INTRODUCTION
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide[1]. Despite advances in early identification and treatment, the prognosis for individuals with metastatic CRC remains dismal, especially those with peritoneal metastases (PM)[2]. Identifying reliable prognostic markers is crucial for optimizing treatment strategies and improving patient outcomes. In recent years, the functions of inflammatory and nutritional indicators have attracted attention as possible predictors of prognosis in many malignancies, including CRC[3].
This editorial aims to elucidate the significance of these markers in CRC, with a focus on their prognostic implications and potential to guide treatment decisions.
INFLAMMATION AND CANCER
The association between inflammation and cancer is extensively established[4]. Chronic inflammation can drive cancer development and progression by fostering a microenvironment conducive to tumor growth. Inflammatory cells and mediators are involved in facilitating genetic mutations, promoting cell proliferation, and inhibiting apoptotic processes[5]. Additionally, inflammation can stimulate angiogenesis and support metastatic spread by modifying the extracellular matrix and aiding the migration of cancer cells[6].
NEUTROPHIL-TO-LYMPHOCYTE RATIO IN CRC
Among the various inflammatory markers examined for their prognostic relevance in CRC, the neutrophil-to-lymphocyte ratio (NLR) stands out as a particularly valuable indicator. Neutrophils can accelerate tumor growth by releasing pro-inflammatory cytokines and proteases, whereas lymphocytes are crucial for antitumor immunity. A high NLR, reflecting a predominance of neutrophil-driven inflammation over lymphocyte-mediated immune response, has been correlated with adverse outcomes in multiple cancers, including CRC[7].
NLR is computed by dividing the absolute count of neutrophils by the absolute count of lymphocytes, and it is a readily available, cost-effective marker derived from routine blood tests. A meta-analysis by encompassing 959 rectal cancer patients from seven studies, assesses the prognostic value of the NLR. Elevated NLR was significantly associated with poor overall survival (OS) [hazard ratio (HR) = 13.408], disease-free survival (DFS) (HR = 4.368), and recurrence-free survival (referred to as RFS) (HR = 3.636). Sensitivity analysis confirmed the reliability and stability of these results, with no significant publication bias detected. These studies suggest that, while NLR is a cost-effective and readily available marker compared to other inflammatory indices like the platelet-lymphocyte ratio and modified Glasgow prognostic score (referred to as mGPS), it is not without limitations. Elevated NLR can also result from non-cancerous conditions, and variability in study design and cutoff values adds heterogeneity. Despite these limitations, NLR remains a promising prognostic tool for rectal cancer, useful for patient stratification and treatment planning[8,9].
The precise mechanisms by which a high NLR contributes to poor prognosis are not entirely clear. However, it is proposed that elevated neutrophil levels might facilitate tumor progression by enhancing angiogenesis, tumor cell proliferation, and metastasis, while a lower lymphocyte count may signify compromised immune surveillance and diminished antitumor immune response. Thus, a high NLR might signal an aggressive tumor phenotype and a weakened immune system, both associated with poorer clinical outcomes[10].
HEMOGLOBIN AND CANCER PROGNOSIS
Anemia, frequently observed in cancer patients, often correlates with unfavorable outcomes[11]. Low hemoglobin (Hb) levels in CRC patients are associated with systemic inflammation, while microcytic anemia is linked to advanced tumor stages and proximal tumor locations. Proximal colon tumors are more likely to cause microcytic anemia, whereas systemic inflammation is related to normocytic anemia. The connection between anemia and systemic inflammation suggests that managing inflammation may help in treating anemia in CRC[12].
An analysis of 592 CRC patients examined the impact of preoperative anemia subtypes—derived from Hb and mean corpuscular volume (referred to as MCV) levels—on patient outcomes, along with related systemic inflammation, nutritional status, and perioperative blood transfusions. Results indicated that preoperative anemia was significantly associated with worse OS and RFS, with microcytic anemia showing a trend toward poorer RFS compared to other anemia types. Preoperative anemia correlated with right-sided tumors, deeper tumor invasion, neoadjuvant chemotherapy use, a poorer prognostic nutritional index (PNI), and higher mGPS. Microcytic anemia, in particular, was strongly associated with greater tumor invasion depth and higher mGPS[13]. Another study by 300 patients who underwent CRC surgery investigated the association between pre-diagnosis symptoms and advanced disease stages. The study found significant correlations between highly advanced CRC (TNM stages 2–4) and factors such as larger tumor size (4.8 cm vs 2.6 cm), presence of any symptoms prior to diagnosis (77% vs 54% anemia (46% vs 29%), and severe anemia (17% vs 4%). Mean Hb levels were lower in patients with highly advanced CRC (12.2 ± 2.2) compared to those with locally advanced CRC (13.1 ± 1.8, P < 0.001). Anemia was notably associated with higher T stages of the tumor, with 66% of patients at stage 4 presenting with anemia compared to 21% at stages 0–1. The findings suggest that anemia is a significant indicator of advanced CRC and should prompt further investigation and management to assess the extent of the disease[14].
NUTRITIONAL STATUS AND CANCER PROGNOSIS
Malnutrition and muscle wasting are common issues in cancer patients, either due to the tumor itself or as a result of oncologic treatments. Cancer-associated sarcopenia significantly impacts morbidity, mortality, treatment-related toxicities, hospitalizations, adherence to therapy, quality of life, and survival. Early detection and management of nutritional problems through baseline screening, regular reassessments, and dietary support can improve patient outcomes. Screening tools such as nutritional risk screening, mini nutritional assessment, and patient generated subjective global assessment are widely used, while more precise tools like skeletal muscle index and bioelectric impedance analysis offer detailed body composition assessments but are more complex. Despite their potential benefits, nutritional assessments are not yet standard practice, and standardization is needed to enhance the effectiveness of chemotherapy and other treatments[15].
Albumin, a major plasma protein produced by the liver, is influenced by factors including inflammation, liver function, and nutritional intake. Nutritional markers such as serum albumin have been studied for their prognostic significance in CRC[16]. Several studies have demonstrated the prognostic value of pretreatment serum albumin levels in CRC patients. Heys et al[17] were among the first to show that lower serum albumin levels independently predict poorer survival in CRC patients. They reported that each 0.5 g/dL decrease in serum albumin was associated with a 25% increased risk of death[17]. Subsequent research highlighted the significance of preoperative hypoalbuminemia, particularly in localized colon cancer. For instance, a Taiwanese study with 3849 patients found that low serum albumin levels predicted higher postoperative mortality and complications, including wound-healing issues and pulmonary morbidities. Another study noted that lower albumin levels in patients with metastatic disease were linked to larger tumor sizes and poorer prognosis due to systemic inflammation affecting albumin production[18].
In terms of surgical outcomes, hypoalbuminemia was identified as an independent risk factor for poor survival in rectal cancer patients, though it did not impact short-term postoperative survival. A systematic review by Gupta et al[19] reinforced that high albumin levels generally correlate with better survival across various gastrointestinal cancers, though the findings were limited by differences in how albumin levels were analyzed and the heterogeneity among studies[19].
Some studies, like Boonpipattanapong et al[20], found that hypoalbuminemia alone did not significantly affect survival but became a useful prognostic marker when combined with other indicators, such as carcinoembryonic antigen (referred to as CEA) levels[20]. Despite these insights, there remains variability in the impact of preoperative serum albumin levels on CRC prognosis, and more standardized approaches are needed to optimize its predictive value[16].
INTEGRATING INFLAMMATORY AND NUTRITIONAL MARKERS IN CRC PROGNOSIS
Combining inflammatory and nutritional markers offers a more comprehensive assessment of CRC prognosis[21]. A study analyzed the prognostic value of the PNI, Systemic Inflammation Response (referred to as SIR) markers, and the GPS in CRC patients. The findings revealed significant associations between PNI and various clinical factors including TNM staging, distant metastasis, and several biomarkers such as NLR, CEA, CA199, and albumin. GPS showed significant correlations with age, TNM staging, distant metastasis, NLR, CA199, albumin, and C-reactive protein (CRP). The study concluded that combining PNI, SIR markers, and GPS with TNM staging provides valuable insights into CRC diagnosis and prognosis, highlighting their importance in evaluating disease staging and predicting metastasis[22]. A study involving 286 patients with stage I-III CRC who underwent curative resection examined the association between OS and factors related to nutritional status and inflammation. Using Kaplan-Meier curves and log-rank tests, the study found that serum albumin, cholesterol, CRP concentration, neutrophil count, and platelet count were correlated with OS. A new risk model, termed Nutrition Inflammation Status, was developed[23]. A retrospective analysis of preoperative fasting blood samples from 2471 CRC patients assessed various prognostic factors using univariate and multivariate analyses. Survival curves were generated with the Kaplan–Meier method, and survival differences were measured with the log-rank test. The analysis identified that the CRP/MCV ratio, TNM stage, tumor differentiation, right-sided tumors, age, CEA levels, and CRP levels were significantly associated with poor prognosis, while adjuvant chemotherapy was a protective factor. Multivariate analysis highlighted that elevated CRP/MCV ratio, advanced TNM stage, and poor tumor differentiation were independent risk factors for poor prognosis. Subgroup analysis confirmed that these factors independently affected survival in patients with lymph node-positive CRC. A novel nomogram incorporating these indicators demonstrated greater prognostic value and clinical significance for predicting outcomes in patients with lymph node-positive, poorly differentiated tumors at advanced stages. The study concluded that early intervention is crucial for advanced-stage patients with severe inflammation and poor nutritional status[24].
The retrospective study involved 262 patients with stage III CRC who underwent curative surgery. Patients were divided into a training set (referred to as TS) of 162 patients and a validation set of 100 patients. The study developed a new prognostic model based on clinicopathological factors assessed using Cox regression analysis in the TS. Multivariate analysis identified lymph node metastasis (N2), low albumin, high monocyte counts, and low platelet counts as independent risk factors for DFS. The Kansai Prognostic Score (referred to as KPS) was created, with C-indices of 0.618 for DFS and 0.708 for OS. The KPS demonstrated significant predictive value for both DFS and OS[25]. A study with 511 CRC patients introduced the Osaka Prognostic Score (OPS), which includes CRP, albumin levels, and lymphocyte counts. The OPS was shown to be a reliable predictor of both DFS and OS, with higher C-indexes compared to other scoring systems. Notably, the integration of OPS with TNM staging improved the predictive accuracy for patient prognosis[26].
Overall, these findings support the integration of inflammation and nutritional scores with traditional staging systems to enhance prognostic accuracy in CRC patients. The combined use of such indicators can provide a more nuanced understanding of patient outcomes, guiding more personalized treatment strategies and improving OS rates.
CONCLUSION
The integration of inflammatory and nutritional markers with conventional staging systems marks a significant progress in CRC prognostication. Research shows that indicators such as the NLR, Hb levels, and albumin, when used alongside PNI, GPS, and OPS, provide crucial insights into patient outcomes. These markers reflect both the systemic effects of cancer and a detailed evaluation of the patient’s inflammatory and nutritional status. Utilizing these markers in prognostic models improves the precision of predicting disease advancement and OS, facilitating more personalized treatment plans. High-risk patients identified through these combined scores may require more intensive treatment and monitoring, which could enhance their prognosis. Furthermore, tailored nutritional support and interventions can lead to better health outcomes and improved quality of life. Future research should aim to validate these results in larger, multicenter studies to confirm their prognostic significance and develop standardized cutoff values for clinical practice. Exploring the mechanisms linking inflammation, nutrition, and cancer progression could uncover new therapeutic targets, offering additional avenues for treatment and better patient management.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: Türkiye
Peer-review report’s classification
Scientific Quality: Grade D
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Yan Y S-Editor: Liu H L-Editor: Filipodia P-Editor: Wang WB
