We retrospectively reviewed a database of 104 patients who underwent palliative combination chemotherapy for unresectable metastatic colorectal cancer at the Department of Surgical Oncology of Osaka City University between 2005 and 2010.

The patient characteristics are listed in Table 1. The patient population consisted of 59 males and 45 females, with a median age of 64 years (range: 27-86). According to the definition of the Eastern Cooperative Oncology Group performance status (PS), 96 patients were classified as having a PS of 0, 6 patients were classified as having a PS of 1, and 2 patients was classified as having a PS of 2. Sixty patients had primary tumors located in the colon and 44 had primary tumors located in the rectum. A total of 42 patients had metachronous unresectable cancer, and 62 patients had synchronous unresectable cancer. Fifty-eight patients had only one organ affected by metastasis and 46 patients had more than one organ affected by metastasis. Among the 104 patients, 88 underwent resection of a primary tumor. All patients underwent combination chemotherapy with oxaliplatin or irinotecan plus 5-fluorouracil/leucovorin or a prodrug of 5-fluorouracil as first-line chemotherapy. There was no initiation of palliative chemotherapy for recurrence while undergoing adjuvant chemotherapy. 64 patients received 5-fluorouracil + leucovorin + oxaliplatin (FOLFOX), 26 patients received capecitabine + oxaliplatin (CapeOX), nine patients received 5-fluorouracil + leucovorin + irinotecan (FOLFIRI), and five patients received S-1 + oxaliplatin (SOX). Seventy-six patients underwent chemotherapy combined with molecular targeted therapy. The median follow-up period in the survivors was 22.4 mo (range: 2.6-69.5). During the follow-up period, a total of 67 patients died.

Response evaluations were performed every eight weeks. A variation of approximately one week was regarded as an allowable error. All patients were followed up with a physical examination, blood tests, and tumor marker level measurements [i.e., carcinoembryonic antigen (CEA), computed tomography, and ultrasonography].

We adopted the response evaluation criteria in solid tumors (RESIST)[23] to classify the treatment response of each patient as one of the following: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). An objective response was defined as either CR or PR, while disease control was defined as CR, PR, or SD.

Pre-treatment blood samples were obtained within one week before the initiation of chemotherapy and post-treatment blood samples were obtained eight weeks after the initiation of chemotherapy. The differential white blood cell count was analyzed using an XE-5000 hematology analyzer (Sysmex, Kobe, Japan) based on the manufacturer’s protocol. In each case, the LMR was calculated from a blood sample by dividing the absolute lymphocyte count by the absolute monocyte count. The neutrophil to lymphocyte ratio (NLR) was calculated from a blood sample by dividing the absolute neutrophil count by the absolute lymphocyte count.

The significance of correlations between the pre-treatment LMR and the clinicopathological characteristics were analyzed using the χ² test, t-test, and Mann-Whitney U-test. The duration of survival was calculated according to the Kaplan-Meier method. Differences in the survival curves were assessed using the log-rank test. A multivariate analysis was performed according to the Cox proportional hazards model. All statistical analyses were conducted using the SPSS software package for Windows (SPSS Japan, Tokyo, Japan). Statistical significance was set at a value of P < 0.05.

This research conformed to the provisions of the Declaration of Helsinki established in 1995. All patients were informed of the investigational nature of the study and provided their written informed consent. This retrospective study was approved by the ethics committee of Osaka City University.

We used the LMR, a continuous variable, as the test variable and the 24.8-mo survival (median survival time: 24.8 mo) as the state variable. When we investigated the cut-off value for the LMR using the receiver operating characteristic (ROC) curve, we found that the appropriate cut-off value for the LMR was 3.38 (sensitivity: 90.0%; specificity: 52.1%) (Figure 1). We therefore set 3.38 as the cut-off value and the patients were classified into high-LMR (n = 66) and low-LMR (n = 38) groups. We also set the cut-off value for the NLR at 2.8 in accordance with the findings of a previous report[10].

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Figure 1 Receiver operating characteristic curve analysis of the lymphocyte to monocyte ratio in patients with unresectable metastatic colorectal cancer. Area under the curve = 0.703, 95%CI: 0.594-0.812, P = 0.001, positive predictive value = 80.65%, negative predictive value = 59.65%.

The overall survival rate was significantly worse in the low pre-treatment LMR group than in the high pre-treatment LMR group (P = 0.0011) (Figure 2A).

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Figure 2 Overall survival. A: According to the pre-treatment LMR. The overall survival rate was significantly worse in the low pre-treatment LMR group than in the high pre-treatment LMR group (P = 0.0011); B: According to the combination of the pre-treatment and post-treatment LMR values. The patients in group C exhibited a worse prognosis than those in groups A and B; C: According to the combination of the pre-treatment and post-treatment neutrophil to lymphocyte ratio values. There was no significant difference between groups E and F. LMR: Lymphocyte to monocyte ratio.

Correlations between the pre-treatment LMR and clinicopathological factors are shown in Table 2. The pre-treatment LMR had no significant relationship with any of the clinicopathological factors, with the exception of the pre-treatment NLR.

The distribution of the chemotherapeutic response after the administration of first-line chemotherapy with reference to the LMR/NLR subgroup is shown in Table 3. The objective response rate did not differ according to the LMR (34.4% vs 28.9%, P = 0.664). However, the disease control rate of the high-LMR group was significantly higher than in that of the low-LMR group (82.8% vs 63.2%, P = 0.033). On the other hand, there was no significant relationship between the NLR and the chemotherapeutic response.

The correlations between overall survival and the various clinicopathological factors are shown in Table 4. According to the results of a univariate analysis, overall survival exhibited significant relationships with performance status (P < 0.001), number of organs affected by metastasis (P = 0.045), response to molecular targeted therapy (P = 0.011), response to chemotherapy (P = 0.006), pre-treatment LMR (P = 0.002), and pre-treatment NLR (P < 0.001). A multivariate analysis indicated that performance status (HR = 3.345, 95%CI: 1.558-7.182, P = 0.002), response to molecular targeted therapy (HR = 0.462, 95%CI: 0.263-0.813, P = 0.007), and response to chemotherapy (HR = 0.432, 95%CI: 0.244-0.765, P = 0.004) were independent prognostic factors for survival.

We evaluated the prognostic significance of normalization of the LMR/NLR eight weeks after the initiation of chemotherapy. We categorized the patients into three groups according to the combination of their pre-treatment and post-treatment LMR values. Patients with high pre-treatment LMR were categorized into group A. Patients with low pre-treatment LMR and normalization of the LMR eight weeks after the initiation of chemotherapy were categorized into group B. Patients with low pre-treatment and post-treatment LMR value were categorized into group C. The patients in group C exhibited a worse prognosis than those in groups A and B (A vs C, P < 0.0001; B vs C, P = 0.0308) (Figure 2B). We categorized the patients into three groups according to the combination of their pre-treatment and post-treatment NLR values. Patients with low pre-treatment LMR were categorized into group D. Patients with high pre-treatment NLR and normalization of the NLR eight weeks after the initiation of chemotherapy were categorized into group E. Patients with high pre-treatment and post-treatment NLR value were categorized into group F. There was no significant difference between groups E and F (Figure 2C).

The absolute neutrophil count tended to decrease after chemotherapy. However, the absolute lymphocyte count did not change after chemotherapy, while the absolute monocyte count tended to increase after chemotherapy (Table 5).

Despite recent major advances in the development of new cytotoxic and molecular targeted therapies, patients with unresectable metastatic colorectal cancer (CRC) still have a poor prognosis. According to the guidelines of the European Society for Medical Oncology, it is recommended that the treatment of patients with metastatic CRC be individualized based on their tumor- and disease-related characteristics. It is therefore necessary to detect biomarkers for predicting survival.

The lymphocyte to monocyte ratio (LMR) is a useful marker for predicting survival and chemotherapeutic response. This marker can therefore be used for the individualization of treatment in patients with unresectable metastatic CRC. By using this marker, the authors can identify patients with a high risk of a poor prognosis, and thereby choose the most appropriate intensive therapy.

It is difficult to predict the prognosis of patients with unresectable metastatic CRC. A few markers for predicting patient survival have been reported previously. Survival prediction is important for planning an appropriate course of treatment. The LMR was revealed to correlate with both survival and the chemotherapeutic response in the present study. The LMR makes a useful clinical biological marker because its measurement by peripheral blood cell count is a quick and easy assay to perform.

The results of the present study suggest that the LMR is a useful prognostic marker for predicting survival and chemotherapeutic response in patients with unresectable metastatic CRC who undergo palliative chemotherapy.

The LMR was calculated from a blood sample by dividing the absolute lymphocyte count by the absolute monocyte count. The LMR reflects the immune status and systemic inflammatory response of the host. Immune status and systemic inflammation have been reported to correlate with tumor progression, invasion, and metastasis. The LMR is thus considered to correlate with the survival of patients with CRC.

This is a good descriptive study in which the authors evaluated the prognostic significance of the lymphocyte to monocyte ratio in patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy. The study is well structured and the subject is clear and interesting. The manuscript is correctly written and the conclusions are justified by the results found in the study.