In the early days of liver transplantation (LT), hepatobiliary cancer was the main indication. However, the transplant community realized soon that the results of LT for this indication were dismal and it was abandoned. Professor Mazzaferro et al1 in 1996 revolutionized the indication of LT for hepatocellular carcinoma (HCC) by describing the well-known Milan criteria, which have been the main and most validated criteria to indicate LT for HCC for decades. Subsequently, these criteria have been challenged in many studies as they were considered to be too restrictive. In recent years, the liver transplant community has been revisiting the concept of utilizing LT as a treatment option to cure hepatobiliary malignancies and this has been named Transplant Oncology.2 Several contributing factors to this development should be considered: (1) great improvements in perioperative management of LT recipients and currently postoperative mortality is thought to be <5%, and 1-y survival is ~90%,3 (2) better understanding of immunosuppression and ability to minimize immunosuppression in patients transplanted for cancer without an increase in rejection, (3) several surgical innovations to increase the organ pool (donation after circulatory death, living donation),4,5 (4) discoveries in molecular profiling and systemic therapies in cancer such as colorectal, HCC, or cholangiocarcinoma6,7 that can be used as neoadjuvant therapies, and lastly (5) with the recent introduction of direct acting agents for hepatitis C virus infection that provide curative rates ~100%, the number of patients in need of an LT for decompensated hepatitis C virus have dramatically decreased.8 All of these factors have contributed to revise the concept of Transplant Oncology.
Transplant Oncology has 4 distinct pillars2:
- 1) Evolution of multidisciplinary cancer care including advancements in solid-organ transplantation.
- 2) Elucidation of self and nonself recognition systems link tumor and transplant immunology.
- 3) Exploration of mechanisms of carcinogenesis and of innovative outcome endpoints that are specific in LT for hepato-biliary malignancies.
- 4) Extension of surgical oncology conventional margins as a distinctive feature of LT applied to hepato-biliary malignancies.
With the advancements of cancer immunotherapy and the increase of molecular profiling and targeted therapies in the management of hepatobiliary malignancies, the future development of Transplant Oncology will only succeed if there is a multidisciplinary effort that includes not only the liver transplant community (surgeons, hepatologists, and anesthesiologists, etc) but also medical and radiation oncologists, pathologists, immunologists, and basic scientists.9 The International Liver Transplant Society (ILTS) is promoting and supporting this initiative through a special interest group in Transplant Oncology and plans to collaborate with other medical societies and industry in the near future.10 This will allow to maximize the impact in this rapidly evolving field, which can help make an impact in this fascinating field.
Although in the last decade several refinements have been made in the management of LT for HCC and hepatoblastoma, studies have investigated the use of LT to treat hilar, intrahepatic cholangiocarcinoma, or metastatic disease to the liver,11,12 yet no contemporary international consensus guidelines exist for the assessment and management of patients undergoing LT for hepatobiliary cancer. On February 7, 2019, the ILTS held a Consensus Conference in Rotterdam, the Netherlands on Transplant Oncology. The meeting covered mainly the multidisciplinary management of patients transplanted for hepatobiliary cancer. Four working groups (WGS) were created: (1) LT for HCC, (2) LT for cholangiocarcinoma, (3) LT for neuroendocrine and colorectal cancer liver metastases and hepatoblastoma, and (4) posttransplant management in the setting of cancer. ILTS convened experts in these 4 WGs, to address the key management issues related to their respective topics. Each WG had key questions that were addressed via a comprehensive review of the literature. Three months before the consensus conference, the WG members collected pertinent literature adhering to specific criteria agreed upon by the WG. At the consensus conference, representatives of each WG presented the questions, collected answers, and proposed statements to the ~100 consensus conference attendees during the plenary session for discussion. Subsequently, each WG reconvened to address open questions on which no agreement had been reached during the plenary discussion. Updated recommendations from each WG were then presented at the concluding plenary session for approval. The quality of the evidence, benefits, and harms, as well as values and preferences, were carefully considered. The quality of evidence was rated as low, moderate, or high. The strength of the recommendation was rated as strong, moderate, or weak, reflecting confidence that adherence to guidance will result in more good than harm. Statements and recommendations were based on the GRADE system.13 The ILTS Transplant Oncology consensus conference recommendations issued for each WG are now published in this special issue of Transplantation. The 4 manuscripts published in this special issue of Transplantation summarize the expert consensus on Transplant Oncology and are as follows:
- LT for cholangiocarcinoma and mixed hepatocellular-cholangiocarcinoma. Recommendations on the potential of LT in patients with this disease are described.
- LT for colorectal and neuroendocrine liver metastases and hepatoblastoma. A review of the current evidence and recommendations in these settings are described.
- LT for HCC. Updated information on the management of this disease in the context of LT is described.
- Posttransplant management of recipients undergoing LT for HCC. A description of the current management and future perspectives is provided.
This contemporary guidance is intended primarily for healthcare professionals caring for patients transplanted for cancer under strict protocols at specialized centers but should also assist policy makers in optimizing the care settings for LT candidates and recipients. Finally, these recommendations should also serve as the starting point for future collaborations with other disciplines.
1. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996; 334:693–699
2. Hibi T, Sapisochin G. What is transplant oncology? Surgery. 2019; 165:281–285
3. Muller X, Marcon F, Sapisochin G, et al. Defining benchmarks in liver transplantation: a multicenter outcome analysis determining best achievable results. Ann Surg. 2018; 267:419–425
4. Goldaracena N, Gorgen A, Doyle A, et al. Live donor liver transplantation for patients with hepatocellular carcinoma offers increased survival vs. deceased donation. J Hepatol. 2019; 70:666–673
5. Kollmann D, Sapisochin G, Goldaracena N, et al. Expanding the donor pool: donation after circulatory death and living liver donation do not compromise the results of liver transplantation. Liver Transpl. 2018; 24:779–789
6. Javle M, Bekaii-Saab T, Jain A, et al. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2016; 122:3838–3847
7. Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019; 380:1450–1462
8. Belli LS, Perricone G, Adam R, et al; all the contributing centers (www.eltr.org
) and the European Liver and Intestine Transplant Association (ELITA)Impact of DAAs on liver transplantation: major effects on the evolution of indications and results. An ELITA study based on the ELTR registry. J Hepatol. 2018; 69:810–817
9. Why interdisciplinary research matters. Nature. 2015; 525:305
10. Hibi T, Sapisochin G, Berenguer M, et al. Liver Transplant Oncology: International Liver Transplantation Society.Available at ILTS.org/about/special-interest-groups/sig-liver-transplant-oncology
. Accessed December 5, 2019
11. Sapisochin G, Facciuto M, Rubbia-Brandt L, et al; iCCA International ConsortiumLiver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology. 2016; 64:1178–1188
12. 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
13. Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working GroupGRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336:924–926