The term NCRNNELM corresponds to a heterogeneous group of patients with liver metastases from various origins. This denomination is mainly used by surgeons to define cases where, in contrast with CRLM , the surgical indication remains controversial. Currently, in the absence of controlled or case-matched studies, the real benefit of surgery in patients with NCRNNELM remains difficult to assess and it is challenging to determine whether long-term postoperative survival in some of these patients results from the surgical treatment itself or from the selection of a subgroup with favorable tumor biology. However, as in patients with CRLM, long-term DFS obtained after surgery for NCRNNELM indicates that some of these patients may have an intermediate tumor progression profile, characterized by a limited metastatic capacity, as defined by oligometastatic status [15–17]. Therefore, as in CRLM, the identification of biomarkers of such oligometastatic behavior would represent highly relevant progress toward a better understanding of the biological mechanisms involved in different modes of tumor progression and for personalized therapeutic decision making. In this view, specific markers of tumor biology that can be used to predict the benefit of surgery in individual cases are critically needed, even more than population-based prognostic models. To address this question, the characterization of the long-term disease-free survivors after surgery for NCRNNELM (oligometastatic cases who benefited from surgery) as compared with the patients who developed rapid postoperative recurrences (the diffuse metastatic cases who did not benefit from surgery) may represent a first step toward identifying accurate, clinically-available selection criteria. In particular, in such a heterogeneous group of patients, the respective contributions of surgery and systemic treatment for improving the outcome could be difficult to discriminate. In that sense, it might be assumed that both the patients with prolonged DFS and those with rapid recurrence after surgery represent appropriate target-groups to be identified preoperatively, corresponding to the good candidates for surgery and to those in whom surgery should be contraindicated, respectively.
In this series, we observed postoperative outcomes that were similar overall to those recently reported in the literature [1,2,7,18,19]. At 3 and 5 years, OS rates were 75% and 55% and DFS rates were 40% and 30%, respectively, and surgery was associated with limited operative morbidity and no mortality, confirming that surgery may represent an effective and safe therapeutic option in selected patients with NCRNNELM  . Furthermore, the fact that prolonged DFS was obtained in approximately a third of the patients may serve as a proof-of-concept for the existence of oligometastatic progression in some of these cases. In contrast with other studies, we could only identify a few prognostic factors, related to the primary tumor stage and the extent of liver involvement [2,6,18,19]. In multivariate analysis, only the nodal status of the primary tumor and the size of liver metastases were associated with postoperative OS but not with the risk of recurrence. In addition, a delay of longer than 2 years between the primary and the diagnosis of liver metastases appeared to be predictive for improved DFS, but not for OS. Furthermore, the prognostic value of the model proposed by the AFC was not verified . Several factors could be responsible for these discrepancies [2,3,7]. Primarily, the present results were obtained in highly-selected patients, as indicated by the fact that almost half of them had single liver metastases and that the patients who progressed on systemic therapy were excluded. This criterion is likely to have excluded the patients with the poorest tumor biology. Our cohort included only patients with low- or moderate-risk according to AFC score. Nevertheless, in the original series published by Adam, only 3% of the population had a high-risk AFC score, while ranging from 3% to 6% in other series [3,7]. In addition to the AFC score, we also evaluated the prognostic value of a simple mCRS, derived from the traditional CRS established for patients with CRLM. Interestingly, this 4-point mCRS appears, in this series, to be of potentially higher prognostic value as compared with the AFC score. In univariate analysis, mCRS was predictive for OS but not for DFS. Even though mCRS was not prognostic in multivariate analysis and this very preliminary observation has to yet be confirmed in larger groups, it may suggest that similar pathways, eventually reflected by similar surrogates, could be responsible for tumor aggressiveness in CRLM and NCRNNELM. Along this line, even if the numbers in each category are limited, we did not observe a prognostic impact of the origin of the primary tumor, such as breast versus non-breast or digestive versus non-digestive. Also, this observation may potentially encourage others to test candidate biomarkers that have been recently demonstrated in CRLM in patients with NCRNNELM [20–26].
Based on our initial definition of the ER and LTS groups, with a postoperative DFS cut-off of ≤1 year and >5-years, respectively, we observed that approximately a quarter of the patients underwent oncologically futile surgery, whereas surgery was associated with a strong oncological benefit in less than 20% of the cases, underlining the lack of accuracy of current selection processes. Among baseline characteristics of primary tumors and liver metastases, none appeared to be reliable for distinguishing these two groups. Only positive nodal status of the primary tumor and the size of liver metastases when they were diagnosed were different between these groups. However, due to large overlaps, these factors do not appear as potentially usable exclusion criteria for surgery. Furthermore, neither the AFC score, nor the mCRS was found to discriminate between LTS and ER patients. When we compared the ER group with the patients with a DFS >3 years, in whom a plausible surgical benefit could have been obtained, the rate of positive nodal status of the primary tumor and the number of liver metastases at preoperative staging were significantly increased in the ER group. Interestingly, although the AFC score was not discriminating between these groups, the mCRS was significantly increased in ER patients as compared with the patients with a DFS >3 years.
This work had several limitations. Mainly, this is a limited retrospective series, including highly selected patients. In addition, similarly to most of the studies in patients with NCRNNELM [2,3,7,27,28], the present series included a majority of patients with breast cancer liver metastases. However, no significant difference was observed when we compared postoperative outcomes in patients with breast and non-breast NCRNNELM.
In conclusion, although our overall results confirm that surgery could be effective in some patients with NCRNNELM, they also highlight the lack of accurate selection criteria for personalized therapeutic decision making. In this series, the previously described AFC score was unable to preoperatively identify the individual patients who would benefit from surgery. At the same time, a simple clinical score adapted from a prognostic model in CRLM showed some promising prognostic value, suggesting that similar biomarkers could be relevant in liver metastases, irrespective of the primary tumor origin. Taken together, these results underline the need for translational research to identify new biomarkers of individual tumor behavior in patients with NCRNNELM.