Mazaki et al.

BMC Cancer (2020) 20:922

https://doi.org/10.1186/s12885-020-07429-5

RESEARCH ARTICLE Open Access

Neutrophil-to-lymphocyte ratio is a
prognostic factor for colon cancer: a
propensity score analysis
Junichi Mazaki* , Kenji Katsumata, Kenta Kasahara, Tomoya Tago, Takahiro Wada, Hiroshi Kuwabara,
Masanobu Enomoto, Tetsuo Ishizaki, Yuichi Nagakawa and Akihiko Tsuchida

Abstract
Background: A large number of patients suffer recurrence after curative resection, and mortality from colon cancer
remains high. The role of systemic inflammatory response, as reflected by neutrophil-to-lymphocyte ratio (NLR), in
cancer recurrence and death has been increasingly recognized. This study aimed to analyze long-term oncologic
outcomes of Stage II-III colon cancer to examine the prognostic value of NLR using a propensity score analysis.
Methods: A total of 375 patients with colon cancer underwent radical surgery between 2000 and 2014 at Tokyo
Medical University Hospital. Long-term oncologic outcomes of these patients were evaluated according to NLR values.
A cut-off NLR of 3.0 was used based on receiver operating characteristic curve analysis. Primary outcomes were overall
survival (OS) and relapse-free survival (RFS). An analysis of outcomes according to tumor sidedness was also performed.
Results: Patients with lower NLR values (“lower NLR group”) were more likely to have lymph node metastasis
compared to those with higher NLR values (“higher NLR group”) before case matching. After case matching, clinical
outcomes were similar between the two groups. There were no significant differences in 5-year OS and 5-year RFS
rates between the two groups before case matching based on propensity scores. After case matching, 5-year OS rates
were 94.5% in the lower NLR group (n = 135) and 87.0% in the higher NLR group (n = 135), showing a significant
difference (p = 0.042). Five-year RFS rates were 87.8% in the lower NLR group and 77.9% in the higher NLR group, also
showing a significant difference (p = 0.032). Among patients with left-sided colon cancer in the matched cohort, 5-year
OS and 5-year RFS rates were 95.2 and 87.3% in the lower NLR group (n = 88), respectively, and 86.4 and 79.2% in the
higher NLR group (n = 71), respectively, showing significant differences (p = 0.014 and p = 0.047, respectively).
Conclusions: The NLR is an important prognostic factor for advanced colon cancer, especially for left-sided colon cancer.
Keywords: Neutrophil-to-lymphocyte ratio (NLR), Relapse-free survival, Overall survival, Propensity score, Propensity score
matching, Colon cancer, Sidedness

* Correspondence: [email protected]
Department of Gastrointestional and Pediatric Surgery, Tokyo Medical
University, Tokyo, Japan

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Mazaki et al. BMC Cancer (2020) 20:922 Page 2 of 8

Background Surgical treatment

Treatment strategies for colon cancer are well- All patients underwent curative surgery. Gross speci-
established, and include surgical resection and chemo- mens were opened up along the antimesenteric border,
therapy. However, many patients suffer recurrence after and lymph nodes were harvested from the mesocolon.
curative surgical resection, and mortality rates from The specimens were then laid out on a board and fixed
colon cancer remain high. The role of systemic inflam- in 10% formalin.
matory response in cancer recurrence and death has
been increasingly recognized [1]. In addition to tumor Postoperative systemic adjuvant chemotherapy
characteristics, the host immune system plays an import- Postoperative systemic adjuvant chemotherapy is gener-
ant role in the development of colon cancer [2]. Many ally performed for pStage III colon cancer at our insti-
immunological and nutritional markers have been re- tute. In the present study, adjuvant chemotherapy was
ported to be prognostic factors for different types of can- performed in 19 of 216 patients (8.8%) with pStage II
cer, including colon cancer [3–7]. Among these, disease and 86 of 202 (42.5%) patients with pStage III
neutrophil-to-lymphocyte ratio (NLR) is calculated from disease. Oxaliplatin-based and 5-fluorouracil-based regi-
white blood cell (WBC) differential counts and can be mens were most commonly used.
obtained easily in preoperative patients. Previous stud-
ies have reported on the predictive potential of NLR Follow-up
as a prognostic factor in various types of malignan- Median follow-up period was 73.2 months (range, 0.2–
cies, including resectable colon cancer [8–14]. How- 225.1 months). For follow-up, patients with Stage II or
ever, since these previous studies analyzed data by III tumors were examined for up to five years postopera-
univariate or multivariate analysis, the possibility of tively. Specifically, tumor marker measurements were
selection bias and confounding factors could not be performed every three months for the first two years,
ruled out. Moreover and up to our knowledge, no and both tumor marker measurements and CT scans
prospective cohort studies have been conducted. To were performed every six months for the next three
address these limitations and to increase the strength years. When the first recurrence occurred, the recur-
of evidence, two studies used a propensity score ana- rence site and date were recorded.
lysis [15, 16]. However, one of these studies had a
small sample size (n = 200) and included patients of Statistical analysis
all disease stages (Stage I-IV), while the other study Primary outcomes were 5-year overall survival (OS) and
targeted only those with early-stage colon cancer. 5-year relapse-free survival (RFS). OS was defined as the
The present study aimed to analyze long-term onco- interval between the date of operation and the date of ei-
logic outcomes of patients with Stage II-III colon cancer ther death or the end of the observation period. Patients
at our institute to examine the prognostic value of NLR alive at the end of follow-up were censored. RFS was de-
using a propensity score analysis. fined as the interval between the date of operation to
date of recurrence, or death from underlying disease.
Observations were censored when patients died for a
Methods reason other than colon cancer. Survival characteristics
Patients were assessed using the Kaplan-Meier method and were
Medical records of 422 patients who underwent radical compared using the log-rank test. Propensity score ana-
surgery for Stage II-III colon cancer between 2000 and lyses were performed to adjust for heterogeneity be-
2014 at Tokyo Medical University Hospital were retro- tween two groups by NLR. Multivariate logistic
spectively reviewed. Of these, 47 patients without NLR regression was used to generate a propensity score pre-
values were excluded, and the remaining 375 patients dicting condition by NLR (NLR > 3.0 or NLR ≤ 3.0). The
were divided into two groups based on NLR values following six covariates were included: age, sex, body
(lower NLR and higher NLR groups). In general, patients mass index (BMI), tumor size, pathological T-stage, and
were admitted to our hospital two days before operation, pathological lymph node metastasis. Each patient was
and NLR values were obtained on the day of admission. assigned an estimated propensity score, which repre-
According to receiver operating characteristic (ROC) sented the patient’s predicted probability of the NLR sta-
curve analyses and previous reports, a cut-off value of tus. We specified matching IDs based on the propensity
3.0 was set for both mortality and recurrence (mortality: scores. According to the matching IDs, we divided the
area under the curve (AUC) = 0.521, 95%CI 0.449–0.592; patients into two groups by their NLR values, in which
recurrence: AUC = 0.502, 95%CI 0.423–0.581). This patients were paired by similarities in their characteris-
study was approved by the institutional review board of tics. Then, propensity score matching was performed.
Tokyo Medical University Hospital. Each patient with a NLR < 3.0 (lower NLR) was matched
Mazaki et al. BMC Cancer (2020) 20:922 Page 3 of 8

to a patient with a NLR ≥ 3.0 (higher NLR) and had of pathological lymph node metastasis compared to those
the closed propensity score on the logit scale with a in the higher NLR group (42.5% vs 52.5%, p = 0.006). No
caliper of 0.05. Standardized mean difference (SMD) significant differences were observed in other covariates.
was calculated to evaluate variable balance after pro- A matched analysis was performed according to pro-
pensity matching. Propensity scores were used for pensity scores to adjust for heterogeneity in the lower
regression adjustment, in which the treatment effect NLR and higher NLR groups, with six covariates (i.e.,
was estimated by adjusting for the impact of back- age, sex, BMI, tumor size, pathological T-stage, and
ground covariates in a regression model. We also per- pathological lymph node metastasis). Distributions of
formed analyses by dividing patients into two groups propensity scores before and after case matching are
according to tumor sidedness (right-side colon: from shown in Fig. 1a and b. Both lower NLR and higher
cecum to transverse colon; left-side colon: from NLR groups (135 matched pairs) showed a well-matched
splenic flexure to rectosigmoid colon). All statistical distribution with respect to patient and tumor character-
analyses were performed using SPSS software (IBM® istics in the adjusted analysis after case matching (Table
SPSS® Statistics for Windows, Version 25.0; IBM, Chi- 1). No significant difference was observed between the
cago, IL, USA). The level for statistical significance two groups in pathological lymph node metastasis rate.
was set at p < 0.05.
Regression adjustment including propensity scores
Results Cox models were created by applying propensity scores
NLR to adjust for group differences via regression adjustment.
The median NLR was 2.5 (range, 0.2–56.2) for the entire In the entire cohort (n = 375), hazard ratios (HRs) for
cohort (n = 375). There were 230 patients in the lower OS and RFS in NLR > 3.0 versus NLR < 3.0 were 1.546
NLR group and 145 patients in the higher NLR group. (95%CI 0.879–2.718) and 1.419 (95%CI 0.910–2.215), re-
The median NLR was 3.0 (range, 0.4–56.2) after case spectively (Tables 2, and 3).
matching (n = 270 and 135 in each group, respectively).
OS and RFS rates
Patient and tumor characteristics In the entire cohort, 5-year OS and 5-year RFS rates
Baseline characteristics are summarized in Table 1. Pa- were 90.1 and 81.7%, respectively. Before case matching,
tients in the lower NLR group had significantly higher rates 5-year OS and 5-year RFS rates were 91.5 and 83.7% in

Table 1. Baseline characteristics.

Data are expressed as median (range) or n (%)

NLR Neutrophil-to-Lymphocyte Ratio, BMI Body Mass Index, SMD Standardized Mean Difference
*Others included mucinous adenocarcinoma and papillary adenocarcinoma
Mazaki et al. BMC Cancer (2020) 20:922 Page 4 of 8

Fig. 1 Distributions of propensity scores before and after case matching. a Distribution of propensity scores in the entire cohort. b Distribution of
propensity scores in the propensity score-matched cohort

the lower NLR group (n = 230), respectively, and 87.1 respectively) (Figs. 4 a and 5 a). Among patients with
and 77.7% in the higher NLR group (n = 145), respect- left-sided colon cancer, 5-year OS and 5-year RFS
ively, with no significant differences (p = 0.233 and p = rates were 95.2 and 87.3% in the lower NLR group
0.227, respectively) (Figs. 2a and 3a). (n = 88), respectively, and 86.4 and 79.2% in the
The analysis of survival data after case matching higher NLR group (n = 71), respectively, showing sig-
revealed a significant difference in 5-year OS rate nificant differences (p = 0.014 and p = 0.047, respect-
between the lower NLR group (n = 135; 94.5%) and the ively) (Figs. 4b and 5b).
higher NLR group (n = 135; 87.0%) (p = 0.042) (Fig. 2b).
A significant difference was also observed in 5-year RFS
rate after case matching betw0een the lower NLR group Discussion
(87.8%) and the higher NLR group (77.9%) (p = 0.032) Colorectal cancer is the second leading cause of can-
(Fig. 3b). cer death in Japan. Since local recurrence and distant
metastasis occur in a large number of patients even
after curative surgery, a new focus has been placed
Tumor sidedness on identifying biomarkers that predict prognosis.
To evaluate the prognostic value of NLR by tumor While tumor-related factors have been investigated in
sidedness, patients were divided into two groups ac- many previous studies, host-related factors have only
cording to tumor location in the colon. Survival data recently started to draw attention [1].
were analyzed for case-matched patients. Among pa- The host immune system is an important factor
tients with right-sided colon cancer, 5-year OS and 5- which affects the outcome of cancer [16–18]. NLR has
year RFS rates were 92.9 and 88.8% in the lower NLR been suggested to be a simple index of systemic inflam-
group (n = 47), respectively, and 87.8 and 76.5% in the matory response. Neutrophilia occurs during systemic
higher NLR group (n = 64), respectively, showing no inflammation, and lymphopenia is a maker for de-
significant difference (p = 0.941 and p = 0.460, pressed cell-mediated immunity [19]. That is, cell-

Table 2. Hazard ratios for overall survival to measure the effects of NLR

NLR Neutrophil-to-Lymphocyte Ratio

Mazaki et al. BMC Cancer (2020) 20:922 Page 5 of 8

Table 3. Hazard ratios for recurrence free survival to measure the effects of NLR

NLR Neutrophil-to-Lymphocyte Ratio

mediated immune responses are dependent largely on Stage II-III advanced colon cancer using propensity
lymphocytes. A large number of lymphocytes at tumor scores to minimize selection bias. The present study
sites has been shown be associated with a good progno- cohort consisted of 375 patients with Stage II-III
sis, whereas lymphopenia has been reported to be a colon cancer, and no significant differences were ob-
predictor of poor prognosis [20]. On the contrary, neu- served between the lower NLR and higher NLR
trophils suppress lymphocyte-mediated cytolysis and groups in terms of OS and RFS before case matching.
has been reported to be associated with a poor progno- After case matching according to propensity scores,
sis [21]. The prognostic NLR in malignancy may due to however, NLR was found to predict prognosis both in
the high tumor angiogenesis activity of tumor-induced terms of OS and RFS with a cut-off value of 3.0.
neutrophils contributing to tumor progression, lympho- The colon originates from the midgut and hindgut
cyte count associated with disease severity, and immune during embryonic development and differentiates into
escape of tumor cells from tumor infiltrating lympho- the right-side colon and left-side colon. Tumors in
cyte [22]. the cecum, ascending colon, and the proximal part of
Walsh et al. first reported a correlation between the transverse colon are defined as midgut tumors,
preoperatively elevated NLR had a relationship with and those in the distal transverse, descending, and
overall and cancer-specific survival in colon cancer sigmoid colon and the rectum are defined as hindgut
[23]. The predictive potential of NLR in evaluating tumors. Differences have been reported between right
the prognosis of patients with various types of malig- and left-sided colon tumors in terms of clinical symp-
nancies, including resectable colon cancer, has been toms, incidence, molecular pathways involved, and
demonstrated in previous studies [8–11]. However, no oncologic outcomes, as well as embryologic origin
study has analyzed a large cohort of patients with [24–28]. However, no reports have examined the

Fig. 2 Overall survival rates in the entire cohort and propensity score-matched cohort. a Overall survival rates in the entire cohort (n = 375). b
Overall survival rates in the propensity score-matched cohort (135 matched pairs)
Mazaki et al. BMC Cancer (2020) 20:922 Page 6 of 8

Fig. 3 Relapse-free survival rates in the entire cohort and propensity score-matched cohort. a Relapse-free survival rates in the entire cohort (n =
375). b Relapse-free survival rates in the propensity score-matched cohort (135 matched pairs)

predictive potential of NLR in colon cancer with a localized perforation, and close, indeterminate, or posi-
focus on tumor sidedness. The present study evalu- tive margins. The guidelines, however, also state that
ated the prognostic value of NLR by tumor sidedness, there are no data correlating risk features with selection
and found that both 5-year OS and 5-year RFS rates of chemotherapy. In the present study, preoperative
were significantly lower in patients with left-sided NLR was associated with both RFS and OS, suggesting
colon cancer who had a higher NLR. In contrast, no that NLR could be used as a tool to identify patients for
significant differences were observed among patients whom adjuvant chemotherapy should be performed/
with right-sided colon cancer. avoided, especially for left-sided colon cancer. A pro-
National Comprehensive Cancer Network (NCCN) spective study will be needed to further explore this
guidelines recommend adjuvant chemotherapy for possibility.
high-risk Stage II and Stage III colon cancer [29]. High- This study has some limitations. First, we used a
risk factors for recurrence include poorly differentiated single-center retrospective design. However, to
histology, lymphatic/vascular invasion, bowel obstruc- minimize selection bias, we analyzed the data according
tion, < 12 lymph nodes examined, perineural invasion, to propensity scores. Second, our data did not include

Fig. 4 Survival rates in the propensity score-matched cohort of right-sided colon cancer patients. a Overall survival. b Relapse-free survival
Mazaki et al. BMC Cancer (2020) 20:922 Page 7 of 8

Fig. 5 Survival rates in the propensity score-matched cohort of left-sided colon cancer patients. a Overall survival. b Relapse-free survival

records of whether patients had hematologic or auto- Competing interests

immune disease, which may have influenced preopera- The authors declare that they have no competing interests.

tive NLR values. Third, no molecular assessment was Received: 13 April 2020 Accepted: 16 September 2020
performed in this study, e.g., to determine microsatel-
lite instability. A prospective study will be needed to
examine confounders and further clarify the prognostic
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