Evaluation of the Prognostic Utility of the Postoperative Inflammatory Burden Index in Colorectal Cancer

Abstract

Introduction

This study aimed to evaluate the significance of the postoperative inflammatory burden index (IBI) as a prognostic marker and to investigate the clinical outcomes of patients with stage II and III colorectal cancer who underwent colorectal surgery.

Methods

This retrospective study included 223 patients who underwent colorectal surgery for stage II and III colorectal cancers. The patients were divided into four groups based on postoperative IBI on days 1 and 7 (high or low): Group 1 (low & low, n = 118), Group 2 (high & low, n = 18), Group 3 (low & high, n = 56), and Group 4 (high & high, n = 31). The clinical impact of the postoperative IBI on recurrence-free survival (RFS) and overall survival (OS) was also evaluated.

Results

High postoperative IBI was significantly associated with decreased RFS and OS. The Kaplan-Meier survival curves for RFS and OS in stage II and III colorectal cancer showed a decline in Groups 2, 3, and 4, with a more pronounced decline observed in Group 4 (p = 0.001 and p = 0.007, respectively).

Conclusions

This study suggests that the postoperative IBI may be a prognostic marker for RFS and OS in patients with stage II and III colorectal cancer. When postoperative IBI on days 1 and 7 is high, these findings may indicate a high-risk factor for the recurrence of colorectal cancer. Postoperative IBI is useful in establishing postoperative oncological surveillance and adjuvant chemotherapy strategies.

Keywords

Inflammatory burden index - colorectal cancer - stage II and III - postoperative

Introduction

Colorectal cancer is one of the most commonly diagnosed malignancies worldwide and is associated with a high frequency of morbidity and mortality.[1] [2] The Tumor Node Metastasis (TNM) classification system has played a crucial role in guiding therapeutic decisions; however, significant prognostic variations can exist, even among patients at the same stage of the disease.[3] The systemic inflammatory response has a significant impact on the progression and prognosis of various cancers.[4] Therefore, easily predictable markers for predicting recurrence are necessary to improve the prognosis of patients with colorectal cancer.

In this study, we evaluated the inflammatory burden index (IBI), which has recently been highlighted as a practical prognostic predictive marker.[5] [6] [7] The IBI score was calculated as the C-reactive protein (CRP) level multiplied by the neutrophil-to-lymphocyte ratio (NLR).[5] [6] [7] The NLR is an inflammation-based score calculated as the serum neutrophil count divided by the lymphocyte count.[8] Relative to other inflammatory markers, the IBI has emerged as an accurate biomarker for predicting survival outcomes in patients with cancer.[9] Among the most frequently used indices related to the systemic inflammatory response, the IBI has shown the best predictive capability in terms of cancer-specific survival.[10] There are few reports on the IBI in colorectal cancer, and all have focused on the preoperative IBI.[5] [6] [7] No previous studies have analyzed the prognosis of colorectal cancer patients with a focus on postoperative changes in IBI. This is the first report to focus on postoperative IBI in colorectal cancer patients and provide an evaluation of clinical outcomes.

Methods

Patients and Methods

This study was a retrospective analysis involving 223 consecutive patients who underwent colorectal surgery for stage II and III colorectal cancer at the Department of Surgery, Japanese Red Cross Society Karatsu Red Cross Hospital, between January 2013 and July 2019. A thorough review of the patients' medical records was conducted. The inclusion criterion was histological confirmation of colorectal adenocarcinoma. Patients with missing postoperative IBI data were excluded from the analysis.

In this study, 223 patients were categorized into four groups based on the postoperative IBI on days 1 and 7: Group 1 (low & low, n = 118), Group 2 (high & low, n = 18), Group 3 (low & high, n = 56), and Group 4 (high & high, n = 31). All the patients and their family members were given information about the surgery and signed written informed consent. The study received approval from the Medical Ethics Committee of our institution (approval number: 23-I-17–01).

Approach

Preoperative confirmation of colorectal cancer was made through colonoscopy and pathological examination. Detailed analysis was conducted on patient characteristics as well as preoperative, intraoperative, and postoperative parameters. The medical records were reviewed to collect patient characteristics as well as preoperative, operative, and postoperative parameters, with the details presented in [Table 1].

Table 1 Background of the patients and the results of the univariate analyses

	Recurrence
	(-) n = 180	(+) n = 43	P-value
Patient factors
Gender (male: female)	97:83	24:19	0.866
Age (years.; median [IQR])	71 [64–80]	72 [66–81]	0.563
Body mass index (kg/m2; median [IQR])	22.4 [20.2–24.7]	22.4 [20.5–24.8]	0.811
ASA-PS (PS1: PS2,3)	33:147	6:37	0.656
Currently smoking (yes:no)	34:146	11:32	0.397
Currently drinking alcohol (yes:no)	70:110	16:27	0.864
Diabetes mellitus (yes:no)	32:148	15:28	0.021
Hemoglobin (g/dl; median [IQR])	11.6 [9.6–13.3]	12.2 [10.3–13.4]	0.326
Albumin (g/dl; median [IQR])	3.9 [3.4–4.2]	3.9 [3.3–4.3]	0.580
CEA (median [IQR])	3.7 [2.2–6.2]	7.7 [3.0–25.8]	0.001
CA19–9 (median [IQR])	8.4 [3.4–17.5]	20.1 [5.6–48.8]	0.001
Preoperative bowel obstruction (yes:no)	25:155	12:31	0.038
Preoperative chemotherapy (yes:no)	8:172	5:38	0.138
Tumor factor
Tumor location (right: left)	76:104	13:30	0.168
T category (T0–3: T4)	75:105	19:24	0.864
N category (negative:positive)	92:88	9:34	<0.001
Lymphatic invasion (negative:positive)	40:140	12:31	0.428
Venous invasion (negative:positive)	25:155	5:38	0.808
Histological type (tub: por, sig)	166:14	37:6	0.233
Operative factor
Surgical procedure (open: laparoscopic)	7: 173	2:41	0.686
Operative time (min; median [IQR])	282 [210–392]	353 [213–450]	0.205
Intraoperative bleeding (ml; median [IQR])	35 [10–119]	95 [10–250]	0.019
Blood transfusion (yes:no)	10:170	4:39	0.481
Additional operative procedure (yes:no)	18: 162	5: 38	0.781
Lymph node dissection (D1&2: D3)	16:164	2: 41	0.537
Postoperative factor
Any complication ≥CD3 (yes:no)	16:164	9:34	0.033
Infectious complication ≥CD3 (yes:no)	8:172	4:39	0.253
Anastomotic leakage ≥CD3 (yes:no)	2:178	2:41	0.168
Postoperative stay (days; median [IQR])	13 (10–18)	18 (11–28)	0.007
Postoperative chemotherapy (yes:no)	94: 86	22: 21	>0.999
Inflammatory burden index
Preoperative (median [IQR])	0.41 [0.17–1.34]	0.63 [0.17–3.92]	0.268
POD1 (median [IQR])	34.51 [22.00–58.76]	47.96 [25.58–81.32]	0.021
POD7 (median [IQR])	3.83 [1.49–9.67]	8.61 [2.65–25.28]	0.004

Abbreviations: CD, Clavien-Dindo; IQR, interquartile range; POD, post-operative day.

Ratio Numbers in bold represent statistically significant findings.

Operation and Patient Follow-up

All patients underwent either open or laparoscopic surgery with comprehensive lymph node dissection. For colon cancer, a complete mesocolic excision was performed, while for rectal cancer, tumor-specific mesorectal excision or total mesorectal excision was performed. The pathological tumor stage was classified according to the eighth edition of the UICC-TNM classification. Postoperative complications were defined using the Clavien–Dindo (CD) classification.[11] [12] Following surgery, CEA and CA19–9 levels were monitored every three months at a minimum, with computed tomography performed every six months and annual colonoscopies for cancer monitoring. The study's primary outcomes were recurrence-free survival (RFS) and overall survival (OS), based on postoperative IBI. The length of follow-up was calculated from the time of surgery to the most recent clinical note in the patient's medical record.

Statistical Methods

Continuous variables were presented as the median with interquartile range (IQR), while categorical variables were represented by frequencies. In the univariate analysis, Wilcoxon's rank-sum test was used for continuous variables, and Fisher's exact test was used for binary variables. Receiver operating characteristic (ROC) analyses and calculation of the area under the curve (AUC) were used to determine the cutoff values for postoperative IBI on days 1 and 7, which were then used to divide the patients into four groups. Continuous variables were converted into binary categories based on the optimal cutoff values identified through ROC analysis, with the optimal cutoff being the point on the ROC curve corresponding to the highest Youden index. Univariate and multivariate analyses of RFS were performed using a Cox regression analysis. A stepwise multiple Cox regression analysis was performed as a multivariate analysis. Variables that showed statistical significance (p < 0.1) in the univariate analysis were included in the multivariate analysis. The data are expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). RFS and OS during the follow-up period were assessed using the Kaplan-Meier method. P values of <0.05 were considered to indicate statistical significance. All analyses were conducted using SPSS (ver. 25; IBM Japan, Tokyo, Japan).

Results

Among 223 colorectal cancer patients (102 males and 121 females) who underwent curative surgery, 118 (52.9%) had low IBI values on both postoperative day 1 (POD1) and day 7 (POD7) (Group 1, low & low), 18 (8.1%) had high IBI values on POD1 and low IBI values on POD7 (Group 2, high & low), 56 (25.1%) had low IBI values on POD1 and high values IBI on POD7 (Group 3, low & high), and 31 (13.9%) had high IBI on both POD1 and POD7 (Group 4, high & high).

[Table 1] shows the results of the univariate analysis of the patients' backgrounds and their characteristics. During the observation period, 19% (43/223) of the patients experienced recurrence. Univariate analyses identified significant differences in the following factors between patients with and without recurrence: diabetes mellitus (p = 0.021), carcinoembryonic antigen (CEA) (p = 0.001), carbohydrate antigen 19–9 (CA19–9) (p = 0.001), preoperative bowel obstruction (p = 0.038), lymph node metastasis (P < 0.001), intraoperative bleeding (p = 0.019), any complication (CD ≥3) (p = 0.033), postoperative stay (p = 0.007), IBI at POD1 (p = 0.021), and IBI at POD7 (p = 0.004). There were no significant differences in the following factors: sex, age, body mass index, ASA-PS, smoking and drinking habits, hemoglobin, albumin, preoperative chemotherapy, tumor location, T category, lymphatic invasion, venous invasion, histological type, surgical procedure, operative time, blood transfusion, additional operative procedure, lymph node dissection, infectious complications (CD ≥3), anastomotic leakage (CD ≥3), postoperative chemotherapy, and preoperative IBI.

[Table 2] shows the results of univariate and multivariate Cox regression analyses of RFS. In univariate analysis, diabetes mellitus (p = 0.032), increased CA19–9 (p < 0.001), lymph node metastasis (p = 0.037), any CD Grade ≥3 complication (p = 0.019), CD Grade ≥3 anastomotic leakage (p = 0.018), high IBI on POD1 (p < 0.001), and high IBI on POD7 (p < 0.001) were identified as risk factors for recurrence. In the multivariate analysis, increased CA19–9 (HR 1.005, 95% CI 1.002–1.009, p = 0.002), high IBI on POD1 (HR 1.959, 95% CI 1.094–3.597, p = 0.024), and high IBI on POD7 (HR 2.047, 95% CI 1.121–3.740, p = 0.020) were identified as independent risk factors for recurrence.

Table 2 Univariate and multivariate analysis of Recurrence -Free Survival using the Cox regression analysis

Variables	Univariate		Multivariate
	HR (95% CI)	P-value	HR (95% CI)	P-value
Diabetes mellitus	1.832 (1.052–3.190)	0.032	1.417 (0.781–2.570)	0.251
CEA	1.005 (0.998–1.010)	0.075	0.999 (0.990–1.007)	0.826
CA19–9	1.005 (1.002–1.007)	<0.001	1.005 (1.002–1.009)	0.002
Tumor location: right	1.520 (0.880–2.626)	0.133	0.706 (0.389–1.280)	0.159
Preoperative bowel obstruction	1.590 (0.859–2.945)	0.140	1.240 (0.629–2.444)	0.535
Lymph node metastasis	1.767 (1.030–3.029)	0.037	0.732 (0.416–1.286)	0.278
Any complication ≥ CD3	2.187 (1.135–4.214)	0.019	1.056 (0.467–2.387)	0.897
Anastomotic leakage ≥ CD3	4.117 (1.280–13.248)	0.018	0.719 (0.091–5.659)	0.754
High IBI on POD1	2.526 (1.502–4.248)	<0.001	1.959 (1.094–3.597)	0.024
High IBI on POD7	2.514 (1.490–4.244)	<0.001	2.047 (1.121–3.740)	0.020

Abbreviations: CI, Confidence intervals; CD, Clavien-Dindo; POD, Post-operative day.

Numbers in bold represent statistically significant findings.

To examine the impact of postoperative IBI on the prognosis, an ROC analysis was performed to determine the cutoff value of the IBI. The Youden index was calculated, and the IBI values on POD1 and POD7 were 66.32 (AUC: 0.614, P-value: 0.025, sensitivity: 39.5%, specificity: 82.2%) and 6.142 (AUC: 0.643, P-value: 0.009, sensitivity: 62.8%, specificity: 66.7%), respectively. The Kaplan-Meier analysis of RFS in stage II and III colorectal cancer showed a significant decrease in patients with high postoperative IBI (Groups 2–4), with an even more pronounced decrease observed in patients with high IBI on both POD1 and POD7 (Group 4) (p = 0.001, [Fig. 1a]). Similarly, the Kaplan-Meier analysis of OS in stage II and III colorectal cancer showed a significant decrease in patients with high postoperative IBI (Group 2–4), with an even greater decrease observed in patients with high IBI on both POD1 and POD7 (Group 4) (p = 0.007, [Fig. 1b]).

Fig. 1 Comparisons among the four groups (Group 1, low & low; Group 2, high & low; Group 3, low & high; Group 4, high & high) in stage II and stage III colorectal cancer. The correlation between postoperative IBI and RFS (a). The correlation between postoperative IBI and OS (b).

Discussion

This study aimed to evaluate the prognostic impact of postoperative IBI in patients with stage II and III colorectal cancer who received curative treatment. In addition, this study is the first to investigate postoperative IBI and the significance of postoperative changes. The main finding was that postoperative IBI could be a prognostic factor for both RFS and OS in colorectal cancer patients. The systemic inflammatory response associated with cancer is an important sign of tumor progression.[6] In recent years, various prognostic indicators combining existing biomarkers have been reported. Inflammation-based prognostic markers, including the NLR,[5] [6] [7] platelet-to-lymphocyte ratio,[13] [14] [15] Glasgow Prognostic Score,[16] [17] [18] and CRP-albumin-lymphocyte index (CALLY),[19] [20] [21] have been identified as prognostic factors in patients with colorectal cancer. These markers are readily available in routine blood tests for cancer patients, and their effectiveness has been reported. However, IBI demonstrated the best predictive capability in terms of cancer-specific survival among all the most frequently used systemic inflammatory response-related indices.[5] [10]

IBI is an indicator composed of three important parameters: the serum CRP level, neutrophil count, and lymphocyte count. CRP is a noninvasive biomarker produced by the liver in response to acute infection, and it can activate complement and promote inflammation, potentially leading to more severe disease.[22] [23] Neutrophils are not only the main component of white blood cells but also induce various cancer-promoting factors, including neutrophil elastase, matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor (VEGF).[24] Lymphocytes are immune defense cells that inhibit tumor cell growth and proliferation by enhancing immune surveillance, and the increased infiltration of lymphocytes into the tumor microenvironment is associated with better outcomes.[25] [26] IBI not only provides a comprehensive depiction of the host's immune response and systemic inflammation but also offers a reliable prognostic tool, potentially demonstrating superior power for predicting patient outcomes.[6]

Several studies have confirmed that the IBI is an effective prognostic marker for various types of cancers. The IBI was demonstrated to be a significant prognostic factor for both RFS and OS in patients with esophageal cancer who received curative treatment.[27] Additionally, the IBI may be associated with postoperative complications and OS in patients with gastric cancer who receive multimodal treatment.[9] Furthermore, high IBI was a poor prognostic factor for both RFS and OS in patients with hepatocellular carcinoma after hepatectomy,[28] and it was independently associated with OS, length of hospitalization, hospitalization expenses, and cachexia in patients with non-small cell lung cancer.[29] In the past, there have been three reports on the prognostic value of IBI in colorectal cancer patients, all of which focused on the preoperative IBI.[5] [6] [7] However, there have been no reports on the postoperative IBI. Therefore, the present study examined the usefulness of the postoperative IBI as a prognostic biomarker for patients with colorectal cancer. In addition, since single-point assessments, such as those in past reports, lack reliability,[4] this study evaluated two points (POD1 and POD7).

The present study suggests that colorectal cancer patients with high postoperative IBI values have significantly worse RFS and OS than those with low postoperative IBI values; in particular, patients with high IBI values at both postoperative time points (Group 4) showed especially poor outcomes. Interestingly, patients with high postoperative IBI values at one of the two time points (Groups 2 and 3) had relatively good OS despite having poor RFS. These results suggest that patients with potentially stronger immune responses may benefit more from postoperative adjuvant chemotherapy.

It is possible that different mechanisms are involved in the increase in IBI on POD1 and POD7. A high IBI on POD1 is associated with abnormalities in the patient's inherent immune function and with severe surgical invasion. In cancer patients, dysregulation of the balance between pro-inflammatory and anti-inflammatory processes has been suggested to contribute to tumor growth, progression, and metastasis.[30] On the other hand, a high IBI on POD7 was associated with postoperative infectious complications. The association with decreased long-term survival after colorectal cancer resection is primarily driven by infectious complications, particularly severe postoperative infections.[31] Given the critical role of systemic inflammation and the immune response in the progression of colorectal cancer, regular monitoring of postoperative IBI could help identify high-risk patients. In addition to staging based on the TNM classification, the identification of postoperative IBI could lead to the identification of high-risk colorectal cancer patients, potentially significantly improving patient outcomes through postoperative adjuvant chemotherapy and other appropriate treatment approaches.

This study was associated with several limitations. First, this was a retrospective study. Second, the study was conducted at a single institution and had a relatively small population. Third, the appropriateness of the cutoff value of IBI remains uncertain. Therefore, further studies are needed to confirm the association between postoperative IBI and the prognosis in colorectal cancer.

In conclusion, this study suggests that postoperative IBI may be an independent prognostic marker for RFS and OS in patients with stage II and III colorectal cancer. The evaluation of the postoperative IBI may suggest indications for adjuvant chemotherapy in patients with colorectal cancer and may be useful in developing postoperative surveillance strategies.

Conflict of Interests

The authors declare no competing interests.

Availability of Data and Materials

The data generated in the present study may be requested from the corresponding author.

Authors' Contribution

SF: study design, data collection, interpretation of results, manuscript writing, manuscript editing; MH: study design, data collection, data analysis, interpretation of results, manuscript writing, manuscript editing; NK: data collection, manuscript editing; NKo: data collection, manuscript editing; MS: data collection, manuscript editing; AI: data collection, manuscript editing; RS: data collection, manuscript editing, study supervision, final manuscript approval. All authors read and approved the final manuscript.

Ethics Approval and Consent to Participate

The Medical Ethics Committee of the Japanese Red Cross Society Karatsu Red Cross Hospital reviewed and approved the study design (permission number: 23-I-17–01). All the patients and their families were informed of the surgical procedure and provided written informed consent.

Consent for Publication

Informed broad consent for this study was obtained.

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Publikationsverlauf

Eingereicht: 09. März 2025

Angenommen: 22. Mai 2025

Artikel online veröffentlicht:
10. September 2025