Liver-First Approach for Synchronous Colorectal Metastases: Analysis of 7360 Patients from the LiverMetSurvey Registry

All patients with synchronous CRLM included in the LiverMetSurvey registry (www. livermetsurvey-arcad.org) undergoing liver surgery between January 2000 and December 2017 were reviewed. The characteristics of the LiverMetSurvey registry have been previously reported.23‐25 Patients were divided into three groups according to the adopted surgical strategy: (1) colorectal resection followed by liver resection (classical approach, primary-first group); (2) liver resection followed by colorectal resection (reverse strategy, liver-first group); (3) simultaneous colorectal and hepatic resection (simultaneous group). Exclusion criteria were unresected patients, missing or incomplete data regarding surgical procedures, delay between primary tumor and liver resection of > 1 year in the primary-first group, and two-stage hepatectomy.

Overall, 12,744 patients with synchronous CRLM who were included in the LiverMetSurvey registry were considered. A total of 5384 patients were excluded (908 unresected patients, 2835 patients with missing or incomplete data regarding surgical procedures, 909 patients with a delay between primary tumor and liver resection > 1 year, and 732 two-stage hepatectomies), resulting in 7360 patients being analyzed: 4415 patients (60.0%) in the primary-first group, 552 (7.5%) patients in the liver-first group, and 2393 (32.5%) patients in the simultaneous group (electronic supplementary Fig. 1).

The liver-first approach increased over time, from 2.4% before 2007 to 5.9% in the period 2007–2011, and to 12.6% later on (p < 0.001), while the primary-first approach decreased (68.3%, 58.2%, and 57.3%, respectively; p < 0.001) and the simultaneous group remained stable  (≈ 30%). During the study period, the number of resected metastases did not have a significant increase (three or more nodules: 23.9% before 2007, 24.8% in the period 2007–2011, and 26.1% after 2011), while metastasis size decreased (>50 mm: 27.8%, 23.1, and 22.2%, respectively; p = 0.001). The proportion of patients undergoing preoperative chemotherapy progressively increased (42.1%, 50.9%, and 54.1%, respectively; p < 0.001).

The three groups of patients had major differences. The liver-first group included more patients with rectal tumors (58.0% vs. 31.2% in the other groups; p < 0.001) and fewer patients with right/transverse colon cancers (12.4% vs. 26.4%; p < 0.001). Among patients with rectal tumors, patients undergoing a reverse strategy more often had pelvic radiotherapy (56.6% vs. 33.3%; p < 0.001). The liver-first group had the highest tumor burden in terms of CRLM number (more than three in 34.8% vs. 24.0%; p < 0.001), size (>50 mm in 35.6% vs. 22.8%; p < 0.001), and bilobar distribution (51.5% vs. 38.8%, p < 0.001). In comparison with the primary-first strategy, the reverse strategy was not only associated with more preoperative chemotherapy (75.7% vs. 57.0%; p < 0.001) but also with a shorter treatment (more than six cycles 57.2% vs. 62.78%; p = 0.044) and a shorter interval between the two surgical procedures (colorectal and liver resection, mean 92 vs. 162 days; p < 0.001). Table 1 summarizes the patient characteristics.

In the whole series, the liver-first group had 90-day mortality, overall morbidity, and hepatic morbidity rates similar to the other groups. Staged resections (liver-first and primary-first groups) had a lower infectious complication rate than the simultaneous group (11.4% vs. 18.6%; p < 0.001). The same results were observed considering patients with solitary or multiple unilobar metastases. Considering patients with multiple bilobar metastases, the liver-first group had 90-day mortality, overall morbidity, and infectious morbidity rates similar to the primary-first group (2.3% vs. 2.0%, 31.1% vs. 30.4%, and 12.0% vs. 11.8%, respectively), but lower than the simultaneous group (vs. 5.1%, p = 0.052; vs. 39.9%, p = 0.016; vs. 20.1%, p = 0.006, respectively). Hepatic complication rates were similar among the three groups. Considering patients who require a major hepatectomy, independently of the tumor burden, mortality was lower in the liver-first group (4.8%) and primary-first group (2.9%) than in the simultaneous group (8.1%; p < 0.001). Short-term outcomes are detailed in electronic supplementary Table 1.

The liver-first approach was initially proposed to include radiotherapy in locally advanced rectal tumors with hepatic metastases11 but has generated much interest and obtained good diffusion among patients with synchronous CRLM because of its prioritization to liver disease. Some recent population-based analyses reported its application in up to 20–40% of patients.17,18,26 Nevertheless, the evaluation of its results still relies on a few studies collecting a limited number of cases.19 The snapshot from the LiverMetSurvey registry confirmed that the reverse strategy has been more and more applied since its proposal, passing from 2% before 2007 to 13% in the most recent years. This gave us the possibility of analyzing a large series including more than 550 patients. The liver-first approach was preferentially applied to patients with rectal tumors and high liver tumor burden (one-quarter of cases in the most recent period). We confirmed the expected benefits from reverse strategy: shorter chemotherapy before liver resection with an excellent response rate, and higher inclusion of pelvic radiotherapy. Nevertheless, the role of the liver-first approach in synchronous CRLM is still to be elucidated and its oncologic superiority over the other strategies is still to be proven.

Several studies focused on the short-term results of the three approaches, most comparing simultaneous and staged procedures with controversial results.27‐32 The comparison between the primary-first and liver-first approaches did not generate much interest because, as expected, the two had similar outcomes through all studies.12,13,15‐17,21 In the present series, the three approaches had equivalent results for low-complexity resections, while the simultaneous group had worse outcomes than staged procedures for major hepatectomies and resections of multiple bilobar metastases. Our results are coherent with those recently published by Shubert et al. based on a large US database (n = 43,408).30 They demonstrated that the operative risks of simultaneous resections vary incrementally with the complexity of both hepatectomy and colorectal resection. Even if our picture is incomplete because we lack data about the morbidity of primary tumor resection in staged procedures, we believe that the increased mortality risk of the simultaneous approach in complex procedures is a major point.

Data regarding the long-term outcome are scarce. In 2012, the Geneva group analyzed the LiverMetSurvey registry and demonstrated non-inferiority, but not superiority, of the liver-first approach versus the primary-first approach.15 Other papers confirmed these data,12,13,15‐22,33,34 and, to date, no studies have reported a survival advantage of the liver-first approach over the other approaches. Coherently, the EGOSLIM (Expert Group on OncoSurgery management of LIver Metastases) group,6 stated that simultaneous resection, when feasible without increasing operative risk, is the preferred option, while one of the two-staged procedures (primary-first or liver-first) should be pursued for the remaining patients. A recent network meta-analysis confirmed that no strategy to resect synchronous CRLM has superiority over the others in terms of survival, even if the liver-first approach was ranked as the best treatment for its relative efficacy based on 5-year OS outcomes.19 This evidence is too weak to propose the reverse strategy as standard.

All studies that compared strategies for synchronous CRLM suffered from major heterogeneity among groups. Different approaches are scheduled for different patients. In the literature,17‐19 as in the present series, patients undergoing a reverse approach have more advanced liver disease and more rectal tumors. To face this scenario, we decided to not only adopt a propensity score match to make populations comparable but to also stratify patients according to their hepatic tumor burden. We hypothesized that the surgical strategy may have a different impact on prognosis according to the severity of the disease.

Our hypothesis was confirmed. The liver-first approach had results similar to the other approaches in patients with unilobar synchronous CRLM but was associated with a clear survival advantage over both the primary-first and simultaneous approaches in patients with multiple bilobar metastases. Its superiority was confirmed on multivariable analysis on the whole series and after strict propensity score matching. Three-year survival rates after reverse strategy exceeded 65% and ranged between 50 and 60% in the other groups. These results are even more relevant if we consider that the primary-first group included only patients who completed the two resections, but not those who dropped out. Intention-to-treat analysis is expected to show an even wider difference in favor of the liver-first approach. Factors contributing to these results are still to be investigated, but some hypotheses can be advanced. First, reverse strategy prioritizes the treatment of the tumor site that is judged the most prognostically relevant, i.e. the liver. Second, the liver-first approach requires early management of patients by an expert multidisciplinary liver team. Some studies demonstrated that such management is associated with longer survival.35‐37 Third, the reverse strategy maximizes the effectiveness of neoadjuvant chemotherapy because liver surgery is performed with optimal timing, without any treatment interruption, and at the peak of the response. Any delay in surgery after chemotherapy may lead to early tumor reactivation and poor prognosis.38,39 Fourth, in the primary-first approach, colorectal resection is associated with an immunological alteration that could favor liver metastases proliferation.40 Finally, in comparison with simultaneous resections, the liver-first approach minimized postoperative morbidity that may negatively impact prognosis.41

The main strength of this study was its clinical relevance. We proposed a tumor burden-driven strategy for patients with synchronous CRLM as candidates for a single-stage hepatectomy (Fig. 4). According to our results, the liver-first approach should be the preferred option for patients with multiple bilobar metastases, while simultaneous resection should be the preferred option for patients with solitary metastasis requiring a minor hepatectomy, even if the definition of ‘minor hepatectomies’ is debated.42 In the remaining patients, the staged procedures were equivalent, while simultaneous resections should be cautiously considered because they have increased mortality risk whenever a major hepatectomy is needed. We did not analyze patients undergoing a two-stage hepatectomy, but, according to the favorable results that we observed in patients with simultaneous colorectal resection and unilobar limited resections, we can assume that the first stage of a two-stage hepatectomy can be safely combined with colorectal resection. Some limitations could be argued. This was a retrospective non-intention-to-treat analysis and the three groups had major heterogeneity at baseline. However, we collected a large number of patients from several centers worldwide and performed an accurate propensity score matching to make groups comparable, even if it led to a major reduction in sample size. Some prognostic data, such as CEA or RAS mutational status, were not considered and should be the subject of further analyses.

The surgical strategy in patients with colorectal cancer and synchronous liver metastases should be decided according to the hepatic tumor burden. In patients with multiple bilobar CRLM, we strongly suggest the liver-first approach as the standard because it is associated with excellent short-term results and longer survival than the alternative approaches.

Santiago López-Ben has received grants from Olympus, Baxter and Integra, and Rene Adam has received honoraria for participation at meetings or congresses organized by Sanofi or Merck Serono. Felice Giuliante, Luca Viganò, Agostino M. De Rose, Darius F. Mirza, Réal Lapointe, Gernot Kaiser, Eduardo Barroso, Alessandro Ferrero, Helena Isoniemi, Irinel Popescu, Jean-Francois Ouellet, Catherine Hubert, Jean-Marc Regimbeau, Jen-Kou Lin, Oleg G. Skipenko, and Francesco Ardito have no conflicts of interest to declare.