Prognostic significance of nutritional and inflammatory markers in colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related mortality worldwide, responsible for approximately 900000 deaths annually. Inflammation and malnutrition significantly influence patients' responses to treatment. Markers such as serum albumin concentration, the prognostic nutritional index, nutritional risk index (NRI), geriatric NRI, and the systemic immune-inflammation index enable the early identification of high-risk patients, facilitating timely interventions that can improve survival and reduce morbidity. A comprehensive understanding and application of these markers allow for better risk stratification in CRC patients, optimizing their management and outcomes.

Key Words: Colorectal; Cancer; Markers; Inflammation; Prognosis

Core Tip: Colorectal cancer (CRC) patients are significantly impacted by weight loss, cancer-associated sarcopenia, and malnutrition, all of which affect prognosis and treatment adherence. There is a growing body of evidence highlighting the prognostic significance of nutritional and inflammatory markers in CRC. Integrating these markers into patient screening is crucial for identifying high-risk patients and implementing preemptive measures to improve outcomes.

INTRODUCTION

Colorectal cancer (CRC) is the second most lethal cancer and the third most prevalent cancer worldwide according to the latest data. In 2020, there were over 1.93 million new CRC cases and 935000 deaths globally, representing approximately 10% of all new cancer cases and cancer-related deaths[1]. Growing evidence indicates that malnutrition is a common hallmark in cancer patients, often leading to unintentional weight loss due to inadequate nutrient intake or absorption[2]. Proper preoperative nutrition is crucial in the management of CRC patients, as weight loss, nutrient malabsorption, and metabolic alterations can negatively affect postoperative outcomes and long-term prognosis[3]. Chronic inflammation plays a central role in genomic instability by inducing DNA damage, impairing DNA repair mechanisms, and disrupting cell cycle checkpoints. These processes contribute to carcinogenesis, including in colorectal cells[4]. Furthermore, malnutrition can worsen several aspects of cancer treatment and outcomes by reducing treatment intensity, increasing toxicity, impairing quality of life, and ultimately decreasing survival rates.

The use of biomarkers to predict postoperative complications and guide perioperative management is becoming increasingly common across various types of cancers[5,6]. The ability to combine inflammatory and nutritional markers enables us to achieve a more comprehensive assessment of CRC prognosis. Tez[7] conducted an article evaluating the prognostic value and utility of inflammatory and nutritional markers in patients with metastatic CRC. The nutritional markers assessed included albumin concentration, the prognostic nutritional index (PNI), and the geriatric nutritional risk index (GNRI). The inflammatory markers evaluated were the systemic immune-inflammation index (SII) and the neutrophil-to-lymphocyte ratio (NLR). With this editorial, we aim to provide a comprehensive review of the existing literature and examine the clinical applications and prognostic significance of inflammatory and nutritional markers in CRC.

NUTRITIONAL MARKERS

Serum albumin concentration

Serum albumin is a simple and reliable marker for estimating protein levels in the body. The normal range for albumin is defined as 3.5-5 g/dL, while hypoalbuminemia is characterized by albumin levels below 3.5 g/dL, however, it should be noted that the normal range of serum albumin levels varies between institutions. There is an inverse correlation between body mass index and albumin synthesis. Inflammation in late-stage cancer patients suppresses albumin production[8]. In cancer patients, reduced serum albumin concentrations may be attributed to the production of cytokines, such as IL-6, which modulate albumin synthesis by hepatocytes[9]. Hypoalbuminemia, often seen in patients with poor nutritional status, can impair immune responses[2]. Various observational studies have shown the prognostic significance of pretreatment serum albumin levels in CRC patients. Heys et al[1] were the first to report that low serum albumin levels were independent predictors of poor survival in these patients. Their research showed that each 0.5 g/dL decrease in serum albumin was associated with a 25% increased risk of death[1].

In cancer patients low albumin levels can also be exacerbated by comorbidities such as acute renal failure, and chronic heart failure with prevalence of hypoalbuminemia ranging from 20%-90% of frail cancer patients[10].

Additionally, evidence suggests that serum albumin concentration is linked to in-hospital mortality in cancer patients[11].

PNI

The PNI is used to assess the immune and nutritional status of patients, particularly those undergoing major surgeries. The PNI is calculated as follow: PNI = (10 × serum albumin (g/dL)) + (0.005 × total lymphocyte count)[12]. PNI is a simple, inexpensive, and effective tool for evaluating immunonutritional status. It serves as a valuable prognostic marker in patients with metastatic CRC, as well as other cancer types. A lower PNI score (< 40) indicates poorer nutritional and immune status and is associated with worse postoperative outcomes, including higher morbidity and mortality rates. Moreover, a lower PNI is recognized as an independent predictor of overall survival (OS)[2]. Because PNI is only analyzed in a certain moment of a patients disease, the prognostic impact of PNI trayectory requires further exploration in future studies[13].

Geriatric nutritional risk

GNRI: The GNRI is specifically designed for older patients to assess their nutritional status and predict postoperative outcomes. It is calculated with the equation: GNRI = (14.89 × serum albumin (g/dL)) + (41.7 × present body weight/ideal body weight)[14]. Lower GNRI scores indicate malnutrition and are associated with a higher risk of complications and mortality, particularly in elderly patients[2]. GNRI enables healthcare providers to stratify patients at risk for poor survival in CRC. Meta-analyses support the use of GNRI as a feasible prognostic tool for CRC patients[2]. Notably, CRC patients with a lower baseline GNRI have been shown to experience worse OS. Once a low GNRI is identified, prompt nutritional support should be initiated to improve outcomes[2]. In a study by Wang et al[15] that analyzed clinical data from 391 hospitalized CRC patients, it was demonstrated that, compared to well-nourished patients, malnourished CRC patients exhibited significantly elevated NLR, SII, and PLR levels, along with a decreased PNI value, with statistically significant differences (P < 0.001).

INFLAMMATORY MARKERS

Chronic inflammation can facilitate genetic mutations, stimulate angiogenesis, and support metastatic spread[16]. Assessing a patient’s level of systemic inflammation can provide valuable insights for determining prognosis.

SII

The SII is a marker of systemic inflammation and immune response, calculated using the formula: SII = platelets × neutrophils/lymphocytes. A high SII, characterized by elevated neutrophil and platelet counts and decreased lymphocyte counts, reflects heightened inflammatory activity. This inflammatory state may be associated with poor survival outcomes due to its role in promoting tumor invasion and metastasis[17].

NLR

The NLR is calculated by dividing the absolute count of neutrophils by the absolute count of lymphocytes. Neutrophils promote tumor growth by releasing inflammatory cytokines and proteases. A high NLR has been associated with adverse outcomes in multiple cancers, including CRC, due to the predominance of neutrophil-driven inflammation over lymphocyte-mediated immune response[18]. An elevated NLR is correlated with poorer survival in CRC patients[18]. Understanding the prognostic implications of NLR can help guide therapeutic strategies, enabling a more personalized and targeted approach to CRC treatment.

These inflammatory markers are associated with increased risks of surgical complications and longer hospital stays[19,20].

We observed, as noted by Tez[7], that NLR is associated with OS in various meta-analyses, making it one of the most robust prognostic markers to date[6,21,22]. We can also concur with the importance of the prognostic value of albumin, as demonstrated in the studies by Heys et al[1], who showed that lower albumin levels were associated with a 25% increased risk of death, and by Gibbs et al[11], who found a correlation between serum albumin levels and in-hospital mortality. However, it should be noted that Tez's article primarily focuses on patients with peritoneal metastases, which may inadvertently exclude non-metastatic cases where these markers are equally relevant. Nevertheless, all the markers discussed in this editorial reflect on cancer´s systemic effects and highlight the importance of evaluating a patient's nutritional and inflammatory status. Nutritional status offers crucial insights into patient outcomes and has prognostic significance. For example, as mentioned earlier, serum albumin levels are directly related to both hospital stay length and patient survival[9]. These tools provide valuable information that can help identify patients at higher risk of malnutrition prior to surgery and guide nutritional interventions before surgery.

This approach can help reduce postoperative morbidity and mortality in patients with CRC and should be included in the routine pre-treatment evaluation for CRC patients.

A potential future direction for the use of these markers could be their dynamic monitoring throughout the patient’s treatment process. This approach may allow for timely adjustments to interventions in response to changes in the patient’s nutritional and inflammatory status.

We acknowledge the limitations of our article, primarily the heterogeneity of the studies included, which vary in methodology, sample size, and patient population. Additionally, these studies do not fully account for confounding factors, such as patient comorbidities (e.g., kidney failure and heart failure), which may influence the values of the markers discussed. Furthermore, it should be noted that the reference values for these markers, such as serum albumin levels, may differ between institutions.

CONCLUSION

Performing an adequate evaluation of inflammatory and nutritional markers in CRC patients can significantly aid in prognostication. Markers such as NLR, albumin levels, and PNI provide crucial insights into a patient’s nutritional and inflammatory status, and consequently, their outcomes. Integrating these inflammatory and nutritional biomarkers into prognostic models enhances our accuracy of predicting patients disease progression, which in turn can help us to create personalized treatment plans. Patients who are identified at high-risk through the use of these markers may require more intensive treatment and monitoring, which can improve their prognosis and reduce perioperative complications. Additionally, recognizing nutritional risk through these markers allows for preoperative interventions that can mitigate complications and improve long-term survival.