In the present study, patients with high pre-chemotherapy LMR experienced significant improvements in PFS (9.2 vs. 7.6 months, P < 0.001) and OS (19.4 vs. 16.6 months, P < 0.001) compared with patients with low pre-chemotherapy LMR. Subsequent COX multivariate analysis showed that high pre-chemotherapy LMR (≥3.11) was an independent favorable prognostic factor for PFS and OS. Additionally, patients whose LMR remained high (high–high subgroup), increased (low–high subgroup), or decreased (high–low subgroup) following chemotherapy showed better results in terms of PFS and OS than patients whose LMR remained low (low–low subgroup) after chemotherapy, suggesting that the change in LMR before and after chemotherapy may predict the benefit of chemotherapy.
Approximately half of all CRC patients develop distant metastasis [3], which poses a huge clinical challenge. In clinical practice, the FOLFOX regimen is the treatment of choice for patients with chemotherapy-naïve mCRC and has favorable toxicity profiles compared with the irinotecan-based combination regimen [4, 5]. However, a significant difference in the response to chemotherapeutic agents has been noted among mCRC patients, suggesting that mCRC is a heterogeneous disease. Hence, considerable strides have been made in seeking prognostic or predictive biomarkers to classify heterogeneous mCRC. Inflammation is profoundly involved in promoting pathogenesis and progression of tumor [6]. Nowacki et al. [18] revealed that a prolonged duration of ulcerative colitis dramatically increased the risk of CRC (P < 0.001), whereas the risk could be markedly reduced by anti-inflammatory treatment (P < 0.02), suggesting that inflammation may have a profound influence on the pathogenesis of CRC. Lymphocytes play an important role in constraining the proliferation of malignant cells. As a surrogate marker of weak immunity, peripheral blood lymphopenia is associated with poor survival outcomes in patients with nasopharyngeal carcinoma (NPC) [14]. TILs are observed in the tumor microenvironment and reflect an adaptive immune response [6]. The superior survival outcomes associated with high concentrations of TILs in CRC has been well documented [19–21]. Furthermore, growing evidence suggests that CD8+ cells and other activated T lymphocytes might suppress metastasis rather than tumor growth [22]. Monocytes can differentiate into macrophages in the tumor microenvironment [6]. Experimental evidence has shown remarkable interactions between tumor cells, macrophages, and blood vessels, facilitating angiogenesis and promoting tumor cell motility, which eventually results in distant metastases [23, 24]. In addition, a survival advantage associated with low levels of peripheral blood monocytes has been observed in NPC patients [14]. Taking the above considerations into account, peripheral blood LMR, which is an indicator of systemic inflammation, becomes an ideal candidate due to the advantage of simplicity, accessibility, and inexpensiveness compared with complex molecular markers.
A large cohort study including 1547 non-metastatic NPC patients showed that higher LMR levels (≥5.22) were significantly associated with longer DFS and OS (P < 0.001) [14]. Subsequent multivariate COX proportional hazard analysis confirmed that higher LMR levels remained a significant independent factor for longer DFS (HR = 0.669, 95% CI 0.535–0.838, P < 0.001) and OS (HR = 0.558, 95% CI 0.417–0.748, P < 0.001) [14]. Lin et al. [16] found that newly diagnosed metastatic non-small cell lung cancer patients with increased LMR (≥4.56) obtained longer PFS (5.60 vs. 5.04 months, P = 0.001) and OS (13.20 vs. 11.72 months, P < 0.001) than those with decreased LMR. Moreover, LMR was an independent prognostic factor for PFS (HR = 0.660, 95% CI 0.512–0.851, P = 0.001) and OS (HR = 0.530, 95% CI 0.409––0.687, P < 0.001) [16]. For patients with stage II and III colon cancer, patients with high preoperative LMR (>2.83) showed better results in terms of time-to-recurrence (HR = 0.47, 95% CI 0.29–0.76, P = 0.002) and OS (HR = 0.51, 95% CI 0.31–0.83, P = 0.007) than those with low preoperative LMR [17]. Similar to these aforementioned reports, our study cohort demonstrated that chemotherapy-naïve mCRC patients with high pre-chemotherapy LMR (≥3.11) showed significant improvements in PFS (9.2 vs. 7.6 months, P < 0.001) and OS (19.4 vs. 16.6 months, P < 0.001) compared with patients with low pre-chemotherapy LMR. Furthermore, our subsequent COX multivariate analysis showed that high pre-chemotherapy LMR was an independent favorable prognostic factor for PFS (HR = 0.710, 95% CI 0.558–0.903; P = 0.005) and OS (HR = 0.662, 95% CI 0.501–0.875, P = 0.004). Taking the above considerations into account, pre-treatment LMR seems to be an independent prognostic factor that can classify cancer patients into different prognostic subgroups, improving the personalized management of cancer.
In addition to pre-treatment LMR, the prognostic significance of changes in LMR before and after treatment should also be explored. In our study cohort, the optimal cut-off values of the pre- and post-chemotherapy LMR were both set at 3.11. Subsequently, all patients were divided into four subgroups based on the cut-off values of pre- and post-treatment LMRs. As expected, the low–low subgroup had the worst survival results, whereas the high–high subgroup had the best survival results. Additionally, patients whose LMR increased (low–high subgroup) or decreased (high–low subgroup) after chemotherapy showed longer PFS and OS than patients whose LMR remained low (low–low subgroup) after chemotherapy. A recent study evaluated the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in 199 non-smokers with advanced lung adenocarcinoma receiving gefitinib or standard chemotherapy as first-line therapy [25]. In the high pre-treatment NLR group, patients whose NLR decreased after treatment had a longer OS than those whose NLR remained high following treatment (20.7 vs. 7.9 months, P < 0.001). Similarly, in the low pre-treatment NLR group, patients whose NLR remained low after treatment had a longer OS than those whose NLR increased after treatment (26.4 vs. 18.9 months, P < 0.001) [25]. Therefore, a change in LMR before and after chemotherapy seemed to predict the benefit of chemotherapy in chemotherapy-naïve mCRC patients receiving the FOLFOX regimen.
The strengths of this study are the large sample size and the relatively low heterogeneity of patients who were all diagnosed with chemotherapy-naïve mCRC and treated with FOLFOX chemotherapy. Nevertheless, the major limitation of this study is its retrospective design, which contributes to selection bias. Prospective studies are necessary to validate our results. Additionally, inflammatory factors such as lymphocytes and monocytes may be influenced by many potential confounding factors, such as latent infection and autoimmune disease. Hence, potential confounding factors must be excluded while considering LMR as a prognostic factor for cancer patients.
In conclusion, for patients with previously untreated mCRC receiving FOLFOX chemotherapy, a high pre-chemotherapy LMR is an independent favorable prognostic factor for PFS and OS, and changes in LMR before and after chemotherapy seem to predict the benefit of chemotherapy.