The initial study protocol was quite strict with regard to extent of disease and response to chemotherapy; but after 11 months without included patients, a protocol amendment with wider inclusion criteria was approved. These consisted broadly of minimum 6 weeks of chemotherapy, good performance status (ECOG 0–1), and absence of extra-hepatic disease. Thus, the principal selection criterion was unresectability of metastases assessed at the multidisciplinary conference in our institution. Accordingly, the study population ended up being very heterogeneous with regard to T and N stage, CEA levels, previous exposure, and response to oncological treatment. At the time of liver transplantation, 16 patients had progressed on first or later lines of chemotherapy, six patients had progressed on all standard lines of chemotherapy, and 38% of the patients had received second-line chemotherapy. The hepatic tumor load was extensive; median number of metastatic lesions was eight (range 4–40 metastases), and median diameter of the largest lesion was 4.5 cm (range 2.8–13.0 cm) [26].

In liver resection surgery for CLM, there is a strong relationship between postoperative survival and clinical scoring systems [27]. Since hepatic resection for CLM is routinely performed in resectable patients, these clinical scoring systems are not used in the decision-making on whether to perform hepatic resection or not in single cases.

The selection of patients to liver transplantation for CLM is, however, highly important due to the scarcity of donor livers. Outcome for a new indication should in general be comparable or better than outcome for established transplant indications. The heterogeneity of the SECA population made it likely that the prognostic profiles of the patients were highly diverse.

The two patients demonstrating the shortest survival in the material had tumor breaching the liver capsule, and cancer infiltration of diaphragm were found after vital structures were divided and transplantation unavoidable [26]. In hindsight, these cases would not have been transplanted with our current knowledge. By analyzing preoperative status and outcome following liver transplantation, four factors were found to be significantly associated with decreased survival:

These are established clinical prognostic factors known from studies on liver resection, and are included in clinical scoring systems. Five of the six deceased patients had all of these factors present (Fig. 20.2). Very cautious interpretation of these findings is stressed because of the small study population, but the results indicate a possible potential for selecting patients based on established clinical parameters, and by this further improving outcome [26]. Since the first report in 2013, the SECA data has matured with more than 2 years. At median follow-up of 65 months (range 19–85 months) post liver transplantation, the four prognostic factors were still significantly associated with survival, and if the five patients with all four factors present are excluded, the survival at 6 and 7 years was 60% [26, 28].

All patients in the SECA study who were observed for more than 11 months experienced recurrence of disease. The median time to recurrence was 6 months (range 2–24 months); 17 patients experienced lung metastases, and seven patients recurred in the liver graft. At the end of follow-up, seven patients were alive with no evidence of disease, eight patients were alive with recurrence, and six patients were deceased.

The initial recurrence pattern was: 68% lung metastases, 11% liver and lung metastases, 11% lymph node metastases, 5% liver and ovarian metastasis, and 5% experienced local recurrence of rectal tumor as first recurrence [29]. No patient had metastases to the new liver only as first site, and liver metastases developed exclusively as part of disseminated disease. At end of follow-up, six of the seven patients that developed liver metastases were dead. Median time from diagnosis of liver metastases to death was 14 months (range 4–21 months). In contrast, all the 12 patients with recurrences that did not include the liver were alive at end of follow-up, and patients with pulmonary first-site recurrence had a 5-year overall survival of 72% [29]. One might speculate to what extent the pulmonary metastases are true recurrences, or represents selection failures in the sense that they were present at the time of transplant. In order to address this question, reassessment of CT scans by one experienced radiologist was performed. Tracing back from evident metastases in all the 17 patients with pulmonary manifestations, it became evident that seven of them had pulmonary metastases appearing as small nodules at time of liver transplantation. Four of them had pulmonary deposits on earlier CT scans as well (2, 2, 3, and 12 months prior to liver transplantation respectively). The survival analysis showed that the presence of these metastases at the time of liver transplantation did not have negative impact on survival. An interesting clinical observation regarding lung metastases were that they proved to be very slow-growing. Thus, they were observed over extended periods in most patients, and treated surgically, or by radiofrequency ablation whenever possible. For lung surgery, a nodule size of about 15 mm was chosen to ensure that the metastases should be readily identifiable at surgery.

The SECA study was an uncontrolled pilot study; thus the results, although very favorable for nonresectable liver metastases, could not be easily compared to standard treatment. In order to evaluate a survival comparison between transplantation and a modern chemotherapy study, data from a similar cohort of patients included in the NORDIC-VII study were obtained [30]. The NORDIC-VII study was a three-arm, multicenter Phase III trial, on Nordic FLOX and two different regimens containing cetuximab and FLOX, as first-line treatment of metastatic CRC [31]. Patients that had nonresectable CLM, no extrahepatic disease, no BRAF mutation, and similar age were extracted from the NORDIC-VII database. The study population characteristics ended up comparable to the SECA population; however, 5-year overall survival was 9% after start of first-line chemotherapy (n = 47), significantly lower than the 5-year overall survival in the SECA study [30] (Fig. 20.3).

Several patients in the SECA study had unfortunate tumor characteristics (Fig. 20.4). Six of the patients had progressive disease on all standard lines of chemotherapy; three after three lines of chemotherapy, and three with mutation of Kras after second line of chemotherapy. For these patients, the median overall survival was 41 months and 5-year overall survival was 41%. In the Nordic-VII study, the median overall survival for a similar cohort was significantly shorter, 5.6 months, and all patients were dead before 2 years [32].

In comparison, the only drug that has demonstrated prolonged survival in treatment of metastatic CRC after progression on all lines of chemotherapy is regorafenib. In a multicenter trial with this drug, the median survival was enhanced from 5.0 (placebo) to 6.4 months [33]. In addition, the comparison with the matched group of CLM only in the NORDIC-VIII study strengthens the impression that liver transplantation for nonresectable CLM is superior to chemotherapy alone.

Thus, the results clearly suggest that liver transplantation for CLM can be indicated in properly selected patients. However, this is the only study currently reported on the subject, the sample size was small and the frequency of recurrences almost universal, and the data need to mature further to evaluate the true long-term results [34]. Thus, the role of liver transplantation for CLM is not sufficiently clarified, and should still be subject to scientific prospective studies.