Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females, with 1.8 million new cases and almost 861 000 deaths in 2018 according to the WHO. CRC incidence and mortality rates vary markedly around the world [1,2].
Colorectal liver metastases (CRLM) is present in 15–25% of patients at the time of diagnosis of CRC and another 25–50% will develop liver metastases within 3 years after resection of the primary tumor. Curative hepatic resection is possible in less than 25% of those patients with disease limited to the liver, which translates into 5–10% of the original group developing CRC. When liver metastases are resected, the 5-year survival increases significantly (30–40%). For patients with unresesectable stage IV disease (i.e. 70–80% of patients with CRLM), the expected median overall survival (OS) from start of first-line chemotherapy (CTx) is about 2 years and the 5-year OS is about 10%, although longer median OS has been obtained in selected patients with good performance status (i.e. Eastern Cooperative Oncology Group 0–1), no (K)RAS or BRAF mutations, and left-sided tumors [3,4▪▪,5,6▪,7] Furthermore, even the combination of CTx with locoregional approaches like selective internal radiotherapy seems not to improve the outcome .
LIVER TRANSPLANTATION FOR CRLM
Liver transplantation may represent the only alternative solution for the problem of limited OS in patients affected with unresectable CRLM (u-CRLM). As recently reported by Gorgen et al.[6▪], the history of liver transplantation for u-CRLM can be divided into two main eras, before and after 2000. Before 2000, 93 cases had been reported worldwide, with the biggest series being from Vienna with 25 cases at a single center [9–11].
In this first period, the long-term results were very poor with 5 years OS ranging between 12 and 21%. Since 2000, through improved selection of patients significant better results have been reported, with OS at 5 years ranging between 50 and 60% in a total amount of 33 new cases [12,13]. It should be noted that in both eras, the major drawback of the procedure was represented by high rates of tumor recurrence (mainly extrahepatic) ranging between 50 and 90% with disease-free survival (DFS) rate around 35% at 1 year [6▪].
In the Norwegian SECA I trial (2006–2011), 21 patients with u-CRLM without extra hepatic disease following systemic CTx (≥6 weeks; 1st–3rd line) underwent whole liver transplantation and reached a five OS rate of 60% . The results of this series were then compared with a similar group of patients with liver metastases only (n = 47 out of 571) who joined the Nordic VII trial, in which similar patients with u-CRLM were treated with systemic CTx alone with or without Cetuximab . The authors showed OS rate at 5 years of 8.5% in the Nordic VII trial and 56% in the SECA patients; this can be translated in a sort of survival benefit more than 50% in favor of liver transplantation . The benefit of liver transplantation could be further increased when the Oslo Criteria were applied: maximal tumor diameter less than 5.5 cm, carcino embrionary antigen (CEA) level before liver transplantation less than 80 ng/l, no tumor progression under CTx and time interval diagnosis to liver transplantation longer than 2 years [12,15▪]. In addition, the presence of each single factor and their different combinations influenced significantly the results with 5 years OS ranging from 0 to > 75% [16▪].
To better evaluate the benefit and efficacy of liver transplantation as treatment for ultra-selected patients with u-CRLM a randomized controlled clinical trial was performed by the Oslo group (SECA-II Trial-NCT01479608). The preliminary results of the SECA II trial (i.e. 15 cases between 2012 and 2016) have been very recently reported [4▪▪]. The authors showed that in case of hyper selection (i.e. lower number of metastatic lesions, size of largest liver lesions less than 5.5 cm, CEA levels less than 80 ng/l, Fong Clinical Risk Score ≤2, and Oslo score ≤1) extraordinary results could be reached, that is OS rate at 5 years up to 80% notwithstanding DFS rates at 1, 2 and 3 years of 53, 44 and 35%, respectively. The authors additionally showed excellent results also in patients with recurrence of disease (mainly in the lungs), that is OS at 1, 2 and 4 years 100, 73 and 73%, respectively. Based on this data they concluded patients affected of tumor recurrence do benefit from maximal treatment of recurrent disease (surgery and aggressive CTx) .
According to the recently introduced concepts of ‘Transplant Oncology’ [18,19▪] the long-term outcomes of liver transplantation for malignant neoplasms should be similar to those of liver transplantation for nonmalignant disease as also reported by Clavien et al.. Also in this context the Oslo group demonstrated that liver transplantation for selected patients affected with u-CRLM can offer similar or even better results than liver transplantation for patients affected with hepatocellular carcinoma (HCC) within Milano criteria .
At the moment three clinical trials about deceased donor liver transplantation (DDLT) for CRLM are running worldwide (Table 1):
- (1) SECA II NCT01479608 (Oslo, Norway): open label, randomized controlled trial to assess the OS between patients undergoing liver transplantation or liver resection.
- (2) TRANSMETT: international multicentric randomized trial open label trial from France (NCT02597348). Patients with u-CRLM will be randomized to receive standard of care CTx or liver transplantation and CTx. The main outcome is 3-year and 5-year DFS/progression-free survival.
- (3) COLT: Italian investigator-driven, multicenter, nonrandomized, open-label, controlled, prospective, parallel trial (NCT03803436), aimed at assessing the efficacy (in terms of OS) of liver transplantation in liver-only CRC metastases vs. a matched cohort of patients bearing the same tumor characteristics, collected during the same time period and included in a phase III Italian radiochemotherapy on triplet CTx + anti-epidermal growth factor receptor.
In summary, it can be stated that based on data on whole DDLT, there is an actual international consensus that liver transplantation for u-CRLM does represent a viable option in highly selected patients with only liver involvement (ILTS Consensus Conference in Transplant Oncology, Rotterdam, The Netherlands, and 7 February 2019).
Although this procedure may seem promising for a large number of patients we still have to face the problem of organ paucity to satisfy the need of liver transplantation for standard indications. Therefore in some European countries (e.g. Germany) today standard DDLT for u-CRLM is impossible and almost unlikely within the next future. The only chance to get a DDLT for u-CRLM is to join one of the above-mentioned trials or to use marginal/discarded liver grafts.
In this regard the Oslo Group proposed to use segmental grafts from split-deceased donor, which could not be allocated according to standard indication and allocation rules. In this particular context, Line et al. developed the revolutionary RAPID procedure (i.e. resection and partial liver segment 2–3 transplantation with delayed total hepatectomy).
The RAPID does actually represent the most actual and modern fusion of the two most challenging procedures of modern hepatobiliary and liver transplant surgery: that is auxiliary partial orthotopic liver transplantation , and ALPPS (associating liver partition and portal vein ligation for staged hepatectomy [24,25]). It consists mainly of a two-step procedure: in steps 1 a left hepatectomy with ligature of right portal vein has been performed. This is followed immediately by an auxiliary orthotopic transplantation of the left lateral lobe as a split graft from deceased donor (which normally results in an insufficient future remnant liver (FRL) volume for adult patients). After that, an intermediate period of almost 2 weeks follows during which the volumetric and functional regeneration of the FRL occurs according to the physiological regeneration process at the basis of ALPPS [26–30]). Finally, as soon as the transplanted graft has reached sufficient volume and function  the 2nd step of the procedure will be performed, similarly to step 2 of the ALPPS procedure (a completion of the naive total hepatectomy with removal of the residual metastatic right lobe) [22,32].
Up to now only one successful case of RAPID procedure from deceased donor (DD-RAPID) has been officially published by Line et al.. A clinical trial has been recently started by the Oslo group with the aim to evaluate benefit and efficacy of the DD-RAPID-procedure (NCT02215889) (see also Table 1). Up to now five patients with DD-RAPID have been included in this trial .
Even though the DD-RAPID procedure may show promising results, the basic problem of scarcity of organs from deceased donors and mainly the lack of splittable organs still remains. In addition, in countries without split policy and low deceased donor donation rates, using left lateral grafts for u-CRLM would mean taking away the chance of liver transplantation to a child or a small recipient waiting for a liver according to standard allocation rules. Last, but not least, using deceased donor grafts for this procedure is usually associated to logistic problems like the scheduling of the CTx and performing the liver transplantation at the right moment of stable disease during a CTx-free window.
THE AUXILIARY LIVING DONOR LIVER TRANSPLANTATION COMBINED WITH TWO-STAGE HEPATECTOMY FOR UNRESECTABLE COLORECTAL LIVER METASTASES
In consideration of the aforementioned problems we recently proposed the living donor RAPID (LD-RAPID) as feasible and safe (for both donor and recipient) alternative to the original DD-RAPID procedure [34▪].
Considering this procedure still experimental, after approval of ethical committee and accurate multistep evaluation of living donor and recipient the surgical steps of LD-RAPID procedure can be summarized as follow:
Donor operation (procurement of left lateral graft, i.e. segments II and III)
Following precise exploration of the abdominal cavity, the left lateral segments 2 and 3 are procured according to standard technique. The liver remains transected without division of hilar structures until the recipient's left lobe has been resected and the feasibility of the procedure has been completely guaranteed.
After removal, the graft is perfused through the stumps of left portal vein and hepatic artery and stored in perfusion solution at 4 °C until implantation .
- (1) Explorative laparotomy and exclusion of extrahepatic disease (i.e. local recurrence, peritoneal carcinomatosis and lymph node metastases).
- (2) Isolation of both right and left hepatic artery and portal vein.
- (3) Left hepatectomy (segments 1–4) along Cantlie line including the middle hepatic vein (MHV) (Fig. 1). In this context, we would like to stress the importance of performing a true left hepatectomy instead of a left lateral hepatectomy as originally described by Line et al. to assure an adequate wide orifice for venous outflow of the graft consisting of the conjunction of both orifices of MHV and left hepatic vein (LHV).
- (4) After parenchyma transection the left bile duct is divided and its stump closed, leaving the right biliary system intact.
- (5) Graft implantation according to the auxiliary partial orthotopic liver transplantation technique (Fig. 2):
- (a) The donor LHV is anastomosed to the common ostium of the MHV and the LHV of the recipient by using the piggyback technique.
- (b) Transection of the right branch of the recipient's portal vein.
- (c) Both left branches of portal vein of both donor and recipient are anastomosed and the graft ante grade reperfused.
- (d) Thereafter, the arterial anastomosis is performed by means of microsurgical technique with/without vascular interposition.
- (e) Roux-en-Y hepaticojejunostomy to the graft.
- (f) Preparation of the interphase, preventing adhesions between both resection surfaces and postoperative bleeding by applying collagen sponge coated with human coagulation factors fibrinogen and thrombin (i.e. Tachosil, Ethicon, Germany).It should be noted that, according to the original RAPID technique and based on the lessons learned by standard living donor liver transplantation (LDLT), intraoperative hemodynamics measurements of portal venous flow, hepatic artery flow and portal vein pressure should be performed and according to the results a graft inflow modulation should be performed too .
- (6) Interphase: monitoring of volume and function of liver graft (i.e. computed tomography scan once a week until a FRL volume body weight ratio more than 0.8 has been reached, standard qualitative liver function tests and eventually Limax or Tc99m-hepatobiliary iminodiacetic acid-Scintigraphy [37,38]).
Phase 2: Completion of right hepatectomy, according to Step 2 of standard ALPPS procedure (Fig. 3).
Since our detailed report of the first case worldwide of LD-RAPID, an investigator-initiated, bi-institutional (University Hospital Tübingen and Jena, Germany), one-arm trial has been recently started aimed to evaluate the feasibility, safety and efficacy of LD-RAPID for u-CRLM [The LIVER-T (W)O-HEAL study NCT03488953]  (see also Table 1). Primary endpoint of the study is an OS of 36 months. Secondary endpoints are as follows:
- (1) The recurrence-free survival of the patients 36 months after the second stage of hepatectomy.
- (2) The medical and psychological morbidity of both donor and recipient, defined as complications at least IIIb .
Up to now five LD-RAPID procedures for u-CRLM have been reported worldwide (one in Tübingen and four in Jena) [34▪,39]. No donor morbidity and mortality have been reported. The 1st patient from Tübingen experienced extrahepatic tumor recurrence (bone and lungs) already at post operative month (POM) 5 and died at POM 24 secondary to complication of radionuclide therapy of bone metastases. One patient in Jena died due to a lung artery embolism approximately 4 months after the transplantation procedure without any evidence for a tumor recurrence. The remaining three recipients from Jena are still alive and disease free after a mean follow-up period of 7 months.
Nowadays, according to the new concepts of ‘transplant oncology [18,19▪] liver transplantation represents a viable option in highly selected patients with u-CRLM. Refined clinical selection criteria can additionally improve 5 years OS rates to a level that is comparable (if not even better) with other indications for liver transplantation [4▪▪] (Table 2).
It is essential to mention that the selection process of the ideal candidates is a very demanding process and requires an intensive interdisciplinary work and the inclusion rates are less than 10%. In the Norwegian experience almost 600 potential candidates with u-CRLM have been screened and only almost 60 liver transplantation have been performed [4▪▪]. In Germany, we share a similar experience, with almost 30 patients screened for one LD-RAPID in Tübingen and 45 for four in Jena. In addition it should be mentioned that even if the potential recipients fulfil the preoperative inclusion criteria, there is still a chance they may be excluded at explorative laparotomy, as it happened in our experience in which three patients were excluded because of peritoneal carcinosis in one and lymph node metastasis in two.
The main drawback of this procedure is an early recurrence of disease (usually extrahepatic and mainly pulmonary). Notwithstanding, an aggressive treatment of all resectable recurrences is recommended and justified by long-term OS [4▪▪,21].
All the above-mentioned concepts are mainly based DDLT experience and mostly coming from the Oslo group. The major criticisms to the procedure are represented by the fact that it is still an experimental procedure (actually based on <50 published cases) and still noncurative (due to the high recurrence rates). Therefore the use of deceased donor per se, and particularly in times of scarcity/paucity of deceased donor, has been considered ethically unfair by taking away a life-saving opportunity for a patient with nonmalignant disease on the waiting list. In addition to that, the ‘uncertain and unpredictable availability’ of deceased donors makes the situation more complicated in terms of difficult planability/scheduling of CTx and liver transplantation .
The DD-RAPID recently proposed by Line et al. may represent a possible alternative in terms of using left lateral split grafts from deceased donor. But, additionally to the points of criticisms reported above, in this case particularly the pediatric recipient population may be disadvantaged.
Therefore the LDLT may represent the only way out of this dilemma. In this regard, the Toronto group recently started a clinical trial with LDLT for i-CRLM limited to the liver and stable on standard CTx, aimed to evaluate combination CTx + LDLT in terms of OS, DFS and quality of life for 5 years (NCT02864485) (see also Table 1). At the moment two patients have been included in the study/cases performed.
One of the major point of discussion is if, in the context of ‘double equipoise for LDLT’  the risks taken by the living donor in a standard right/left LDLT [43,44] can be ethically justified in such a novel still experimental procedure with good OS rates but high recurrence rates .
In this regard Miller described a similar critical scenario of a hypothetical case of LDLT for recipients with HCC beyond the standard inclusion criteria . Although the risk of HCC recurrence was 100% and the procedure had a clear palliative intent, the authors demonstrated that weighing the risk to the donor against the benefit to the recipient (including psychosocial benefits for the recipient and the family members) moved the case from ethically questionable to ethically acceptable provided that both donor and recipient are adequately informed about the long term of results in terms of OS and DFS.
To further minimize the risks taken by the donor, the LD-RAPID concept may represent a valid alternative in terms of safety and efficacy when applied in selected patients and performed in very experienced hepato-biliary-pancreatic (performing ALPPS procedures) and liver transplantation centers (with both experience in DDLT and LDLT and mainly in pediatric liver transplantation). From pure technical /surgical point of view, the key of success of this procedure is based on the possibility to use very small graft in absence of portal hyperfow and portal hypertension. Therefore, the LD-RAPID procedure could be additionally applied in similar settings for standard indications like primary sclerosing cholangitis (PSC) patients (without cirrhosis but at high risk of ph-cholangiocarcinoma) and liver metastatized neuro endocrine tumor (L-NET).
In summary, liver transplantation for u-CRLM is a viable option in selected patients fulfilling the Oslo criteria, with good tumor biology and with good performance status [4▪▪]. Among different liver transplantation procedures, standard or segmental DDLT are limited by the actual scarcity of deceased donor grafts and potential disadvantage for patients listed for standard indications and therefore feasible only within clinical trials. A standard LDLT does not to justify the imbalance of the donor's risk and recipient's benefits. Therefore, the LD-RAPID concept may be the only solution that can minimize the donor risk but at cost of a very challenging high end transplantological procedure and its indication can be extended to patients in need of liver transplantation but without portal hypertension like L-NET and PSC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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