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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 438-444

Systemic inflammation-based predictors of pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients


Department of Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, China

Date of Submission11-Oct-2021
Date of Decision20-Jan-2022
Date of Acceptance25-Jan-2022
Date of Web Publication20-May-2022

Correspondence Address:
Wenliang Li
Department of Oncology, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Kunming 650032
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_1807_21

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 > Abstract 


Aim: To investigate whether systemic inflammation-based predictors can predict tumor response to neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC).
Materials and Methods: Totally, 205 LARC patients undergoing neoadjuvant CRT and curative surgery between 2008 and 2017 were analyzed. After propensity score matching, 132 patients were included in the study. Hematological parameters were collected, and their relationship with tumor response was investigated.
Results: After propensity score matching, patients in good response group before CRT displayed significantly lower neutrophil-lymphocyte-ratio (NLR) and platelet-lymphocyte-ratio (PLR) than those in poor response group, while there were no significant differences in all hematological characteristics between the two groups after CRT. The cutoff values of pre-CRT NLR and pre-CRT PLR after receiver operating characteristic analysis were 3.10 and 198.7, respectively. Multivariate analysis revealed that while there was no association between pre-CRT PLR and tumor response, pre-CRT NLR ≥3.1 was identified as the predictor of poor tumor response (P = 0.007).
Conclusion: An increased NLR before CRT can serve as a hematological factor for predicting a poor tumor response in LARC.

Keywords: Hematological parameters, locally advanced rectal cancer, neoadjuvant chemoradiotherapy, pathological tumor response, systemic inflammation-based predictors


How to cite this article:
Xu N, Li W, Huang F, Yang J, Wen Z, Yin L, Zhang Y, Zhao J, Zhou R, Yang J. Systemic inflammation-based predictors of pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients. J Can Res Ther 2022;18:438-44

How to cite this URL:
Xu N, Li W, Huang F, Yang J, Wen Z, Yin L, Zhang Y, Zhao J, Zhou R, Yang J. Systemic inflammation-based predictors of pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:438-44. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/438/345531




 > Introduction Top


Colorectal cancer is a common digestive tract malignant tumor with high morbidity and mortality.[1] Rectal cancer accounts for approximately a third of all colorectal cancers.[2] 45%–55% of patients with rectal cancer were diagnosed with locally advanced rectal cancer (LARC) and received neoadjuvant chemoradiotherapy (CRT).[3] After CRT, 50%–60% of the patients may show different degrees of tumor regression, while 10%–30% of them may have complete pathological response.[4] For those subjects with complete clinical response, conservative operation plan or watch-and-wait strategy is recommended.[5] However, the remaining 50% of nonpathological responders[6] fail to reduce tumor stage and benefit from CRT, thereby bearing a heavy financial burden as well as serious adverse consequences, such as side effects of CRT and tumor progression.[7] Therefore, evaluation of the pathological response of neoadjuvant CRT before surgery could contribute to improving the clinical treatment. In this case, blood test has good maneuverability for predicting or reflecting the therapeutic effect of CRT due to its simplicity.[8]

Tumor-related inflammation has been proved to be a key determinant of disease progression and survival.[9] According to Global Cancer Statistics, chronic inflammation can increase the risk of developing cancer, while it is linked to more than 15% of all cancer deaths.[10] Local and systemic inflammatory response is considered an important prognostic factor for colorectal cancer patients.[11] In recent years, much attention has been paid to systemic inflammatory response indicators for predicting the prognosis of rectal cancer after CRT.[12],[13] In particular, neutrophil-lymphocyte-ratio (NLR), monocyte-lymphocyte-ratio (MLR), and platelet-lymphocyte-ratio (PLR) have been identified as prognostic biomarkers for patients with rectal cancer.[13],[14],[15],[16] It has been suggested that NLR alone or pre-CRT NLR and PLR are independently related to tumor response.[17],[18] Ishikawa et al. proposed that NLR after CRT was more significant than that before the treatment.[12] At the same time, Shen et al. reported that an elevated baseline NLR was a predictor of long-term mortality in LARC patients treated with CRT.[19]

Herein, the purpose of this retrospective observational trial was to investigate the relationship between pathologic tumor response and hematologic parameters in LARC patients before and after CRT using propensity score-matched method. The findings in this study will help to determine whether blood parameters can serve as a potential indicator for predicting tumor pathological response in the patients.


 > Materials and Methods Top


Patients

This study enrolled a total of 205 LARC patients from January 2008 to December 2017. The inclusion criteria were specified as follows: The distance to the anal verge was <15 cm, and patients were histologically diagnosed as adenocarcinoma. LARC (cT3-4 and/or N+) was evaluated by pelvic high-resolution magnetic resonance imaging, intrarectal ultrasound, and computed tomography. All participants received neoadjuvant CRT and total mesorectal excision surgery.

This study was approved by the Ethics Committee of the XXX, and all subjects agreed to participate in the study with written informed consent.

Preoperative chemoradiotherapy and surgery

All patients underwent intensity-modulated radiation therapy (IMRT). The whole pelvis was covered in the radiation field, including the tumor or tumor bed, the surrounding tissues 2–5 cm away from the tumor, presacral lymph nodes, and internal iliac lymph nodes. A total radiation dose of 45–50.4 Gy with 1.8–2.0 Gy per fractions was used in IMRT. These patients received radiotherapy combined with oral administration of capecitabine (825 mg/m2) twice a week for 5 weeks. After CRT, they were given two cycles of consolidation chemotherapy (oxaliplatin 85 mg/m2 and capecitabine 1000 mg/m2).

Curative surgery was performed 8–11 weeks after the end of CRT, including laparoscopic or open anterior resection and abdominal-perineal resection surgeries. After surgery, the tumor node metastasis (TNM) staging and pathological tumor regression grading were conducted according to American Joint Committee on Cancer 8th edition TNM staging system[20] and TRG system proposed by Mandard et al.[21] Meanwhile, all cases were categorized into good response (GR) group (ypTNM0-1) and poor response (PR) group (ypTNM2-4) based on pathological TNM (pTNM) classification. The primary endpoint of the study was to determine the relationships between hematologic indicators and pathological response.

Hematologic markers

Hematologic parameters were collected at baseline (pre-CRT) and before surgery (post-CRT). Hemoglobin concentration, white blood cell count, neutrophil count, lymphocyte count, monocyte count, platelet count, and albumin level were measured by fully automatic hematology analyzer (Sysmex XE-2100). NLR, MLR, and PLR were defined as the ratios of neutrophils, monocytes and platelets to lymphocytes, respectively.

Statistical analysis

SPSS software (version 23.0, IBM, Armonk, NY, USA) and R (version 3.5) was used for the statistical analysis. A propensity score-matched method was adopted to construct multivariable logistic regression model based on age, gender, body mass index, distance to the anal verge, histologic grade, clinical stage, operation type, time of receiving CRT, TR surgery, as well as hemoglobin and albumin concentrations. Patients were matched by using 1:1 nearest-neighbor within a PS score of 0.03. This strategy produced 66 matched pairs in each group [Figure 1].{Figure }1

Continuous variables were described as either mean ± standard deviation for normally distributed ones or median (interquartile range) for abnormally distributed ones. In the meantime, categorical variables were expressed as absolute numbers (percentage). A Student's t-test or Mann–Whitney U-test and Chi-square or Fisher exact test were performed for between-group comparisons of continuous variables and categorical variables, respectively. After matching, both Mcnemar test for categorical variables and pared-samples Wilcoxon rank-sum test for continuous variables were carried out. The cutoff point for continuous variables was determined by the receiver operating characteristic (ROC) curves. Conditional logistic regression was conducted to determine the correlation between the main potential parameters and pathological response of tumors. A two-side P < 0.05 was considered statistically significant.


 > Results Top


Patient characteristics

This study included 105 patients in GR group and 100 cases in PR group. As illustrated in [Table S1], there was a significant difference in histologic grade between the two groups. The propensity score matching produced 66 pairs of patients in the two groups. Notably, the difference in histologic grade between the two groups of the matched patients was insignificant, suggesting that the data were comparable. Meanwhile, the elevated levels of pre-CRT and post-CRT carcinoembryonic antigen (CEA) were associated with the poor tumor response (P = 0.029 and 0.031, respectively).



Hematological characteristics

Before CRT, there were significant differences in lymphocyte count, NLR, PLR, and MLR between GR and PR groups (P = 0.006, 0.002, 0.008 and 0.043, respectively). After the adjustment with propensity score matching, GR group displayed notably lower NLR and PLR than PR group (P < 0.001 and = 0.013, respectively), while no significant differences in lymphocyte count and MLR were observed between the two groups [Table 1]. By contrast, after CRT, there were no statistically significant differences in all hematological parameters between the two groups before or after propensity score matching [Table 2].
Table 1: Hematological characteristics before chemoradiotherapy

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Table 2: Hematological characteristics after chemoradiotherapy

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Predictive factors for tumor response

The ROC curve analysis showed that the cutoff values of pre-CRT NLR and pre-CRT PLR were 3.10 and 198.7, respectively [Figure 2] and [Table 3]. Based on the cutoff values, all patients were divided into the two groups. We then performed a multivariate analysis model-based analysis to identify the factors with significant differences between the two groups. As shown in [Table 4], the analysis revealed that pre-CRT NLR could serve as a predictor of tumor response (P = 0.007), while pre-CRT PLR was not related to the tumor response (P = 0.486).
Figure 2: Receiver-operating characteristic curves of prechemoradiotherapy neutrophil-lymphocyte-ratio (preche moradiotherapyneutrophil-lymphocyte-ratio) and pre-chemo radiotherapy platelet-lymphocyte-ratio (pre-chemoradiotherapy platelet-lymphocyte-ratio) in predicting the tumor response

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Table 3: Predictive values of prognostic factors

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Table 4: Multivariate analysis of tumor response

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Survival analysis

In the study, all the patients were followed up until December 31, 2019 or until death. Among them, 59 were lost to follow-up. The median follow-up time was 41 months (range, 11–132 months). During the follow-up period, 32 patients suffered a cancer-specific death, while 40 cases had recurrence or metastasis. Patients were divided into two groups based on a pre-CRT NLR threshold of 3.1, and survival analysis was performed. As depicted in [Figure 3], the 5-year overall survival (OS) for patients with NLR ≥3.10 and those with NLR <3.10 was 64.5% and 82.2%, respectively, while the 3-year disease-free survival (DFS) for the two groups of patients was 38.7% and 77.2%, respectively. Statistically, there were significant differences in OS and DFS between the two groups (P = 0.024 and P < 0.001, respectively).
Figure 3: Kaplan − Meier curves of overall survival (a) or disease-free survival (b) of locally advanced rectal cancer patients with neutrophil-lymphocyte-ratio ≥3.10 or neutrophil-lymphocyte-ratio <3.10

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As illustrated in [Table 5], univariate analysis identified the worse TNM stage as a risk factor for OS and DFS. We then undertook the multivariate analysis by using the COX proportional hazards model. The analysis showed that while the high value of post-CRT CEA was a related factor for the 5-year OS (hazard ratio [HR] = 2.509, P = 0.049), poor TNM staging was related to the 3-year DFS (HR = 3.025, P = 0.002) [Table 6]. Clearly, elevated pre-CRT NLR was not an independent prognostic factor for OS or DFS.
Table 5: Univariate analysis of overall survival and disease-free survival

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Table 6: Multivariate analysis of overall survival and disease-free survival

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The relationship between neutrophil-lymphocyte-ratio and pathologic response

We collected and analyzed the NLR values before, during, and after CRT. As shown in [Figure 4]a, the values were elevated during the CRT and then decreased after CRT. Statistically, there was no significant difference in the lowest NLR value between the GR and PR groups (P = 0.805) [Figure 4]b.
Figure 4: (a) The distribution of neutrophil-lymphocyte-ratio values of locally advanced rectal cancer patients with a 10-day interval during chemoradiotherapy. (b) The neutrophil-lymphocyte-ratio nadir values of locally advanced rectal cancer patients with good response or poor response

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 > Discussion Top


The immune response of patients has important predictive significance in clinical prognosis as well as the efficacies of radiotherapy and chemotherapy.[22] The interaction of systemic and local inflammatory responses leads to a varying degree of leukocyte infiltration into tumors. Moreover, each leukocyte subtype, including neutrophils, lymphocytes, natural killer cells, and dendritic cells, participates in the formation of tumor microenvironment, being involved in cancer invasion and metastasis.[10] Thus, the degree of inflammation in cancer can serve as a biomarker for clinical prognosis and treatment response. The analysis of circulating leukocyte subsets such as NLR, PLR, and MLR has become the most convenient method, and numerous studies have demonstrated that the leukocyte subsets are linked to the prognosis of different cancers including gastric cancer, ovarian cancer, pancreatic cancer, and colorectal cancer.[15],[16],[23],[24],[25],[26] NLR, PLR, and MLR have been shown to be the predictors of pathological response in LARC patients. For examples, Kim et al. reported that NLR <2.0 and PLR <133.4 before CRT were associated with a better tumor response.[27] Moreover, while patients with baseline NLR >3 had poor tumor response,[17] NLR <5 before CRT was found to be related to a better tumor response.[18] In this study, we analyzed hematologic parameters including NLR, PLR, and MLR in LARC patients before and after CRT to identify the predictors of pathological tumor response, while adjusting the selection bias by using propensity score-matched method. The initial univariate analysis showed that while there were statistically significant differences in NLR, PLR, and MLR between the two groups of patients before CRT, no significant difference in MLR between the two groups after the matching was found. Moreover, the multivariate analysis identified NLR as the only significant predictor, suggesting that NLR >3.1 was related to a poor tumor response with an odds ratio of 4.452. This finding was similar to the previous study.[27] Besides, the survival analysis in this study revealed that patients with NLR >3.1 had poor OS and DFS, while pre-CRT NLR was not found to be an independent prognostic factor for OS or DFS. Overall, pre-CRT NLR may serve as a potential marker for predicting the tumor pathological response in LARC patients.

The cytotoxic effects of radiotherapy and chemotherapy can increase antigen recognition of necrotic tumor cells, thus affecting the local and systemic inflammatory response.[28] Therefore, it is possible to predict tumor response based on the values of NLR, PLR, and MLR after CRT. Caputo and Ishikawa suggested that NLR >3.80 and 3.85 after CRT could be used as the predictors of poor tumor response.[12],[29] However, no relationships between hematological factors and tumor response in patients after CRT were observed in the present study. This observation may be attributed to the uncontrolled factors affecting the systemic inflammatory response in the phase of case enrollment. Moreover, six cases had abnormally elevated neutrophils due to radiotherapy complications, whereas nine cases received treatment with granulocyte colony-stimulating factor during radiotherapy. Besides, hidden infections might underlie the differences in the data between the present study and others.

Multiple studies have shown that lymphopenia was correlated with poor survival.[30],[31] In this study, we identified NLR before CRT rather lymphocyte count as the predictive factor for tumor response. As shown in [Figure S1], the absolute lymphocyte count (ALC) declined during CRT and recovered after CRT. This dynamic change in ALC was consistent with the previous study.[32] Contrary to ALC, NLR exhibited an opposite trend during CRT. Strikingly, there were no differences in ALC and NLR nadir values between the different pathological response groups. Since the hematologic parameters will dynamically change with the accumulation of radiotherapy dose during CRT, it was difficult to accurately grasp the lowest point of the entire dynamic process by collecting blood data at a certain point in time. In the present study, the blood sampling interval during CRT was 10 d, which was different from that in other studies.[32] Thus, the difference in the intervals might yield different values of the parameters. In addition, the lack of control over confounding factors in retrospective studies could result in a difficulty in reproducing the data, although PSM was used to correct some confounding factors in the study. Therefore, prospective studies need to be conducted to verify these results.



There are still some limitations in this study. First, this was a retrospective study without controlling the factors that affect systemic inflammatory response. Second, the propensity matching reduced the sample size, leading to an insufficient evidence strength. Thus, prospective studies with a larger sample size are required for validating the conclusions.


 > Conclusion Top


The elevated NLR before CRT can serve as a hematological factor for predicting poor tumor response. NLR detection before CRT may help make a better treatment plan for LARC patients and ultimately improve their prognosis.

Financial support and sponsorship

This work was supported by National Natural Science Foundation of China (grant number 31660312), Yunnan Fundamental Research Projects (grant number 2019FA039) and Leading Medical Talents in Yunnan Province (grant number L-2017001).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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