LMR predicts outcome in patients after preoperative chemoradiotherapy for stage II-III rectal cancer

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LMR predicts outcome in patients after preoperative chemoradiotherapy for stage II-III rectal cancer Shinya Abe, MD, PhD,a,* Kazushige Kawai, MD, PhD,a Hiroaki Nozawa, MD, PhD,a Keisuke Hata, MD, PhD,a Tomomichi Kiyomatsu, MD, PhD,a Teppei Morikawa, MD, PhD,b and Toshiaki Watanabe, MD, PhDa a b

Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan Department of Pathology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

article info

abstract

Article history:

Background: Recently, lymphocyte-to-monocyte ratio (LMR) has attracted attention as a new

Received 15 June 2017

marker of the chronic systemic inflammatory response and has been associated with pa-

Received in revised form

tient prognosis in those who underwent chemoradiotherapy (CRT) for several solid can-

9 August 2017

cers. This study aimed to evaluate the association between LMR and the prognosis of

Accepted 29 September 2017

patients with rectal cancer.

Available online xxx

Methods: A total of 183 stage II-III rectal cancer patients who underwent preoperative CRT followed by surgical R0 resection were retrospectively reviewed. The LMR was calculated

Keywords:

from pre- and post-CRT blood samples. To determine the optimal cutoff value for pre- and

Lymphocyte-to-monocyte ratio

post-CRT LMR for predicting relapse-free survival (RFS) and overall survival (OS), a receiver

Prognostic marker

operator characteristic curve was used. Cox’s proportional hazard models were applied to

Rectal cancer

identify risk factors for recurrence and overall mortality.

Chemoradiotherapy

Results: Low LMR was observed in 54 patients (pre-CRT <4.0) and 29 patients (post-CRT

Outcome

<1.5). Although pre-CRT LMR correlated with tumor size and ypT stage, post-CRT LMR showed no correlation to any pathologic features. Median follow-up term was 66.3 months; the 5-year RFS and OS of all patients were 72.5% and 88.7%, respectively. We found that a low pre-CRT LMR was an independent risk factor for OS (hazard ratio, 2.83; 95% confidence interval 1.03-8.13; P ¼ 0.043). Conclusions: In rectal cancer patients who have undergone preoperative CRT, a low pre-CRT LMR is a poor prognostic factor for OS. ª 2017 Elsevier Inc. All rights reserved.

Introduction Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision for locally advanced rectal cancer

contributes to local control because of a decreasing local recurrence rate.1,2 Therefore, in the Western world, preoperative CRT is one of the standard treatments for locally advanced rectal cancer.

* Corresponding author. Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: þ81 3 3815-5411x33246; fax: þ81 3 3811-6822. E-mail address: [email protected] (S. Abe). 0022-4804/$ e see front matter ª 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2017.09.053

abe et al  lmr predicts outcome in rectal cancer patients

Several factors predicting prognosis of rectal cancer patients who underwent preoperative CRT have been reported, including tumor depth and lymph node metastasis; however, these factors can only be assessed after surgery. On the other hand, pretreatment prognostic factors would be more useful than postoperative factors, as surgeons would be able to use them to determine treatment strategies, including the chemotherapy regimen or indication for CRT. Since Virchow first reported the association between inflammation and tumorigenesis in 1863,3 studies have investigated the inflammation response and the progression of cancer. Inflammation is a host immune response to remove the invasion of foreign matter or to eliminate tissues recognized as heterogeneous. White blood cells, containing mainly neutrophils, lymphocytes, and monocytes, play a central role in the host immune response.4 Because the systematic inflammatory response (SIR) indirectly reflects host immune status, it probably also reflects the prognosis of various malignancies, including gastrointestinal cancers. Formerly, some SIR-related factors were used as prognostic indicators, such as elevation of C-reactive protein,5 hypoalbuminemia, thrombosis,6,7 and elevation of interleukin (IL) 6/IL17.8,9 Recently, the neutrophil-to-lymphocyte ratio (NLR)10-12 and platelet-to-lymphocyte ratio (PLR)13,14 have been reported as SIR-related prognostic markers for cancer. Increased neutrophil and platelet counts are characteristic changes in an acute SIR period. In contrast, cancer causes chronic SIR. Therefore, some authors suggest that neutrophils and platelets are not necessarily directly related with cancer prognosis.15,16 Alternatively, the lymphocyte-to-monocyte ratio (LMR), the ratio of the number of monocytes to the number of lymphocytes of peripheral blood, has been spotlighted as a new marker of chronic SIR. This is because monocytes, macrophages derived from monocytes, and lymphocytes play primary roles in chronic rather than acute inflammation. Some studies have reported that LMR is a prognostic factor for shorter diseasefree survival (DFS) and overall survival (OS) in colorectal cancer,17,18 hematological tumor,19 pharyngeal cancer,20 lung cancer,21 and pancreatic cancer.22 Although the utility of LMR as a predictive indicator in colorectal cancer patients has been demonstrated in several studies,23 most focused on colorectal cancer, with only two including rectal cancer patients.24,25 In one study, LMR indicated poor prognosis for DFS in T3N0 rectal cancer patients,24 but another study showed no prognostic value of LMR for DFS and OS in stage II or III rectal cancer patients.25 Thus, the prognostic value of LMR in rectal cancer patients is controversial. In addition, two recent studies demonstrated the prognostic value of LMR in head and neck26 and esophageal cancer27 patients who had undergone preoperative CRT. Previously, we reported that immunological measurements depending on host condition affected the effect of preoperative CRT.28,29 Accordingly, we hypothesized that LMR in the rectal cancer patients who underwent preoperative CRT may demonstrate better prognostic value than that in those who did not. Therefore, we conducted this study to investigate the prognostic ability of both pre- and post-CRT LMR in rectal cancer patients who underwent preoperative CRT.

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Materials and methods Patients We retrospectively evaluated 183 consecutive middle and low rectal cancer patients who underwent preoperative CRT followed by surgical R0 resection from October 2003 to December 2014 at The University of Tokyo Hospital. Inclusion criteria were histologically confirmed adenocarcinoma with Stage II-III staging, diagnosed using chest and pelvic computed tomography and magnetic resonance imaging. Patients who developed distant metastasis during CRT were excluded. Pre-CRT blood samples were obtained between 2 and 4 weeks before CRT, and post-CRT blood samples were obtained between 3 and 5 weeks after CRT. Blood samples were examined in a general laboratory in our institute.

Treatment All patients received long-course preoperative CRT (55 Gy/ 25 fractions/5 weeks or 50.4 Gy/28 fractions/5 weeks); radiation was delivered to the whole pelvis. Oral administration of tegafur/uracil with or without infusion of CPT-11, oral administration of tegafur/gimeracil/oteracil potassium with infusion of oxaliplatin, or continuous infusion of 5-fluorouracil (5-FU) were included in the concurrent chemotherapy regimen. Curative radical resection was performed at 6 to 8 weeks after CRT was completed.

Pathologic evaluation Histopathological examination performed after surgery and the pathologic tumor-node-metastasis classification and staging of rectal tumors were recorded according to the classification established by the American Joint Committee on Cancer.30 Tumor regression grading was determined according to the General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus of the Japanese Society for Cancer of the Colon and Rectum.31 Briefly, grade 0 was defined as neither necrosis nor regressive change. Grades 1a and 1b were defined as >2/3 viable tumor cells and approximately 1/3 to 2/3 viable tumor cells, respectively. Grade 2 was defined as <1/3 viable tumor cells, and grade 3 was defined as no viable tumor cells.

Patient follow-up Postoperative surveillance was performed at 3-month intervals after surgery. Blood analysis was performed every 3 months, computed tomography was performed every 6 to 12 months, and a colonoscopy examination was performed every 1 to 2 years. This study was approved by the Ethics Committee at The University of Tokyo. Relapse was defined as either local recurrence or distant metastasis.32

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Adjuvant treatment

were analyzed using the Kaplan-Meier survival curve and logrank tests. Variables with a P value of <0.10 in the univariate analyses were further evaluated in the multivariate analyses using the Cox proportional hazards model to determine the predictive factors. All statistical analyses were performed using JMP Pro 11.0 statistical software (SAS Institute Inc, Cary, NC). P values < 0.05 were considered statistically significant.

The FOLFOX regimen, the XELOX regimen, or tegafur/uracil oral administration were recommended in this study for 6 months after surgery.

Statistical analysis To determine the optimal cutoff value for pre- and post-CRT LMR, a receiver operating characteristic (ROC) curve was used. Associations between pre- and post-CRT LMR and clinicopathological variables were analyzed using Wilcoxon rank sum tests. Relapse-free survival (RFS) and overall survival (OS)

Results A total of 183 patients who underwent CRT for rectal cancer were enrolled, including 117 (63.9%) male and 66 (36.1%)

Table 1 e Patient characteristics. No. of patents (%) Total

Pre-CRT

Post-CRT

38.0  14.5*

22.6  15.5*

183

Gender Male

117 (63.9%)

Female

66 (36.1%)

Age (years)

63.2  10.2*

Regimen of chemotherapy Tegafur/uracil

149 (81.4%)

Tegafur/uracil þ CPT-11

19 (10.4%)

Tegafur/gimeracil/oteracil

5 (2.7%)

Tegafur/gimeracil/oteracil þ oxalipalatin

2 (1.1%)

5-Fluorouracil

8 (4.4%)

Surgical procedure Anterior resection

122 (66.7%)

Abdominoperineal resection Hartmann’s resection Others

5 (2.7%) 12 (6.6%)

Tumor size (mm) Depth of invasion

44 (24.0%)

y

T0 (complete pathologic response)

25 (13.7%)

T1

19 (10.4%)

T2

2 (1.1%)

52 (28.4%)

T3

170 (92.9%)

77 (42.1%)

T4

11 (6.0%)

10 (5.4%)

N0

109 (59.6%)

137 (74.9%)

N1

52 (28.4%)

33 (18.0%)

N2

22 (12.0%)

13 (7.1%)

Regional lymph node metastasisy

TNM stagey Stage 0

28 (15.3%)

Stage 1

56 (30.6%)

Stage 2

108 (59.0%)

Stage 3

75 (41.0%)

46 (25.1%)

CEA (ng/mL)

12.7  24.7*

5.29  7.69*

LMR

5.11  2.50*

2.51  1.33*

CEA ¼ carcinoembryonic antigen; TNM ¼ tumor-node-metastasis. * Data are presented as mean  SD. y Data are presented as cTNM and ypTNM for pre-/post-CRT.

53 (29.0%)

abe et al  lmr predicts outcome in rectal cancer patients

female patients with a mean age of 63.2 years (range 3285 years). Patient characteristics are shown in Table 1. The most frequent concurrent chemotherapy regimen with radiation therapy was tegafur/uracil (148 patients [72.9%]), followed by tegafur/uracil with CPT-11 (19 patients [9.4%]) and 5fluorouracil (8 patients [4.0%]). By performing preoperative CRT, mean tumor size decreased from 38.0 to 22.6 mm, and tumor depth and lymph node metastasis were downgraded. Twenty-five patients (13.7%) achieved complete pathologic response, whereas 40 patients (21.8%) were diagnosed as regression grade 0 or 1a (poor response). Median pre- and post-CRT LMR were 5.11 (range: 1.1-24) and 2.51 (range: 0.5-10), respectively. Pre- and post-CRT optimal LMR cutoff values for OS were 4.0 and 1.5, respectively, and areas under the curve (AUCs) were 0.53 and 0.52, respectively (Fig. 1); 54 patients (29.5%) were observed to have low pre-CRT LMR (<4.0), and 29 patients (15.8%) were observed to have low post-CRT LMR (<1.5). Table 2 shows associations between pre- and post-CRT LMR and clinicopathological variables. Low pre-CRT LMR significantly correlated with sex, age, pre-CRT tumor size, and pathologic T stage. However, clinical T stage was not associated with pre-CRT LMR. In contrast, post-CRT LMR correlated with neither tumor size nor T stage in pre- and post-CRT. In addition, pre- and post-CRT LMR showed no correlation with clinical and pathological N stage, lymphatic invasion and venous invasion, or tumor regression grade. Because the depth of tumor invasion after CRT had a stronger correlation with pre-CRT rather than post-CRT LMR, we further evaluated which ratio was the better prognostic maker. The median follow-up interval was 66.3 months (range 14.1-159.3); the 5-year RFS and OS of all patients were 72.5% and 88.7%, respectively. Kaplan-Meier curves are shown in Figure 2. With respect to 5-year RFS rates, neither low pre- nor post-CRT LMR discriminated Kaplan-Meier curves (88.1% vs. 93.4%; P ¼ 0.544, 85.0% vs. 93.1%; P ¼ 0.158, Fig. 2A and B). In contrast, 5-year OS rates for patients with low pre-CRT LMR, but not post-CRT LMR, were significantly lower than that of

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patients with high pre-CRT LMR (78.8% versus 93.6%; P ¼ 0.037, 81.6% versus 91.2%; P ¼ 0.217, Fig. 2C and D). The majority of the patients received oral intake of tegafur/uracil treatment as part of CRT (Table 1). The percentage of patients who received other treatments was 13.1% in the high pre-CRT LMR group and 5.46% in the low pre-CRT LMR group (P ¼ 0.989). Therefore, the prognostic difference between high and low LMR groups may not be a consequence of the difference in treatment between the groups. Table 3 shows associations between LMR and prognosis. Pre-CRT LMR, but not post-CRT LMR, was an independent prognostic factor (hazard ratio: 2.83; 95% confidence interval 1.03-8.13; P ¼ 0.043) together with ypT stage, ypN stage, histopathological type, and pre-CRT carcinoembryonic antigen levels.

Discussion LMR decreases in patients with chronic inflammatory states such as inflammatory bowel disease and cirrhosis after chronic hepatitis C.33,34 In contrast, in the cancer microenvironment, inflammatory cytokines such as tumor necrosis factor-a, IL-1, IL-6, and chemokines secreted by cancer cells recruit immune cells such as lymphocytes, macrophages, and dendritic cells and elicit an inflammation response.35 Therefore, chronic inflammation occurs locally in solid cancer and contributes to tumor growth and progression.36 Because colorectal cancer also exhibits local chronic inflammation,37 we hypothesized that LMR of patients with colorectal cancer would be lower than that of healthy persons. Mean LMRs in healthy persons have been reported to be from 3.465.30,33,34,38 whereas the mean LMR value in colorectal cancer patients in this study was 5.11. Mean LMR values in other solid cancer patients had a wider range: 3.23,39 3.51,40 4.55,41 and 5.4820 in renal cell carcinoma, esophageal squamous cell carcinoma, colorectal cancer, and nasopharyngeal carcinoma. Thus, LMR is not necessarily lower in cancer patients than in

Fig. 1 e Correlation between pre-CRT and post-CRT LMR and overall survival. Receiver operating characteristic curves predicting overall survival by pre-CRT LMR (A) and post-CRT LMR (B) are represented. The area under the curve for pre-CRT and post-CRT are 0.53 and 0.52, respectively. The optimal cutoff values, as determined by each curve, for pre-CRT and postCRT are 4.0 and 1.5, respectively.

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Table 2 e Association between pre- and post-CRT LMR and clinicopathological variables. Variables

Pre-CRT LMR*

Post-CRT LMR* P value

P value

<0.001

Gender Male

4.47  0.21

Female

5.99  0.28

Age

0.003 2.28  0.12 2.88  0.16

0.042

<70 years

4.87  0.22

70 years

5.71  0.35

Tumor size before CRT

0.147 2.42  0.12 2.74  0.19

0.035

<50 mm

5.33  0.21

50 mm

4.41  0.37

Tumor size after CRT

0.221 5.17  0.19 3.98  0.95

0.638

0.672

<50 mm

2.53  0.11

2.50  0.10

50 mm

2.42  0.20

2.71  0.50

Clinical T stage

0.701

cT2/3

5.13  0.19

cT4

4.83  0.76

Clinical N stage

0.249 2.53  0.10 2.06  0.40

0.172

N0

5.32  0.24

N1/2

4.80  0.29

Pathological T stage

0.642 2.54  0.13 2.45  0.15

0.031

0.070

ypT0/1

5.67  0.37

2.89  0.20

ypT2/3

5.05  0.22

2.36  0.12

ypT4

3.41  0.78

Pathological N stage

2.65  0.42 0.813

N0

5.08  0.21

N1/2

5.18  0.37

Histopathological type

0.799 2.52  0.11 2.46  0.230

0.775

Moderate/well differentiated

5.02  0.18

Others

4.80  0.75

Lymphatic invasion

0.354 2.52  0.10 2.12  0.42

0.249

Absent

5.17  0.19

Present

4.37  0.67

Venous invasion

0.650 2.51  0.10 2.34  0.36

0.315

Absent

5.28  0.25

Present

4.90  0.27

Tumor regression grade

0.346 2.58  0.13 2.40  0.15

0.806

0.066

0/1a

5.23  0.40

2.03  2.07

1b

5.29  0.34

2.65  0.18

2

4.87  0.31

2.54  0.16

3(pCR)

5.13  0.50

Adjuvant chemotherapy

2.82  0.26 0.634

Absent

5.06  0.21

Present

5.27  0.39

Pre-CRT CEA

0.621 2.53  0.11 2.41  0.21

0.752

0.909

<5 mg/L

5.18  0.30

2.48  0.16

5 mg/L

5.06  0.24

2.51  0.13

CRT ¼ chemoradiotherapy; CR ¼ complete response; CEA ¼ carcinoembryonic antigen; SD ¼ standard deviation; pCR ¼ pathological complete response. * Mean  SD. Values were presented except for age and tumor size.

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Fig. 2 e Correlation between pre-CRT and post-CRT LMR, and RFS and OS. (A) RFS curves stratified according to pre-CRT LMR level (the 5-year RFS for low pre-CRT 88.1%, high pre-CRT 93.4%). (B) RFS curves stratified according to post-CRT LMR level (the 5-year RFS for low pre-CRT 85.0%, high pre-CRT 93.1%). (C) OS curves stratified according to pre-CRT LMR level (the 5-year OS for low pre-CRT 78.8%, high pre-CRT 93.6%). (D) OS curves stratified according to post-CRT LMR level (the 5-year OS for low pre-CRT 81.6%, high pre-CRT 91.2%).

healthy persons. However, as shown in Table 2, pre-CRT LMR was lower with larger tumor size pre-CRT or with higher T stage in rectal cancer patients. In addition, pre-CRT LMR was especially low in ypT4. In other words, pre-CRT LMR correlated with persistent serosal invasion or invasion to adjacent organs even after CRT. Because ypT4 after CRT has been reported to be a poor prognostic marker,42 low pre-CRT LMR might be indicative of aggressiveness or high malignant potential of the tumor, which in turn, is predictive of shorter OS. LMR was also lower in patients with a larger size or more advanced T stage in other solid cancers such as esophageal squamous cell carcinoma40 and gastric,43 colorectal,18 and

hepatocellular cancers.44 In contrast, with regard to N factor, LMR decreases in lymph node metastasis in esophageal squamous cell carcinoma40 and gastric cancer.42 Although there was no correlation with other cancers,45 our results in rectal cancer were similar. In addition, LMR mainly correlated to local cancer progression rather than metastasis; this is similar to other markers such as NLR,46 PLR,47 platelet counts,6 and fibrinogen,48 although these markers mostly correlated with T stage, but not always to N stage. Although reports are lacking concerning the association of LMR with the effect of CRT and LMR in rectal cancer patients, two recent studies reported the effects in other solid cancer

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Table 3 e Uni and multivariate analysis of OS by Cox proportional hazards model. Parameter

Overall survival Univariate analysis

Multivariate analysis

HR

95% CI

Female vs. male

1.91

0.73-5.91

0.196

Age (years)

<70 vs. 70

1.04

0.33-2.72

0.948

Tumor size before CRT (mm)

<50 vs. 50

1.99

0.74-4.95

0.165

ypT stage

0-2 vs. 3-4

5.6  109

11.7-NA

<0.001

ypN stage

0 vs. 1

4.29

1.72-10.8

0.002

Absent vs. Present

2.53

0.59-7.62

0.185

3.46

1.32-10.7

0.011

4.10-34.7

<0.001

Gender

Lymphatic invasion Venous invasion Histopathological type

Absent vs. Present Differenciated vs. Others

12.9

P value

HR

95% CI

P value

3.1  109

4.54-3.5  1030

<0.001

2.88

0.83 15.4

1.03 - 8.18

0.044

0.28-2.81

0.746

3.57-69.4

<0.001 0.185

Tumor regression grade

2/3 vs. 0/1a/1b

3.65

1.32-12.8

0.011

2.26

0.69-9.05

Adjuvant chemotherapy

Present vs. Absent

0.35

0.14-1.02

0.054

0.56

0.15-1.87

0.352

<5 vs. 5

2.54

0.92-8.93

0.073

5.28

1.36-29.0

0.014

2.83

1.03-8.13

0.043

Pre-CRT CEA (mg/mL) Pre-CRT LMR

>4 vs. 4

2.53

1.00-6.28

0.049

Post-CRT LMR

>1.5 vs. 1.5

1.88

0.61-4.92

0.250

CEA ¼ carcinoembryonic antigen; HR ¼ hazard ratio; CI ¼ confidential interval.

patients. Kano et al. reported that pre-CRT LMR correlated with DFS and OS after CRT in head and neck cancer patients,26 and Liu et al. reported that pre-CRT LMR correlated with the effect of CRT in esophageal carcinoma patients.27 Therefore, we evaluated the association between LMR and the effect of CRT in rectal cancer patients. LMR decreased from 5.11 to 2.55 following CRT. CRT usually decreases lymphocytes in peripheral blood, but monocytes in peripheral blood do not decrease29; accordingly, CRT decreases LMR. CRT is highly effective in rectal cancer49-51 and cervical carcinoma52 when patients exhibit a high peripheral lymphocyte count before treatment, while the treatment response of chemotherapy is reported to be better in patients with metastatic colorectal cancer with high pre-treatment LMR.41 Based on these reports, we hypothesized that CRT would be more effective in rectal cancer patients with higher LMR; however, there was no correlation between high LMR and the effect of CRT. Furthermore, regarding post-CRT LMR, there was no correlation with cancer progression (yT stage, yN stage, and tumor regression grade) and the effect of CRT. We next evaluated the association between LMR and prognosis of rectal cancer patients who received preoperative CRT. Because past studies evaluating the correlation between LMR and OS obtained cutoff values for LMR using ROC curve analysis,22,53 the cutoff values in this study were determined similarly: pre- and post-CRT LMRs were 4.0 and 1.5, respectively. However, the AUCs were 0.53 and 0.52, respectively; thus, LMR alone does not seem to be a strong prognostic indicator. However, pre-CRT LMR <4.0 had significantly shorter OS, and pre-CRT LMR correlated with OS in multivariate analyses. Although, pre-CRT tumor size correlated with low pre-CRT LMR, it showed no correlation with OS. Therefore, pre-CRT LMR was helpful for the treatment of rectal cancer not simply as an alternative for tumor size in pre-CRT imaging, but also as an effective predictor of prognosis after surgery.

In a meta-analysis of studies that reported the prognostic values of LMR in a wide variety of solid cancers, Nishijima et al. divided studies into four cutoff value categories, based on LMR cutoff values: <3.0 (11 studies), 3.0 to <4.0 (5), 4.0 to <5.0 (5), and 5.0 (4); each cut-off value range correlated to OS, with lower values indicating better prognostic indicator.54 However, this meta-analysis did not include studies focusing on rectal cancer patients who had undergone preoperative CRT. Including the present study, three studies have focused on the association between LMR and long-term prognosis in rectal cancer patients. Xiao et al. (cutoff value 3.75)24 and the present study (cutoff value 4.0) showed that LMR correlates with longterm prognosis. In contrast, Wu et al. (cutoff value 5.13)25 reported no such correlation. These studies, in conjunction with the meta-analysis, suggest that an LMR cutoff value of 4 is a good candidate for rectal cancer patients. Intrinsic inflammatory response in tumor tissue has been reported to not only play a defensive role against cancer but also serve as a promoter for cancer progression and metastatic spread.55 Therefore, high chronic inflammation could correlate with both poor and good prognosis. However, several markers of chronic inflammation such as high NLR, high platelet count, or elevated plasma fibrinogen have been investigated with respect to their correlation with prognosis in solid cancers. Activation of chronic inflammation correlated with poor prognosis, in every study investigating these markers.6,46,48 Similar to these chronic inflammation markers, decreased LMR showed a strong correlation with shorter OS. Because lymphocytes conduct immune surveillance in cancer patients and eliminate cancer cells, low lymphocyte count in peripheral blood weakens defenses, leading to an insufficient immune response to cancer and resulting in worse outcome.56,57 Pre-CRT low lymphocyte count is also a poor prognostic factor in rectal cancer patients who have undergone preoperative CRT.58 In tumor tissue, circulating monocytes have subsets such as M1 and M2 macrophages

abe et al  lmr predicts outcome in rectal cancer patients

and monocytic myeloid-derived suppressor cells (MDSCs); the number of macrophages reflects the number of M2 macrophages.17,59 M2 macrophages induce regeneration of tumor tissues damaged by irradiation, via chemokine receptor type 4.60 Monocytic MDSCs suppress anti-tumor immunity by reducing immune cell function, including that of cytotoxic T lymphocytes and natural killer cells via IL-10 and transforming growth factor-b, and by inducing immunosuppressive cells, such as regulatory T cells. In addition, MDSCs also induce resistance to 5-FU through IL-1b secretion.61 It is therefore expected that higher circulating monocytes indicate lower CRT efficacy and poorer prognosis. Accordingly, high LMR was expected to be associated with a good prognosis. Because a low pre-CRT LMR may be indicative of poor prognosis, the reinforcement of chemotherapy regimen with additional drugs might be beneficial for such patients. Chemotherapeutic agents such as oxaliplatin as part of CRT or induction/consolidation chemotherapy (chemotherapy before and after CRT) might be alternative options for such patients. Because physicians can predict prognosis using LMR, which is easily calculated from blood tests before treatment, unlike information obtained from surgical specimens after treatment, LMR is useful to decide treatment strategies. Furthermore, obtaining blood samples is minimally invasive and performed at all institutions. This study has several limitations. It is a retrospective study of a small cohort conducted at single institution; a large cohort, multi-institutional, prospective study is needed. The post-CRT LMR could be affected by the interval between the completion of CRT and sample collection. Thus, further investigation is needed to clarify the optimal interval between CRT completion and blood sampling. In addition, since the reported LMR cut-off values in rectal cancer patients vary, there is a need to determine the optimal cut-off value. In conclusion, low pre-CRT LMR predicted shorter OS in rectal cancer patients who underwent preoperative CRT.

Acknowledgment Authors’ contributions: S.A. acquired, analyzed, and interpreted the data, drafted the article, and approved the final submission. K.K. conceptualized and designed the study, interpreted the data, critically revised the manuscript, and approved the final submission. H.N. acquired and interpreted the data, critically revised the manuscript, and approved the final submission. K.H., T.K. acquired the data and approved the final submission. T.M. interpreted the data, critically revised the manuscript, and approved the final submission. T.W. conceptualized and interpreted the data, critically revised the manuscript, and approved the final submission. This research is supported by Grants-in-Aid for Scientific Research (A, grant number 16H02672; C, grant number 16K07143; C, grant number 16K07161; C, grant number 17K10620; C, grant number 10621; and C, grant number 17K10623) from Japan Society for the promotion of Science.

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This research is supported by the Project for Cancer Research and Therapeutic Evolution (P-CREATE, grant number: 16cm0106502h0001) from the Japan Agency for Medical Research and Development (AMED).

Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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