We examined the correlation between NLR and cancer-related prognosis after colectomy for elderly stage II/III CC patients using propensity score matching. Before matching, ASA-PS was worse and the presence of comorbidities was higher in the NLR-H group than the NLR-L group. After matching, the background was similar between the groups. Five-year RFS and CSS were significantly lower in the NLR-H group.
Systemic inflammation and malnutrition are important patient-related factors that affect cancer prognosis [16, 17]. Neutrophil count is usually elevated in systemic inflammation, and lymphocyte count is often low when immunity is depressed [18]. Low lymphocyte levels reportedly correlate with poor prognosis; in addition, neutrophilia suppresses lymphocyte-mediated cytolysis and is also associated with poor prognosis [19, 20]. NLR utilizes two factors (neutrophil/lymphocyte count) and high NLR score is reported to correlate with poor prognosis in patients with colorectal cancer [21–23].
In general, the various comorbidities and the performance status of elderly patients are considered to be heterogeneous [12]. In addition, elderly patients have a greater tendency than younger patients to die from non-cancer causes [14, 15]. A correlation has also been reported between NLR and non-cancer death from such as cardiovascular disease and pulmonary disease [18, 24].
Few reports have examined the correlation between NLR and prognosis in elderly patients with colorectal cancer [25]. Cruz-Ramos and colleagues assessed the impact of NLR on prognosis in patients aged over 65 years with colorectal cancer, and found that NLR-H was correlated with worse outcome in terms of RFS (10 months vs. 16 months, p = 0.002) and OS (20 months vs. 26 months, p = 0.002), which was in agreement with previous results [25]. However, that study examined only patients with metastatic CRC, who vary in their general condition because of the influence of systemic chemotherapy and the degree of disease progression. Furthermore, their study examined RFS and OS, but not CSS. In the present study, we examined elderly CC patients who underwent curative resection and were diagnosed with stage II/III disease pathologically. In addition, we used propensity score matching analysis to minimize background selection bias. Our results showed poor RFS and CSS in the NLR-H group after matching. This finding suggests that NLR is a potential prognostic factor even in elderly patients with CC.
A previous study of colorectal cancer patients identified an NLR cut-off value ranging from 2.0 to 5.0 using ROC curve analysis [26]. The heterogeneity of the cut-off value might be due to tumor stage, tumor location (colon or rectum), and patient background. An optimal cut-off value has not yet been established. In the present study, we used a cut-off value of 4.5, which is higher than those used in previous reports [26]. One possible explanation for the discrepancy is the gradual change in blood cells with aging [27]. The number and percentage of lymphocytes decrease along with the reduction in lymphoid tissue that occurs with age [27]. Furthermore, the elderly have high rates of comorbidities that increase production of inflammatory cytokines, leading to neutrophilia. Large-scale studies that examine age-stratified cut-off values for NLR are necessary.
A previous study that reported NLR as a predictor of the recurrence pattern of colorectal cancer [28]. Verter and colleagues examined the correlation between NLR and the survival/recurrence pattern in patients with R0 resection after colorectal cancer liver metastasis [28]. Median OS (3.8 years vs. 5.2 years, p = 0.01) and RFS (0.8 years vs. 1.2 years, p = 0.049) were significantly shorter in the NLR-H group compared with the NLR-L group. In terms of recurrence pattern, recurrence with an extrahepatic pattern (but not intrahepatic pattern) was higher in the NLR-H group (p = 0.03). They hypothesized that high NLR was a surrogate marker for aggressive systemic disease, which in turn is correlated with high risk of extrahepatic recurrence. In the present study, there was no significant difference in recurrence pattern between the NLR-H and NLR-L groups (p = 0.723). These conflicting results might be due to the small number of patients with recurrence. However, recurrence was significantly higher in the NLR-H group, and NLR-H was clearly correlated with aggressive tumor progression.
Several guidelines recommend adjuvant chemotherapy after curative resection to improve prognosis in pathological stage III patients, even in elderly patients [29–31]. In our study, no significant difference was found in RFS, OS, or CSS in terms of the presence or absence of adjuvant chemotherapy (Supple Fig. 1a–c). Indeed, due to the age of the patients, there were few pathological stage III patients in the present study and only a small number of stage III patients received adjuvant chemotherapy, which would have influenced the results. However, adjuvant chemotherapy tended to improve CSS in the NLR-H group (Supple Fig. 1d–f). NLR could be a surrogate marker for selecting candidates for adjuvant chemotherapy among elderly patients with pathological stage III CC.
There were several limitations in this study. First, the study was a retrospective, single center study, and we enrolled only a small number of patients. Second, the choice of whether or not to perform adjuvant chemotherapy and selection of the chemo-regimen was at the discretion of the surgeon. Third, there was no significant correlation between IBS using C-reactive protein (CRP) and/or albumin including prognostic nutritional index (PNI), CRP to Albumin ratio (CAR), modified Glasgow prognostic index (mGPS) and cancer prognosis (Supple Fig. 2a–i). Close correlations of CRP and albumin to production of inflammatory cytokines and malnutrition have been reported [32]. It has also been shown that CRP/albumin-based IBSs such as PNI, CAR, and mGPS were closely correlated with prognosis in colorectal cancer patients [8, 32]. However, these scores were not correlated with prognosis in the present study, possibly because our study only included patients who underwent surgery. Before surgery, we could improve their general condition and nutritional status to enable them to better tolerate invasive surgery. Indeed, serum CRP/albumin levels were normal in most patients, and the median status of CRP was 0.12 (range, 0.01–11) and of albumin was 4.0 (2.0–5.0), which might have influenced the results.