trial Identifier

Country Protocol Timeline

Design Phase

SECA II NCT01479608 Norway 2011-2027 LT vs. surgical Resection Phase 3 Randomized RAPID NCT02215889 Norway 2014-2028 Liver resection and

partial section 2-3 transplantation with two- stage hepatectomy

Phase 1-2

TRANSMET NCT02597348 France 2015-2027 Chemo + LT vs. Chemo Phase 3 Randomized SECA III NCT03494946 Norway 2016-2027 LT vs. chemo or ablation Phase 3

Randomized Toronto

Protocol

NCT02864485 Canada 2016-2023 Chemo + LDLT vs.

Chemo

Open Label

LIVERT(W) OHEAL

NCT03488953 Germany 2018-2023 LDLT with two-stage hepatectomy

Open Label

COLT NCT03803436 Italy 2019-2024 Chemo + LT vs. Chemo Open Label SOULMATE NCT04161092 Sweden 2020-2029 Chemo+LT with ECD vs.

Chemo

Open Label Randomized Table 2: Current clinical trials for incorporating liver transplantation for the treatment of unresectable colorectal liver metastases. Abbreviations: LT, liver transplantation; Chemo, chemotherapy; ablation; local therapy with transarterial chemoembolization or radiotherapy; LDLT, living donor liver transplantation;

ECD, extended criteria donor

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Figure 1: Comparison of recurrence patterns from SECA I and II from and a cohort of patients undergoing liver resection for colorectal liver metastases [7,27].

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Figure 2. Kaplan-Meir analysis of overall survival from pooled SECA I and II patients stratified by A) Right vs Left sided primary tumors, B) Oslo Score greater than or less than two, C) Metabolic tumor volume greater than or less than 70 cm³, and D) FCRS greater than and less than two. Dashed red line denotes a target 5-year OS of 75%. Reproduced with permission from Dueland et. al. American Journal of Transplantation, 2019.

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Highlights:

● Liver transplantation (LT) for patients with liver-only unresectable colorectal liver metastases (CRLM) has resurged in interest in the last two decades.

● Following LT, the recurrence pattern of highly selected patients appears to be favorable, and dissimilar from chemotherapy or primary surgical resection.

● Patients treated with LT for CRLM experience favorable survival compared to systemic therapy.

● Various selection criteria can be employed to improve expected survival in patients being offered LT for colorectal liver metastases with similar benefit as other accepted indications for LT.

● The level of evidence continues to build supporting LT for CRLM, and future trials in Europe, Norway, and North America are poised to answer key questions about feasibility and efficacy of this approach.

● LT for CRLM should be employed under investigational protocols through clinical trials.

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1

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2 Author contribution

Please specify the contribution of each author to the paper, e.g. study design, data collections, data analysis, writing. Others, who have contributed in other ways should be listed as contributors.

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Roberto Hernandez-Alejandro, MD

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1 1 2

3 4

Abstract:

5 6

Adenocarcinoma of the colon and rectum (CRC) is the second leading cause of cancer 7

mortality, driven by stage IV disease [1]. While surgical resection of liver metastases has 8

demonstrated a survival advantage, a minority of patients are candidates for resection due to 9

anatomic involvement of disease. Recent advances in liver surgery, chemotherapy, and decision 10

making guided by stratification at the time of presentation has better equipped us to perform 11

aggressive metastasectomies, with resulting improved survival [2–4]. As a result, there is a 12

resurgent interest in the concept of total hepatectomy and liver transplantation (LT) for colorectal 13

liver metastases (CRLM). As of this writing, eight prospective clinical trials in six countries are 14

assessing the viability of split or whole LT for CRLM. However, LT for CRLM remains 15

controversial. Recent prospective trials have illustrated the importance of patient selection, and 16

a disciplined respect for tumor biology. Here we present the current status of LT for CRLM, and 17

suggest clinical decision criteria aimed at matching survival benefit comparable to other 18

indications for LT.

19

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2 Introduction:

Surgical resection of colorectal liver metastases (CRLM) remains the standard of care for patients’ whose disease is amenable for surgery. Robust data has buttressed the concept of aggressive curative intent metastasectomy for CRLM, including repeated resection, two stage hepatectomies to clear future liver remnant, and the use of pro-regenerative techniques as associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) for patients with insufficient future liver remnants [5–7]. However, only 10-20% of patients present with disease amenable for resection, and 5 year overall survival for patients treated with systemic therapies alone remains dismal at less than 10% [4,8,9]. Furthermore, patients who are candidates for primary resection experience recurrence in the majority of cases, often involving the remnant liver [10,11]. Thus the concept of local disease control through total hepatectomy and transplantation is an intriguing approach for local disease control for patients with unresectable primary or recurrent CRLM anatomy.

LT for CRLM is not a new concept, indeed LT for CRLM was first reported in the 1980s.

The largest series reported from this era are the outcomes from the European Liver Transplant registry. These LT for CRLM were performed prior to the implementation of multidisciplinary tumor boards, selection criteria for disease stage, or effective systemic chemotherapy. Notably, perioperative mortality approached 30%, and 40% of patients recurred within one year [12]. As a result 5 year overall survival ranged from 0-18% [12,13]. Not surprisingly, LT was abandoned for this disease, considered a futile procedure with unacceptable disease control, especially within the context of widespread liver allograft shortages for end-stage liver disease.

Since the poor outcomes of the 1980s and 90s, medical and surgical management of metastatic CRC has improved considerably. The use of VEGF and EGFR targeting antibodies, in combination with Oxaliplatin and Irinotecan chemotherapy has enhanced response and

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3 disease control dramatically, doubling median overall survival compared to a decade ago [14–17]. Our understanding of risk factors for CRLM risk of recurrence, and drivers of CRC biology have also improved [2,18,19]. Lastly, perioperative mortality following LT and effective immunosuppression regimens have also vastly improved since the failed LT trials for CRLM [20]. Put simply, medical science has matured such that we can now more judiciously offer surgical therapy for CRLM, with better operative outcomes, and following more effective systemic therapies. In this review, we present available data for stratifying and selecting candidate patients for LT in the setting of liver-only CRLM. Additionally, we discuss future areas of investigation for incorporating biomarker, molecular, and advanced imaging modalities to more effectively select patients for LT, and target comparable overall survival as currently accepted indications for LT.

The Current State of LT for Unresectable CRLM:

In 2013 the Oslo group sparked a new wave of interest in LT for CRLM following a pilot, proof-of-concept prospective trial utilizing the unique surplus of organs within the Norwegian system [21]. The Secondary Cancer (SECA) I study included 21 patients with liver-only stage IV CRC, which was not amenable for primary resection. Encouragingly, the Oslo group reported 1, 3, and 5 year overall survival of 95%, 68%, and 60% respectively, which when compared to a disease and demographic matched cohort from the NORDIC VII first-line chemotherapy trial outperformed the best available systemic therapy overwhelmingly [22].

SECA I included a heterogeneous population of patients, in part due to relatively broad inclusion criteria. From this population, a number of risk factors were demonstrated to be synergistic in conferring superior survival following transplantation including tumor < 5.5cm, CEA < 80ng/L, > 2 years between resection of primary and date of transplantation, and evidence of tumor partial response or stable disease on chemotherapy [21]. The validity of the

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4 Oslo Score (See Table 1) was later supported in a retrospective cohort of patients who underwent LT for CLRM, notably finding the risk of recurrence is predicted by the interval from disease treatment to LT and the presence of a serum CEA below 80ug/L [23]. Not surprisingly, many of these variables map similarly to Fong’s Clinical Risk Score for recurrence after liver resection for colorectal liver metastases (FCRS) [2]. SECA I Included carefully screened patients, all with ECOG 0-1, who demonstrated no evidence of extrahepatic disease on contrasted computed tomography and 14-FDG-PET imaging. It is worth noting the utility of 14-FDG-PET to not only identify occult disease undetected by contrast computed tomography, but also the observed prognostic value of elevated metabolic tumor volume and tumor glycolysis [24]. Thus all patients in consideration for LT or CRLM should routinely undergo 14-FDG-PET in addition to conventional cross sectional imaging.

Additional key insights from the SECA I trial was the observed tumor recurrence pattern and the growth of metastases. Part of the reticence to offer LT for CRLM is the observed high rate of recurrence following partial hepatectomy, and the belief that this could be worsened by systemic immunosuppression [25,26]. Indeed while 90% of patients from SECA I developed recurrence of disease, the natural history of the disease was dissimilar from that of hepatectomies for CRLM. Of all patients demonstrating recurrence of disease, 68% developed isolated pulmonary metastases, of which 38% were able to undergo curative intent pulmonary resection [27]. This pattern appears to be repeated when evaluating data from SECA II [28]. In this more selective trial, pulmonary recurrences are the sole or primary location in 75% of patients. In comparison, contemporary series report recurrence following hepatectomy for CRLM shifted towards the remnant liver, with only 26% of patients presenting with isolated lung metastases (Figure 1) [7]. Furthermore, a subanalysis of the growth kinetics of these pulmonary metastases suggested that they grow at a similar rate in the immunosuppressed patients

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5 compared to immunocompetent patients [29]. Thus, total hepatectomy and transplantation, in the highly selected patient, may have an advantageous recurrence profile, which may in part explain the observed survival advantage in SECA I and II.

With these early encouraging results, a number of institutions across Scandinavia, Europe, and North America initiated transplant protocols for patients with unresectable colorectal liver metastases. Through these trials, important questions will be tested including: 1) the role of adjuvant chemotherapy on disease-free survival 2) the feasibility of split graft techniques such as the RAPID technique, which involves a left lateral sectionectomy and section 2-3 liver transplant followed by an extended right hepatectomy in a second stage after adequate allograft hypertrophy, or a similar operative strategy to mitigate living donation risk in the LD-RAPID fashion [30,31], and 3) the feasibility of utilizing living-donor and extended-criteria donor allografts (Table 2).

Proposed criteria for including patients with unresectable CRLM onto LT Protocols

In theory, a new treatment strategy must only surpass the current standard of care for it to garner adoption. Thus, all other things being equal, LT need only outperform the most effective systemic therapy to warrant consideration for adoption. However, most countries continue to experience severe liver allograft shortages and on-waitlist mortality. Thus, equitable use of allografts for a new indication should match the benefit for current indications requiring LT. 5 year OS for LT for ESLD or HCC are accepted to be 75% [32,33].

It is not unreasonable to consider that one may employ a stringent enough selection criteria to confer equivalent survival benefit for LT for patients with CRLM compared to those for other indications. In fact, an Oslo Score below 4 (0-3) has been demonstrated to afford similar overall survival to LT for HCC within Milan criteria [33]. However, which selection factors one incorporates may swing the pendulum too far, and exclude patients who may otherwise benefit

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6 similarly from LT. For example the interim analysis of the SECA II trial including 15 patients with Oslo Scores equal to or below 1 demonstrated a 5 year OS of 83% [28]. Interestingly, within this cohort, the FCRS demonstrated further ability to stratify patient’s DFS. Thus, incorporating these variables may yield an even higher expected OS, but potentially at the expense of excluding patients who would benefit sufficiently to justify LT.

A recent analysis of SECA I and II patients, all of whom had PET-CT imaging within 90 days of transplantation, explored selection factors and compared the Oslo Score, the FCRS, metabolic tumor volume >70 cm³, and sidedness of the primary lesion [34]. Through these four criteria, the authors were able to demonstrate Kaplan Meier analyses which conferred longer and shorter overall survival. Not surprisingly, the most stringent of these metrics (the FCRS), was able to project a 100% 5 year survival when the FCRS was 0-2 (Figure 2) [34]. However, this selectivity came at the cost of excluding 70% of patients [34]. Conversely, a metabolic tumor volume of 70 cm³served as a sensitive watermark for selecting patients with 5 year survival of 80%. It is noteworthy that right-sided primary tumors were associated with an inferior outcome after transplantation compared to left-sided tumors [34], and this is in line with other reports on the impact of the location of the primary tumor on clinical course [35]. As we strive to balance sufficient benefit with increased access for diverse populations of patients presenting with unresectable CRLM, a continuous reassessment of criteria and consensus around what constitutes the benefit/risk inflection point of this goldilocks dilemma will have to be met.

Molecular risk stratification of colorectal cancer

A number of pathways and driver oncogenes have been well characterized to fuel CRC growth and metastasis, while rendering the disease more difficult to treat. For example, mutations in BRAF and SMAD family proteins are well described to confer worse progression and overall survival [18]. Similarly, constitutive activation of RAS family proteins have been

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7 shown to limit the effectiveness of targeted EGFR therapy, and confer a higher risk of recurrence following R0 resection [14,36]. Furthermore RAS displays a synergistic effect with TP53 mutations, a common deranged tumor suppressor in CRC [19]. Notably, two of the six prospective trials exploring LT for CRLM exclude patients on the basis of mutant BRAF.

Interestingly, clinical criteria may in effect exclude more aggressive tumor biology underpinned by certain oncogene mutations. For example, SECA I which included higher Oslo and FCRS scores compared to SECA II encompassed 43% of patients with (K)RAS mutations compared to just 7% in SECA II [21,22,28]. More broadly, It may be prudent to exclude patients with BRAF, KRAS, or SMAD mutations, however, future trials will need to elucidate the benefit of such strategies, compared to clinical criteria of disease biology.

Perhaps equally challenging is the dilemma of what to do in patients with actionable disease mutations. For example, CRC with impaired DNA mismatch repair have been shown to respond favorably to immune checkpoint blockade [37]. Similarly, tumors with Her2 amplification, though rare, have shown response to Her2 targeted therapy [38]. In these patients, transplantation should be considered with caution, and only after having exhausted approved effective targeted or immune therapies.

Conclusions

The recent rekindling of interest for LT for CRLM is likely to grow if additional centers are able to recapitulate the promising results from SECA I and II. As with the early experience in LT for HCC, strict adherence to selection criteria will maximize benefit, while maintaining dual equipoise with other patients on waitlists for liver allografts [39]. The liver transplant community must proceed with caution into this new domain of transplant oncology. New centers should enroll patients in prospective trials to enhance transparency and maximize the acquired

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8 knowledge. Cross-institutional consortia will be required to tackle many challenges of LT for CRC such as the impact of oncogene mutations and the best management for recurrence.

The pervasive allograft shortage has stimulated the development of living donation programs and split allograft transplantation aided by regenerative techniques (See accompanying article on the RAPID Concept) [30,31]. These strategies, as well as the utilization of extended criteria allografts may serve a starting point for introducing LT for CRLM. However, the future incorporation of unresectable CRLM as an indication for LT, as is the case for HCC, hilar cholangiocarcinomas, and metastatic neuroendocrine tumors begs the consideration of how to incorporate CRLM into the LT ecosystem. Recent work by the Norwegian group has demonstrated that various selection criteria can be used to target a particular OS following LT.

However, to push to the extreme is to exclude patients who likely will meet OS targets.

Conceptually, LT from deceased donors for CRLM must marry patients fit enough for LT, who’s disease can be reasonably cured or the oncologic clock reset such that the gained survival is sufficient to offset the incurred morbidity and peri-operative mortality to match the benefit otherwise gained by another patient on the waitlist. Selection criteria will be central to being able to achieve this balance. Fortunately, the added volume of LT should CRLM join HCC and other indications would be less a tsunami than a drop in the bucket. However, before we open the spigot, we must calibrate the filter through which to determine eligible patients.

Provenance and peer review

Commissioned, externally peer-reviewed

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