Blood Inflammation Ratios Fail to Predict Survival After Liver Resection for Colorectal Metastases

Routine blood counts that oncologists have long hoped could flag which patients fare best after liver surgery for colorectal cancer have largely come up short, according to a retrospective cohort study of 380 patients treated at a single Brazilian center between 2009 and 2020. The three most widely studied inflammation-derived indices—the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the monocyte-to-lymphocyte ratio (MLR)—showed no statistically significant association with overall survival or disease-free survival among patients undergoing curative-intent resection of colorectal liver metastases. The finding, published in Cancer Reports, cuts against a substantial body of literature that has linked these cheap, readily available markers to cancer outcomes across multiple tumor types.

The study, conducted at the Hospital das Clínicas of the University of São Paulo School of Medicine, drew on a prospectively maintained institutional database. Researchers identified 492 consecutive adults with colorectal liver metastases who underwent liver resection with curative intent over the eleven-year period. After applying predefined exclusions—25 patients undergoing two-stage hepatectomy, 70 with concomitant extrahepatic metastatic disease, 10 who had portal vein embolization, and 7 with unavailable medical records—the final cohort comprised 380 patients. Most were men (55.0 percent), the median age at surgery was 62 years, and 72.8 percent had received preoperative chemotherapy, typically an oxaliplatin-based regimen. Minor hepatectomies accounted for 74.7 percent of operations, with major resections of three or more liver segments making up the remainder.

Colorectal liver metastases are the most frequent site of distant spread in colorectal cancer, developing in roughly 20 to 55 percent of patients over the course of the disease, and they are a key determinant of long-term outcomes. Because systemic inflammation has been implicated in tumor growth, metastatic spread, and response to anticancer treatment, blood-cell-derived indices have attracted considerable interest: they can be obtained routinely and at relatively low cost. NLR, PLR, and MLR capture distinct relationships between circulating inflammatory and immune cell populations, and associations with clinical outcomes have been reported across several malignancies—although their prognostic relevance has not been consistent across patient populations or clinical contexts. In patients with colorectal liver metastases undergoing resection, previous studies have reported conflicting results, with differences in patient selection, timing of metastasis, chemotherapy exposure, extent of resection, and cutoff definitions all proposed as contributing factors.

For mortality, the selected cutoffs were 1.40 for NLR, 106.33 for PLR, and 0.28 for MLR; for recurrence, they were 1.56, 102.26, and 0.22, respectively. Crucially, the discriminatory ability of every threshold was poor. The areas under the ROC curve ranged from 0.499 to 0.521 for mortality and from 0.489 to 0.531 for recurrence—values barely distinguishable from the 0.5 expected by chance alone. The authors explicitly caution that these thresholds should not be considered clinically validated cutoffs, and they note that dichotomization may itself have blunted the ability to detect meaningful associations.

The survival analysis bore out the skepticism suggested by those weak ROC statistics. Median overall survival in the cohort was 69.5 months, with estimated survival rates of 88.6 percent at one year, 67.6 percent at three years, and 53.0 percent at five years. Disease-free survival was estimated at 59.4 percent at one year, 39.2 percent at three years, and 36.7 percent at five years. Kaplan–Meier curves compared with the log-rank test showed no statistically significant differences in either outcome according to preoperative NLR, PLR, or MLR categories. Median follow-up, estimated by the reverse Kaplan–Meier method, was 74.8 months, and only one patient was lost to follow-up.

Two exploratory subgroup associations did emerge, however, and both involve the platelet-to-lymphocyte ratio. Among the 96 patients undergoing major hepatectomy, a preoperative PLR at or below 106.33 was associated with significantly higher rates of severe postoperative morbidity—Clavien–Dindo Grade III–IV complications—compared with patients above that threshold (p = 0.021). In that subgroup, 80.0 percent of patients with severe complications had a low PLR, versus 24.7 percent of those with milder or no complications. No significant association was observed between any of the three indices and postoperative mortality in this subgroup. The authors offer one possible explanation: a lower PLR may partly reflect lower circulating platelet counts, and thrombocytopenia has previously been associated with increased morbidity after hepatectomy. They stress, though, that the finding rests on a ROC-derived dichotomous cutoff with limited discriminatory performance and emerged within a restricted patient population, so it requires independent validation.

The second exploratory signal concerned pathological response to preoperative chemotherapy. Changes in NLR, PLR, and MLR were not associated with overall or disease-free survival, and prechemotherapy values of the indices were not significantly linked to complete pathological response. But the magnitude of change in PLR was: patients whose PLR fell by 65.74 points or more (a ΔPLR ≤ −65.74, calculated as the preoperative value minus the prechemotherapy value) achieved a complete pathological response—no viable tumor cells in any resected metastatic lesion, only fibrosis or necrosis—in 20.8 percent of cases, compared with 6.8 percent among patients with smaller reductions (p = 0.002). The authors emphasize that this observation is exploratory, cannot be explained mechanistically from the present data, and needs validation in independent cohorts.

Why might these inflammation ratios behave so inconsistently in this population? The authors point to the clinical heterogeneity of colorectal liver metastases: tumor burden, timing of metastatic presentation, extent of liver resection, response to systemic therapy, chemotherapy regimen, treatment duration, and the interval between chemotherapy and surgery may all influence both prognosis and circulating inflammatory parameters. A single peripheral blood measurement, they argue, may be insufficient to capture the complex interplay between systemic inflammation, tumor biology, and treatment response. Their own exploratory analyses reinforced the point that these indices vary with patient characteristics: NLR and MLR were significantly higher in men than in women, PLR showed a weak inverse correlation with age and was lower among patients aged 62 or older, and none of the indices differed significantly by metastatic timing (synchronous, early metachronous, or late metachronous).

The results sit within a broader, contradictory literature. Several studies have associated elevated NLR with worse survival after liver resection for colorectal liver metastases, and a meta-analysis of 18 studies including 3184 patients reported associations with both overall and disease-free survival. Yet other work has found an independent prognostic association only for postoperative—not preoperative—NLR in patients with solitary metastases, and one study even reported an association between higher preoperative NLR and improved survival. Evidence on PLR and MLR is similarly mixed: a systematic review and meta-analysis of 27 studies involving 13,330 colorectal cancer patients reported that higher PLR was associated with poorer overall survival (hazard ratio 1.40, 95 percent CI 1.21–1.62) and shorter disease-free and recurrence-free survival, whereas in the present cohort neither PLR nor MLR was associated with survival. The authors also cite an analysis of five phase III trials in which baseline NLR was associated with survival but showed limited discriminatory performance, with areas under the curve of 0.49 to 0.57 for overall survival—echoing the weak discrimination observed here.

The study’s limitations are considerable and shape how the findings should be read. The retrospective, single-center design introduces potential selection and confounding biases and may limit generalizability. The cohort was heterogeneous in disease characteristics, extent of resection, and chemotherapy exposure, and residual confounding cannot be excluded. The number of subgroup and exploratory comparisons increases the possibility of chance findings, particularly for the associations identified within restricted populations. Other inflammation-based scores, such as the modified Glasgow Prognostic Score, could not be calculated because preoperative C-reactive protein and albumin data were incomplete. The authors conclude that preoperative NLR, PLR, and MLR do not support use as standalone biomarkers for clinical decision-making in this setting, and they call for prospective, multicenter studies to determine whether longitudinal inflammatory indices add clinically relevant information when integrated with established clinicopathological and treatment-related factors. For now, the message for clinicians is one of restraint: a routine differential blood count, however convenient, does not yet reliably predict who will live longer after liver resection for colorectal metastases.

Subject of Research: Associations of preoperative blood inflammatory indices with survival, postoperative morbidity, and pathological response after liver resection for colorectal liver metastases.

Article Title: Inflammatory Markers and Outcomes After Liver Resection for Colorectal Liver Metastases

Article References: Cedro, R. M., Fonseca, G. M., Novaes, F. T., Meira Júnior, J. D., Jeismann, V. B., Makdissi, F. F., Kruger, J. A. P., Coelho, F. F., & Herman, P. (2026). Inflammatory Markers and Outcomes After Liver Resection for Colorectal Liver Metastases. Cancer Reports, 9(11), Article e70725. https://doi.org/10.1002/cnr2.70725

Image Credits: AI Generated

DOI: 10.1002/cnr2.70725

Keywords: colorectal liver metastases, liver resection, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, inflammatory biomarkers, overall survival, disease-free survival, postoperative morbidity, pathological response, preoperative chemotherapy, retrospective cohort study