Inflammation-Based Markers of Nutrition in Cancer Patients

*Ogochukwu Izuegbuna*

## **Abstract**

Malnutrition and cachexia are common findings in cancer patients, and they predict poorer clinical outcomes. Close to half of cancer patients regardless of cancer type have malnutrition and will require one form of nutritional support either before or during treatment. The early identification of malnutrition is thus important to physicians and caregivers. The role of inflammation in the development and progression of malnutrition and cachexia is being unravelled. Increasing evidence shows that systemic inflammatory response and nutritional status are involved in tumour development and influence the clinical prognosis. Serum proteins such as albumin and prealbumin have traditionally been used by physicians to determine patient nutritional status. More recently, inflammation-based prognostic scores including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), C reactive protein-to-albumin ratio (CAR), prognostic nutritional index (PNI), Glasgow Prognostic Score (GPS) have shown promise and have begun to be used in clinical practice to predict prognosis of cancer patients. This chapter highlights the role and pathophysiology of inflammation-based markers in assessing malnutrition and cachexia and their relationship to clinical screening tools.

**Keywords:** inflammation, malnutrition, cachexia, cancer, nutrition screening

## **1. Introduction**

Cancer is a major public health problem worldwide. It ranks as a leading cause of death along with cardiovascular disease (CVD). Cancer is the leading cause of death in 57 countries (including China), while CVD is the leading cause in 70 countries (including Brazil and India) [1]. In 23 other countries, it ranks either third or fourth. The GLOBOCAN 2020 report showed that there was approximately 19.3 million new cases and 10 million cancer deaths in 2020, thus making cancer the new challenge of the 21st century [2]. This increase in the number of cancer cases implies an increase in cancer-associated complications and morbidities. One such complication is malnutrition.

Cancer-related malnutrition is a broad term that encompasses complex poorly understood processes that are associated with specific types of cancers and their treatment protocols. Specific cancers such as oesophageal and pancreatic cancer are a high risk for malnutrition. Factors such as cancer-related symptoms (e.g. anorexia, early satiety, fatigue), treatment complications (eg, mucositis, nausea, taste changes), and psychologic distress all play a role and/or are risk factors in the development of malnutrition. Malnutrition is a common problem among cancer patients with high negative consequences. In cancer, it is associated with poor prognosis, reduced survival, increased therapy toxicity, reduced tolerance and compliance to treatments, and diminished response to antineoplastic drugs. Surveys done in the past showed a prevalence rate of between 25 and 70% with about 10–20% linked to malnutrition and not the malignancy itself. Malnutrition in cancer patients is distinctly different from malnutrition as a result of starvation, as the former arises from a combination of anorexia and metabolic dysregulation, caused by the tumour itself or by its treatment. Malnutrition when left untreated can progress to cachexia. Cachexia is defined as "a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment" [3]. The pathophysiology of cachexia has an underlying variable combination of reduced food intake and abnormal metabolism leading to a negative protein and energy balance. Cachexia is frequent in chronic diseases, and in cancer, it may account for about 20% of cancer deaths [4]. A diagnosis of cachexia is made in patients when the total body weight loss is >5% in the past six months (in the absence of starvation) or weight loss >2% in patients with body mass index (BMI) of <20 kg/m<sup>2</sup> [5]. Currently, cachexia is classified into three stages of clinical relevance, namely pre-cachexia, cachexia, and refractory cachexia [3]. Blum et al. defined pre-cachexia as weight loss >1 kg but <5% of usual body weight/6 months, but with an increased C- reactive protein (CRP) level and appetite loss, while refractory cachexia was weight loss >15% in the last 6 months + BMI < 23 kg/m2 or weight loss >20% in the last 6 months + BMI <27 kg/m<sup>2</sup> [6]. If untreated, cancer cachexia would lead to a progressive functional loss, poor quality of life, chemotherapy-related toxicity, diminished response to antineoplastic treatments, and poor survival. At the refractory cachexia stage, the cancer is usually refractory to chemotherapy.

The relationship between malnutrition and the systemic inflammatory process is not a new one. Systemic inflammation is closely associated with weight loss and malnutrition in cancer [7–9]. Systemic inflammation has been fingered in the genesis and progression of malnutrition. It is known to affect important metabolic and neuroendocrine pathways as well as cause elevated energy expenditure at rest, decreased lean mass and reduced physical performance [10, 11]. Furthermore, cytokines especially tumour necrosis factor (TNF) alpha, interleukin (IL) 1 and IL-6 have been fingered in the induction of muscle wasting providing evidence for a link between malnutrition and inflammation. As aforementioned, systemic inflammation is thus a harbinger not only for malnutrition but for various comorbidities in cancer patients. Identification of cancer patients at risk of malnutrition is highly recommended. The PreMiO study highlighted the prevalence of malnutrition at the first visit by cancer patients [12]. The European Society for Clinical Nutrition and Metabolism (ESPEN) in its latest preoperative nutritional care assessment highlighted the degree of systemic inflammation among other things for individuals at nutritional risk [13]. Soeters et al. reinforced the urgency of including an assessment of inflammatory activity in the diagnosis of malnutrition [14]. Recent studies have shown that inflammatory models can be used to predict prognosis, as well as cancer-related malnutrition [15]. High level of systemic inflammatory factors which can facilitate tumour cell proliferation and metastasis are also

known to be induced by malnutrition [16]. Thus, malnutrition can enhance a systemic inflammatory response. Control of inflammation in cancer can help modify poor nutritional status resulting in better response to therapy and improved survival. The early recognition of systemic inflammatory response should therefore be an integral part of nutritional management in cancer patients to improve short and long term outcomes.

## **2. Nutritional status**

### **2.1 Prevalence of malnutrition in cancer patients**

Malnutrition is a universal condition in cancer patients with grave clinical implications such as impaired quality of life, poor performance status, weight loss and cachexia. Studies from different countries across Europe shows a high prevalence of cancer-related malnutrition ranging from 25 to 70% based on nutritional assessments [17–19]. However, this differs across cancer types and stages of the disease [12, 20]. In the often-cited landmark study by Dewys et al., cancer type and treatment play a role in cancer-related malnutrition [21]. Tumour stage and age have also been noted as risk factors in malnutrition [22, 23]. In an epidemiological observation study, Pressoir et al. observed that pre-existing obesity (BMI ≥ 30), and Performance status ≥ 2 were associated with increased risk of malnutrition among cancer patients in 17 French Comprehensive Cancer Centres [19]. The Prevalence of Malnutrition in Oncology (PreMiO), a cross-sectional, observational study involving almost 2000 patients in 22 sites in Italy, revealed that 51.1% of treatment-naïve patients at their first visit to a medical oncology centre were already affected by a nutritional impairment, including risk for malnutrition (43%) and overt malnutrition (9%). Poor appetite was present in over 40% of cancer patients, with variable severity scores depending on the tumour type and stage of the disease, and ascribed mainly to early satiety, taste changes, and nausea [24].

The picture is not very different in developing countries. Pastore et al. in Brazil reported only 13.7% of lung and gastrointestinal cancer patients in a study were wellnourished [8]. Opanga et al. in Kenya reported that 33.8% of participants required critical nutrition care, 34. 8% symptoms management, 14.2% constant nutrition education and pharmacological intervention [25]. Ntekim et al. at Ibadan, Nigeria used nutritional screening assessment tools and reported a prevalence of 60% [26]. Children with cancer are also known to develop some form of malnutrition [27], however, the frequency may vary according to the type of cancer [28], and region [29, 30]. Brinksma, et al. reported the prevalence of malnutrition at diagnosis for developed countries, through a systematic review which included patients with different types of childhood cancer, aged from 0 to 18 years of age for acute leukaemias, the prevalence was 10%, 20–50% for neuroblastoma, and those classified as "other malignancies" was 0–30% [31]. This prevalence is lower than what is obtained in developing countries [28–30]. Villanueva et al. reported a prevalence of almost 50% [32]. Lemos et al. in Brazil reported that the prevalence of malnutrition is higher among paediatric patients with malignancies than in the general population though the difference was not significant [33]. These facts high- light the need for nutritional assessment in cancer patients regardless of age or region. Cancer patients should be assessed at several points during their management to identify aetiology and candidates that require nutritional support.

## **3. Pathophysiology**

Cancer-related malnutrition can have profound negative effects on cancer patients' wellbeing and therapeutic outcomes. It usually results from local effects of a tumour, the host response to the tumour and anticancer therapies. Cancer cachexia which is a severe form of malnutrition is characterised by progressive weight loss, anorexia, asthenia, and anaemia. Cachexia is a poor prognostic sign, and is associated with reduced food intake and increased energy expenditure [34]. Cachexia also expresses itself as nutritional imbalances in a number of ways in cancer patients which include glucose intolerance and insulin resistance, loss of adipose tissue and lipolysis with increased fat oxidation rates [35], decreased lipogenesis, impaired lipid deposition and adipogenesis [36]. A decrease in protein synthesis and increase in protein degradation does occur in cancer cachexia [37] which is a key feature of skeletal muscle atrophy. Other features such as altered hormone levels [38], elevated cytokines [39, 40], increased insulin resistance [38], elevated synthesis of acute-phase proteins [34] and altered nutrient utilisation can be attributed to inflammatory mediators as well a host of other factors. Inflammatory markers have been implicated in all metabolic derangements in cancer-related malnutrition, and a better understanding of these markers with either the host or the tumour is necessary for better management of malnutrition and its complications.

#### **3.1 Inflammation and cancer**

Inflammation has been shown to play a major role in cancer development, progression and outcome and has been termed the seventh hallmark of cancer [41]. The observation of leukocytes within tumours by Rudolf Virchow in the 19th century gave a clue of a possible link between inflammation and cancer. This link is due to chronic inflammation which is mediated by pro-inflammatory cytokines, chemokines, adhesion molecules, and inflammatory enzymes with the promotion of all stages of tumorigenesis. Inflammation is the body's physiological response to tissue damage as a result of any pathological insult to the body's homeostasis. The body's inflammatory response can either be a resolution to the insult, or persistence of the insult in the form of chronic inflammation. Chronic inflammation can cause cellular changes and influence innate and adaptive immunity towards tumour growth. When this happens, an imbalance of pro-inflammatory and anti-inflammatory mediators can lead to cell mutation and injury creating an environment that is conducive to the development of cancer. This scenario holds for the onset of cancer but is important for the progression of the disease. Such progression is characterised by clinical signs and symptoms including nutritional impact symptoms and co-morbid metabolic abnormalities. This invariably leads to weight loss, chronic anaemia, wasting syndrome, fatigue with loss of quality of life. These symptoms are very prominent in cancer-related malnutrition. While multiple mechanisms can be associated with these symptoms, however, they are interrelated and the unifying factor is inflammation.

Inflammation is associated with tumorigenesis at every stage of its development including survival and metastasis [42]. On the other hand chronic inflammation is known to facilitate treatment resistance and this form of acquired resistance is a result of the production of cytokines, chemokines and growth factors by the tumour micro-environment rendering chemotherapy ineffective [43]. Besides, inflammatory responses can be induced by anti-cancer therapies [44, 45]. chronic inflammation is also known to worsen chemotoxicity [46]. A better understanding of the relationship between chronic inflammation and cancer can lead to the development of new strategies in the management of cancers as well as some of the complications such as malnutrition and chemotoxicity that arise during treatments.

#### **3.2 Inflammation and malnutrition**

A large number of cancer patients are known to show a form of cachexia syndrome which is characterised by anorexia, loss of adipose tissue and skeletal muscle mass. Most of these symptoms have been linked to inflammation. The Global Leadership Initiative on Malnutrition (GLIM) requires the combination of at least one phenotypic and one etiologic criterion is to establish the diagnosis of malnutrition. The phenotypic criteria include non-volitional weight loss, low body mass index, reduced muscle mass. In addition to this, etiologic criteria include reduced food intake or assimilation and disease burden/inflammatory condition [47].

Inflammation is so intertwined with the pathogenesis of malnutrition that the ESPEN recommended dividing malnutrition into disease-related malnutrition with and without inflammation [48]. For Disease-related malnutrition with inflammation, it is defined as underlying diseases causing inflammation with a consecutive lack of food intake or as uptake with a negative nutrient balance [49]. Inflammation is reported to have several metabolic effects. Cytokines such as IL-6, and TNF-*α* correlate with insulin resistance and appetite reduction and also cause inhibition of nutrients entering cells [5, 50]. Leptin, a 167 amino acid peptide and a member of the adipocytokine family plays a major role in body mass regulation and inflammatory/immune cells modulation. Diakowska et al. reported in a study of leptin and inflammatory markers in oesophageal cancer patients found that leptin correlated directly with BMI, TNF-alpha, albumin, and haemoglobin and indirectly with IL-6, IL-8, and hsCRP [51]. In a secondary analysis of the EFFORT trial by Merker et al., patients with high baseline inflammation (ie, CRP levels >10 mg/ dL) were observed not to benefit from any form of nutritional support concerning the 30- day mortality [52]. However, this study was not tailored to cancer patients primarily. Wang et al. showed a clear association between high inflammation, clinical malnutrition and overall survival in patients with nasopharyngeal carcinoma [16]. These studies show that inflammation could be a key factor in cancer-related malnutrition. Inflammation is known to exert some effects on appetite and food intake, gastrointestinal functioning of the stomach and gut, among a host of other things [53]. These effects are mediated by circulating cytokines released as part of the systemic inflammatory response causing disease-related anorexia, decline in cognitive function, weight loss and anaemia. Thus, inflammation is an integral part of cancer-related malnutrition.

#### *3.2.1 Cancer-related anaemia*

Anaemia is a common problem in cancer patients. Anaemia prevalence is remarkably high and varies widely among cancer patients. It is estimated from various studies that between 30–90% of cancer patients had anaemia [54]. Anaemia is considered an indicator of poor nutrition and poor health especially through the malabsorption or non-utilisation of iron, folate, cobalamin and other micronutrients needed for the production of red blood cells. The prevalence is determined by the definition of

anaemia. According to the World Health Organisation (WHO), normal Hb values are 12 g/dL in women, and 13 g/dL in men [55]. Maccio et al. reported a prevalence of 78.8% of anaemia in lung cancer patients [56]; Akinbami et al. reported a prevalence of 58% among breast cancer patients [57]. Anaemia is known to be associated with several co-morbidities including a decline in patients' performance status (PS), cognitive function, and decreased survival [56, 58]. While anaemia in cancer generally is known to have various aetiopathology, cancer-related anaemia (CRA) is believed to arise as a consequence of chronic inflammation.

Cancer-related anaemia (CRA) refers to a condition occurring without bleeding, haemolysis, neoplastic bone marrow infiltration, kidney and/or hepatic failure [59], and principally results from the chronic inflammation associated with advanced-stage cancer and the synthesis of pro-inflammatory cytokines by both immune and cancer cells. Unlike iron deficiency anaemia, CRA is typically normochromic (MCH >27 pg), normocytic (MCV between 80 and 100 fl), with a low reticulocyte count (<25,000/ mL) and a low value of reticulocyte index (normal range between 1 and 2 which is a more accurate measure of the reticulocyte count corrected against the severity of anaemia based on haematocrit). In addition, it has normal/low serum iron concentrations (normal range 55–160 mg/dl for men and 40–155 mg/dl for women) and reduced total iron-binding capacity (transferrin saturation < 50%); ferritin values may be normal (30–500 ng/ml) or more often increased (>500 ng/mL), with increased iron storage [59]. The normal level of iron within the bone marrow reflects the body tacit handling of iron metabolism which is termed as "functional iron deficiency" which is also present in other types of anaemia associated with chronic inflammation. In addition, circulating levels of erythropoietin (EPO) is often not optimal for the level of anaemia thus presenting with also bone marrow hypoplasia. Adamson highlighted some of the pathogenetic mechanism of inflammation of chronic anaemia which includes: shortened erythrocyte survival in conjunction with increased erythrocyte destruction, suppressed erythropoiesis in bone marrow, effects of inflammation on erythropoietin production and alterations in iron metabolism that result in iron-restricted erythropoiesis induced by hepcidin increase [60]. According to Jain et al., the soluble transferrin receptor/log ferritin index can differentiate pure cases of anaemia of chronic disease from iron deficiency anaemia [61].

Like other types of anaemia in cancer, CRA has multifactorial pathophysiology with immune, nutritional and metabolic components affecting its severity. Many studies have demonstrated that inflammatory cytokines are a major contributor to the aetiopathogenesis of CRA. They achieve this through the derangement of various metabolic pathways including glucose metabolism, impairment of lipoprotein lipase, which controls the uptake of circulating triglycerides into adipocytes, and changing protein synthesis and degradation, with subsequent depletion in lean body mass [62]. In particular, proinflammatory cytokines like interleukin 1 and 6 released by cancer and activated immune cells in response to malignancy, may result in anaemia by inducing changes to iron balance, inhibition of erythropoiesis, impairment of EPO synthesis and activity, reduction of erythrocytes lifespan and changes of energy metabolism. IL-1 and TNF also induce the transcription factors GATA2 and nuclear factor-kB, both of which are negative regulators of the hypoxia-inducible factor 1 (HIF1) expression [63]. Reactive oxygen species (ROS) which are a major player in chronic inflammation are known to inhibit EPO synthesis by mimicking a false O2 signal in the renal peritubular interstitial cells. They equally inhibit erythroid precursor proliferation [64]. IL-6 regulates the synthesis of hepcidin, a 25 amino acid peptide made by the hepatocytes and involved in iron homeostasis by mediating the degradation of the iron export protein ferroportin 1, thereby inhibiting iron absorption from the small intestine and release of iron from macrophages.

The process of CRA is not an isolated one. It has been shown that malnutrition along with weight loss and reduced food intake is correlated with anaemia in patients with the chronic inflammatory disease [65]. CRA is therefore not a single condition, but associated with weight loss and remodelling of energy metabolism; thus CRA is a crossroad for both inflammation and nutritional status. Therefore management of CRA would involve not only anaemia but malnutrition as a whole.

#### *3.2.2 Cancer-related anorexia and wasting*

Anorexia can be defined as a loss of appetite associated with chronic illness in cancer patients and is associated with weight loss [66]. It is common in cancer patients and frequently associated with early satiety and taste changes. It occurs in half of the newly diagnosed cancer patients and up to 70% of patients with advanced disease. Cancer-related anorexia is an important clinical co-morbidity in cancer patients, and it harms nutritional status in advanced cancer. There are many causes of anorexia. They are classified as either being due to central or peripheral mechanisms. Peripheral causes include (i) tumours causing dysphagia or directly impinging on gastrointestinal function; (ii) tumours producing substances that alter food intake, e.g. lactate, tryptophan, or parathormone-related peptide; (iii) tumours leading to alterations in nutrients resulting in anorexia, e.g. zinc; or (iv) tumours producing inflammation leading to cytokine release. Alterations in gastrointestinal function can alter visceral receptor function, leading to altered secretion of gastrointestinal peptides, e.g. peptide tyrosine (PYY), and alterations in stomach emptying can alter feedback of satiating hormones. Peripherally, chemotherapy can alter taste perception and cause nausea, vomiting, mucositis, abdominal cramping, bleeding, and ileus [67]. Depression, pain, or a variety of alterations in central neurotransmitters are some of the central causes. Some centrally acting chemotherapy can also induce anorexia. For example, tamoxifen used in breast cancer treatment can inhibit fatty acid synthase in the hypothalamus, leading to an accumulation of malonyl coenzyme A (CoA). Increased malonyl CoA is associated with anorexia in cancer [68, 69]. The resultant effect of cancer-related anorexia is reduced caloric intake and alteration in nutrient metabolism with consequent loss of fat and lean mass.

Several studies have focused on the mechanisms underlying the metabolic changes observed in cancer-related anorexia and weight loss and some cytokines have been implicated including TNFα, IL-1, and IL-6 [70]. These cytokines are known to mimic leptin signalling and suppress orexigenic ghrelin and neuropeptide Y (NPY) signalling inducing sustained anorexia and weight loss. These cytokines are elevated in many cancers [71] and their chronic administration can induce anorexia and wasting [72, 73]. Interleukin 1 is produced by lymphocytes and macrophages and is a potent anorexigenic cytokine that is at least 1000-fold more effective than leptin [74]. IL-1 is reported to reduce the size, duration, and frequency of meals but does not reduce the desire for food [75]. It achieves this by the stimulation of corticotrophin-releasing factor (CRF) production by the hypothalamus [76]. TNFα is produced by monocytes, tissue macrophages and some tumours, and directly on the CNS to produce its anorectic effects by crossing the blood-brain barrier. An inhibitor of TNFα increased food intake in anorectic tumour-bearing rats [77].

Interferon-γ when administered centrally is known to reduce food intake and duration. Administration of TNF-α to laboratory animals induces a state of cachexia, with anorexia and depletion of adipose tissue and lean body mass [78]. Interleukin-6 is secreted by T-cells and macrophages as well as microglia, astrocytes, and neurons and has a well-established association with the onset of cachexia in both rodent and human wasting conditions [79]. While there are many mediators of anorexia in different disease states, IL-6 has been shown to regulate food intake and metabolism [80], signalling through neural gp130 receptors and even in non-cancer-related cachexia, plasma IL-6 is associated with the incidence of anorexia [81, 82].

Decreased caloric intake alone does not account for the profound weight loss observed in cancer patients. Metabolic abnormalities with subsequent elevation in basal energy expenditure are also contributing factors. Weight loss in cancer though affects both fat and lean mass, the latter seems more affected. In a study of 50 cancer patients by Cohn et al., Weight-losing cancer patients appeared to have lost both fat and lean tissue, but the loss of lean body tissue, particularly skeletal muscle, was the more striking feature [83]. This pattern is in contrast to starvation, in which fat is lost and lean tissue is better preserved. TNF-α, IL-1 and IL-6 have been shown to increase basal energy expenditure causing weight loss [84]. The muscle wasting that occurs in cancer is a result of a decrease in protein synthesis, an increase in protein degradation or a combination of both. These changes are attributed to the upregulation of inflammatory mediators, the activation of related transcription factors and signalling pathways, abnormalities in the expression of angiotensin II (Ang II), insulin-like growth factor-1 (IGF-1) and various receptors, proteins and kinases, and organelle dysfunction [85]. Muscle wasting thus occurs as a result of these processes.

## **4. Inflammatory markers of malnutrition**

There are several clinical, biochemical and physiological indicators to diagnose malnutrition in cancer patients. One commonly used clinical indicator of malnutrition is the percentage of weight loss in a certain period. Α weight loss of more than 5% in the previous month or more than 10% in the last 3–6 months is considered significant malnutrition. Other anthropometric measurements, such as body mass index (BMI), mid-arm circumference and mid-upper-arm muscle area can give information about the nutritional status and body composition of these patients. The ASPEN guidelines for diagnosing malnutrition, which looked at six characteristics that incorporate some of these clinical indices [86].

Biochemical markers which are sometimes indicative of inflammation are often used as markers of malnutrition. They include albumin, prealbumin, C-reactive protein, transferrin, total lymphocyte count etc. However, more recently, inflammation-based scores and ratios are being seen as more sensitive markers than the traditional ones [87, 88]. Other nutritional assessment tools use questionnaires incorporated with factors such as estimation of nutritional intake, laboratory parameters and calculation of unintentional weight loss. Such tools that have been used in cancer patients include the Prognostic Nutritional Index (PNI), the Nutritional Risk Screening 2002 (NRS 2002), the Controlling Nutritional Status (CONUT), Mini Nutrition Assessment (MNA), Malnutrition Screening Tool (MST), the Nutritional Risk Index (NRI) etc. [89]. In children with cancer, the Frisancho table is used to assess their nutritional status [29].

## **4.1 Albumin**

Albumin is a serum hepatic protein with a half-life of 14–20 days. Albumin is the major carrier for many substances in the body, and also help maintain the body oncotic pressure. It enhances immunity, aids DNA synthesis as well as acts as an antioxidant [90, 91]. Due to its relatively long half-life and hepatic synthesis, it is seen as a good marker of malnutrition. However, albumin is a negative acute-phase protein, and its serum levels are down-regulated in response to inflammatory conditions and drugs especially those that affect the liver. Albumin is widely used as a marker of nutrition as well as a prognostic indicator of survival in cancer patients (though it is more of a marker for inflammatory response). Frutenicht et al. reported that albumin was a predictor of mortality in gastrointestinal tumour patients [92]. Das et al. reported that albumin was significantly correlated with Patient-Generated Subjective Global Assessment (PG-SGA) [93], thus hypoalbuminaemia is a marker of malnutrition. This was further affirmed by a study done on colorectal cancer patients where albumin was positively correlated with the MNA [94]. However, In a study of 74 cancer patients, Pastore et al. did not find significant variation between albumin and SGA [8]. In a recent study on 128 colorectal patients, at least two circulating cytokines (TNF-α and IL-10) affected the expression of serum albumin [95]. Albumin correlates with weight loss in cancer patients as well as with BMI. Albumin is equally incorporated into various indices such as the Glasgow prognostic score (GPS) and PNI. Albumin may not be the ideal marker for assessing malnutrition, but its incorporation into nutrition screening tools gives it a sense of validity.

## **4.2 C-reactive protein**

CRP is the most common method used to assess the magnitude of systemic inflammatory response. Unlike albumin, it is a positive acute-phase protein. CRP is a prototype of short pentraxin present only in the pentameric form in plasma. It is synthesised by hepatocytes in response to trauma, inflammation and tissue damage. The synthesis of CRP is under the transcriptional control of cytokines and transcription factors. Interleukin-6 (IL-6) is the main inducer of CRP gene. CRP is associated with the development, progression and outcome of cancer [96]. In addition, some studies have found a positive association between altered CRP levels and weight loss in patients with cancer [97]. In a large international cohort of advanced cancer patients, Laird et al. reported that C-reactive protein was significantly associated with cognitive, physical, emotional and social functions as well as anorexia, pain and fatigue [98]. Yu et al. also observed a significant association between CRP and PG-SGA among patients with malignant tumours [99]. However, some other studies did not see any association between CRP and nutritional status [88, 92]. In a study done by Read et al., patients with advanced colorectal cancer were initially found to have a positive correlation between SGA and CRP. However, when two outliers were excluded, the association did not remain significant [100]. This observation may be a result of the effect of non-nutritional factors like cardiovascular disease and infections. CRP is positively correlated with weight loss, and negatively correlated with PNI. Like albumin, CRP is incorporated into some nutritional screening tools which give it some validity.

#### **4.3 Inflammation scores**

Traditional inflammatory markers like CRP and albumin have been shown to have some limitations in malnutrition diagnosis based on their low specificity. It has been muted that inflammation-based scores that combine CRP and albumin, such as the CRP/Albumin ratio (CAR), may have more significant prognostic value than each of these markers singly in malnutrition. These inflammation-based scores which include inflammatory ratios and indices, and haematological ratios have been reported to be associated with cancer progression and outcomes [101, 102].

The Glasgow prognostic score or modified Glasgow prognostic score indices which combine serum CRP and albumin levels have also been viewed as a prognostic indicator in many cancers. There have been more than 60 studies (>30,000 patients) that have examined and validated the use of the GPS or the modified GPS (mGPS) in a variety of cancer scenarios [103]. Silva et al. demonstrated the clinical utility of modified GPS in a palliative care setting and its association with SGA [104]. SGA was also strongly correlated with the Glasgow prognostic score in oesophageal cancer patients [105]. GPS currently serves an important significance as a nutritional marker in cancer.

The concept of the CRP/albumin ratio (CAR) was first proposed by Ranzani and demonstrated its value for the mortality of septic patients [106]. CAR unlike GPS is a continuous variable and is believed to have a wider clinical application than GPS. A high level of CAR is linked to survival in cancer patients [102, 107]. De Lima reported that CAR was significantly associated with weight loss and SGA in patients with gastrointestinal tumours [108]. A high preoperative CAR and low PNI strongly correlated with poor survival in pancreatic cancer [109]. In oral cancer patients, Park et al. showed that CAR was significantly associated with both PNI and mGPS, and was also a better marker for survival than the other markers [110]. Another related novel marker, CRP/Prealbumin ratio is seen as a prospective inflammatory nutritional prognostic tool in cancer [111], likewise the albumin/CRP ratio [8, 88].

Haematological test i.e. complete blood count is one of the most common, simple and accessible tests in cancer evaluation. As cellular markers of inflammation, they provide prognostic and treatment information about the cancer patient. It is now established that the presence of a pre-operative systemic inflammatory response is predictive of disease progression and poorer outcome, regardless of tumour stage, in patients with various cancers [112, 113]. Inflammation based scoring systems such as the modified Glasgow Prognostic Score (mGPS) and the Neutrophil-Lymphocyte ratio (NLR) have prognostic value in different solid tumours [112]. However, concerning the NLR, multiple thresholds have been used to define high and low NLR values and some have suggested that its prognostic value is mainly derived from the neutrophil count and that the lymphocyte count makes little contribution [114]. Platelets are known to shield tumour cells from shear forces and assault of NK cells, recruit myeloid cells by secretion of chemokines and mediate an arrest of the tumour cell platelet embolus at the vascular wall [115, 116], which indirectly makes the Platelet- lymphocyte ratio (PLR) a prognostic marker in cancer. Studies have revealed that combinations of these parameters could accurately predict the prognosis of a patient than a single index. Like with other inflammatory markers, haematological ratios are associated with malnutrition. Many studies have reported the relationship between NLR and nutritional

status. In a recently published work, Siqueira et al. demonstrated the relationship between NLR and nutritional risk in some cancer patients [117]. Sato et al. equally reported a significant inverse relationship of prealbumin with NLR [118]. NLR was associated with SGA especially in severely malnourished cancer patients [119] as well as with percentage weight loss [92].

PLR is another haematological ratio and inflammation marker that has been reported to be associated with many conditions including cancers. Elevated PLR is associated with increased all-cause mortality in different conditions [120], is a prognostic marker in many cancers [121] and is also associated with nutritional status [122]. As a marker of nutrition, PLR was significantly correlated with PNI and BMI in pancreatic cancer patients [87]; along with NLR was significantly associated with PNI in hepatocellular carcinoma [123]. PLR is also associated with haemoglobin and post-op complications in colorectal cancer patients affecting morbidity rates [124]. Sarcopenia, characterised by a decline of skeletal muscle plus low muscle strength and/or physical performance was reported to be associated with NLR and PLR in both renal cell carcinoma and gastric cancer patients [125, 126]. In addition PLR significantly correlated with both BMI and haemoglobin [125]; while in the gastric cancer patients, both PLR and NLR were significantly associated with NRS, albumin, haemoglobin, and cancer stage [126]. NLR and PLR are also reported to be significantly associated with performance status in cancer [115]. The main shortcomings of the haematological ratios are the different cut off levels in various studies.

Some other haematological ratios and scores such as lymphocyte monocyte ratio (LMR), neutrophil platelet score (NPS) etc. have been reported to have some prognostic value in cancer [101]. The monocyte lymphocyte ratio (MLR) was reported to be significantly correlated to PNI and albumin [87] in pancreatic cancer making it a potential nutritional marker like NLR. Combination haematological indices such as the Combination of Platelet count and Neutrophil to Lymphocyte Ratio (COP-NLR), combination of neutrophil-lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) (CNP), fibrinogen and NLR (F-NLR) etc. have been shown to have good prognostic value, and their association with nutritional indices should broaden the nutrition/inflammation arena further.

#### **4.4 Cytokines**

Cytokines are protein molecules released by lymphocytes, monocytes/macrophages and mediate as well as regulate immunity, inflammation and haematopoiesis. Cytokines are the major players in cancer-associated malnutrition, being involved in every aspect of the pathophysiology as earlier explained. They hold great promise as inflammatory markers in nutrition, however, they pose some challenges, particularly their short half-lives [127, 128]. They can be measured in serum or plasma samples; however, measurements from the different sample types cannot be used interchangeably [129]. Tissues or supernatant from cultured peripheral blood mononuclear cell (PBMC) preparations can also be employed in their measurement. The effect of freezing and thawing can lead to its degradation affecting the measurement. There is an equal lack of standardisation of assays, and because cytokines affect multiple pathways, there is also a lack of specificity [130].

Despite its shortcomings, cytokines are still studied in nutrition research. IL-6 is incorporated into the newly validated CAchexia SCOre (CASCO) for staging cachexic cancer patients [131], although it is not included in the simplified MiniCASCO (MCASCO) [132]. IL-6 is also associated with weight loss, and also correlates with high Prognostic Inflammatory Nutritional Index [133, 134].

## **4.5 Other markers**

Other inflammatory markers for measuring malnutrition include prealbumin, haemoglobin, transferrin, and absolute lymphocyte count (ALC). Many of them are incorporated into nutritional indices either as ratios or as scores. Prealbumin, haemoglobin and ALC are incorporated into the CASCO score [133]. For ALC, levels are associated with various degrees of malnutrition. Levels >2000 cells/m3 (normal), 1200 to 2000 cells/m3 (mild depletion), 800 to 1199 cells/m3 (moderate depletion), and < 800 cells/m3 (severe depletion) [135]. Haemoglobin is part of the haemoglobin platelet ratio (HPR) which has been shown to have diagnostic value in colon cancer [136].

## **5. Conclusion**

As it has been shown, inflammation plays a central role in cancer-related malnutrition which can lead to cachexia and eventually death. Malnutrition accounts for about 20% of all cancer deaths and is associated with reduced quality of life. Markers of inflammation play a prognostic role in cancer and are most times significantly associated with indices of malnutrition in cancer patients. Several studies have shown that inflammatory markers can be used as a screening test for malnutrition in cancer; though their specificity may be below as a result of other disease states. The inflammation-based scores are more sensitive than the single tests. These tests are cheap and easy to apply. However, their major shortcomings are different cut off levels.

## **Conflict of interest**

The author declare no conflict of interests.

*Inflammation-Based Markers of Nutrition in Cancer Patients DOI: http://dx.doi.org/10.5772/intechopen.104428*

## **Author details**

Ogochukwu Izuegbuna Department of Haematology, LAUTECH Teaching Hospital, Ogbomoso, Nigeria

\*Address all correspondence to: ogoizu@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Bray F, Laversanne M, Weiderpass E, Soerjomataram I. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer. 2021;**127**(16):3029-3030. DOI: 10.1002/ cncr.33587

[2] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a Cancer Journal for Clinicians. 2021;**71**:209-249. DOI: 10.3322/caac.21660

[3] Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: An international consensus. The Lancet Oncology. 2011;**12**(5):489-495. DOI: 10.1016/ S1470-2045(10)70218-7

[4] Argilés JM, Busquets S, Stemmler B, López-Soriano FJ. Cancer cachexia: Understanding the molecular basis. Nature Reviews. Cancer. 2014;**14**(11): 754-762. DOI: 10.1038/nrc3829

[5] Morley JE, Thomas DR, Wilson MM. Cachexia: Pathophysiology and clinical relevance. The American Journal of Clinical Nutrition. 2006;**83**(4):735-743. DOI: 10.1093/ajcn/83.4.735

[6] Blum D, Stene GB, Solheim TS, Fayers P, Hjermstad MJ, Baracos VE, et al. Validation of the consensus-definition for cancer cachexia and evaluation of a classification model--a study based on data from an international multicentre project (EPCRC-CSA). Annals of Oncology. 2014;**25**(8):1635-1642. DOI: 10.1093/annonc/mdu086

[7] Tang M, Jia Z, Zhang J. The prognostic role of prognostic nutritional index in nasopharyngeal carcinoma: A systematic

review and meta- analysis. International Journal of Clinical Oncology. 2021;**26**:66- 77. DOI: 10.1007/s10147-020-01791-x

[8] Pastore CA, Orlandi SP, González MC. Association between an inflammatorynutritional index and nutritional status in cancer patients. Nutrición Hospitalaria. 2013;**28**(1):188-193. DOI: 10.3305/nh.2013.28.1.6167

[9] Leal LP, Mognhol MS, Carvalho LR, Echebarrie ÁD, Silva NMF, Petarli GB, et al. Neutrophil-to-lymphocyte ratio and nutritional status in patients with cancer in hospital admission. International Journal of Cancer Research. 2019;**15**:9-16. DOI: 10.3923/ijcr.2019.9.16

[10] Sachlova M, Majek O, Tucek S. Prognostic value of scores based on malnutrition or systemic inflammatory response in patients with metastatic or recurrent gastric cancer. Nutrition and Cancer. 2014;**66**(8):1362-1370. DOI: 10.1080/01635581.2014.956261

[11] Hwang JE, Kim HN, Kim DE, Choi HJ, Jung SH, Shim HJ, et al. Prognostic significance of a systemic inflammatory response in patients receiving first-line palliative chemotherapy for recurred or metastatic gastric cancer. BMC Cancer. 2011;**11**:489. DOI: 10.1186/1471-2407-11-489

[12] Muscaritoli M, Lucia S, Farcomeni A, Lorusso V, Saracino V, Barone C, et al. PreMiO study group. Prevalence of malnutrition in patients at first medical oncology visit: The PreMiO study. Oncotarget. 2017;**8**(45):79884-79896. DOI: 10.18632/oncotarget.20168

[13] Muscaritoli M, Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, et al. ESPEN practical guideline: Clinical Nutrition in cancer. Clinical

*Inflammation-Based Markers of Nutrition in Cancer Patients DOI: http://dx.doi.org/10.5772/intechopen.104428*

Nutrition. 2021;**40**(5):2898-2913. DOI: 10.1016/j.clnu.2021.02.005

[14] Soeters P, Bozzetti F, Cynober L, Forbes A, Shenkin A, Sobotka L. Defining malnutrition: A plea to rethink. Clinical Nutrition. 2017;**36**(3):896-901. DOI: 10.1016/j.clnu.2016.09.032

[15] Zheng K, Liu X, Ji W, Lu J, Cui J, Li W. The efficacy of different inflammatory markers for the prognosis of patients with malignant tumors. Journal of Inflammation Research. 2021;**14**:5769-5785. DOI: 10.2147/JIR. S334941

[16] Wang X, Yang M, Ge Y, et al. Association of Systemic Inflammation and Malnutrition with Survival in nasopharyngeal carcinoma undergoing Chemoradiotherapy: Results from a multicenter cohort study. Frontiers in Oncology. 2021;**11**:766398. DOI: 10.3389/ fonc.2021.766398

[17] Maasberg S, Knappe-Drzikova B, Vonderbeck D, Jann H, Weylandt KH, Grieser C, et al. Malnutrition predicts clinical outcome in patients with neuroendocrine neoplasia. Neuroendocrinology. 2017;**104**(1):11-25. DOI: 10.1159/000442983

[18] Attar A, Malka D, Sabaté JM, Bonnetain F, Lecomte T, Aparicio T, et al. Malnutrition is high and underestimated during chemotherapy in gastrointestinal cancer: An AGEO prospective crosssectional multicenter study. Nutrition and Cancer. 2012;**64**(4):535-542. DOI: 10.1080/01635581.2012.670743

[19] Pressoir M, Desné S, Berchery D, et al. Prevalence, risk factors and clinical implications of malnutrition in French comprehensive cancer Centres. British Journal of Cancer. 2010;**102**(6):966-971. DOI: 10.1038/sj.bjc.6605578

[20] Hébuterne X, Lemarié E, Michallet M, de Montreuil CB, Schneider SM, Goldwasser F. Prevalence of malnutrition and current use of nutrition support in patients with cancer. JPEN Journal of Parenteral and Enteral Nutrition. 2014;**38**(2):196-204. DOI: 10.1177/0148607113502674

[21] Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. The American Journal of Medicine. 1980;**69**(4):491-497. DOI: 10.1016/ S0149-2918(05)80001-3

[22] Bozzetti F. On behalf of the SCRINIO working group. Screening the nutritional status in oncology: A preliminary report on 1,000 outpatients. Support Care Cancer. 2009;**17**:279-284. DOI: 10.1007/ s00520-008-0476-3

[23] Argas-Arce Y, Abarca-Gomez L. Prevalence of cachexia related to cancer in patients at a primary level: A palliative approach prevalence of cachexia related to cancer in patients at a primary level: A palliative approach. *Acta médical costarric* [online]. 2016;**58**(4):171-177

[24] Muscaritoli M, Corsaro E, Molfino A. Awareness of cancer-related malnutrition and its management: Analysis of the results from a survey conducted among medical oncologists. Frontiers in Oncology. 2021;**11**:682999. DOI: 10.3389/fonc.2021.682999

[25] Opanga Y, Kaduka L, Bukania Z, et al. Nutritional status of cancer outpatients using scored patient generated subjective global assessment in two cancer treatment centers, Nairobi, Kenya. BMC Nutrients. 2017;**3**:63. DOI: 10.1186/s40795-017-0181-z

[26] Ntekim AI, Folasire OF, Folasire AM. Prevalence of malnutrition among

cancer patients in a Nigerian institution. Journal of Analytical Oncology. 2017;*6*(2):117-124. DOI: 10.6000/1927-7229.2017.06.02.5

[27] Diakatou V, Vassilakou T. Nutritional status of pediatric cancer patients at diagnosis and correlations with treatment, clinical outcome and the longterm growth and health of survivors. Children (Basel). 2020;**7**(11):218. DOI: 10.3390/children7110218

[28] Sala A, Pencharz P, Barr RD. Children, cancer, and nutrition–a dynamic triangle in review. Cancer. 2004;**100**(4):677-687. DOI: 10.1002/ cncr.11833

[29] Revuelta Iniesta R, Paciarotti I, Davidson I, McKenzie JM, Brougham MFH, Wilson DC. Nutritional status of children and adolescents with cancer in Scotland: A prospective cohort study. Clinical Nutrients ESPEN. 2019;**32**:96-106. DOI: 10.1016/j. clnesp.2019.04.006

[30] Chukwu BF, Ezenwosu OU, Ukoha OM, et al. Nutritional status of children with cancer at the University of Nigeria teaching hospital, Ituku/ Ozalla, Enugu. Nigerian Journal of Cancer Prevention & Current Research. 2016;**5**(4):284-289. DOI: 10.15406/ jcpcr.2016.05.00167

[31] Brinksma A, Huizinga G, Sulkers E, Kamps W, Roodbol P, Tissing W. Malnutrition in childhood cancer patients: A review on its prevalence and possible causes. Critical Reviews in Oncology/Hematology. 2012;**83**(2):249-275. DOI: 10.1016/j. critrevonc.2011.12.003

[32] Villanueva G, Blanco J, Rivas S, Molina AL, Lopez N, Fuentes AL, et al. Nutritional status at diagnosis of cancer in children and adolescents in Guatemala and its relationship to socioeconomic disadvantage: A retrospective cohort study. Pediatric Blood & Cancer. 2019;**66**(6):e27647. DOI: 10.1002/ pbc.27647

[33] Lemos Pdos S, de Oliveira FL, Caran EM. Nutritional status of children and adolescents at diagnosis of hematological and solid malignancies. Revista Brasileira de Hematologia e Hemoterapia. 2014;**36**(6):420-423. DOI: 10.1016/j.bjhh.2014.06.001

[34] Lelbach A, Muzes G, Feher J. Current perspectives of catabolic mediators of cancer cachexia. Medical Science Monitor. 2007;**13**(9):RA168-RA173

[35] Han J, Meng Q, Shen L, Wu G. Interleukin-6 induces fat loss in cancer cachexia by promoting white adipose tissue lipolysis and browning. Lipids in Health and Disease. 2018;**17**(1):14, Jan 16. DOI: 10.1186/s12944-018-0657-0

[36] Ebadi M, Mazurak VC. Evidence and mechanisms of fat depletion in cancer. Nutrients. 2014;**6**(11):5280-5297. DOI: 10.3390/nu6115280

[37] Burckart K, Beca S, Urban RJ, Sheffield-Moore M. Pathogenesis of muscle wasting in cancer cachexia: Targeted anabolic and anticatabolic therapies. Current Opinion in Clinical Nutrition and Metabolic Care. 2010;**13**(4):410-416. DOI: 10.1097/MCO.0b013e328339fdd2

[38] Figueras M, Busquets S, Carbó N, Almendro V, Argilés JM, López-Soriano FJ. Cancer cachexia results in an increase in TNF-alpha receptor gene expression in both skeletal muscle and adipose tissue. International Journal of Oncology. 2005;**27**(3):855-860

[39] Inui A. Cancer anorexia-cachexia syndrome: Current issues in research and management. CA: a Cancer Journal *Inflammation-Based Markers of Nutrition in Cancer Patients DOI: http://dx.doi.org/10.5772/intechopen.104428*

for Clinicians. 2002;**52**(2):72-91. DOI: 10.3322/canjclin.52.2.72

[40] Argilés JM, Busquets S, Toledo M, López-Soriano FJ. The role of cytokines in cancer cachexia. Current Opinion in Supportive and Palliative Care. 2009;**3**(4):263-268. DOI: 10.1097/ SPC.0b013e3283311d09

[41] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;**100**(1):57-70. DOI: 10.1016/ S0092- 8674(00)81683-9

[42] Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB. Inflammation and cancer. Annals of African Medicine. 2019;**18**(3):121-126. DOI: 10.4103/aam.aam\_56\_18

[43] Vyas D, Laput G, Vyas A. Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Oncotargets and Therapy. 2014;**7**:1015-1023. DOI: 10.2147/OTT. S60114

[44] Demaria M, O'Leary MN, Chang J, Shao L, Liu S, Alimirah F, et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discovery. 2017;**7**(2):165-176. DOI: 10.1158/2159-8290.CD-16-0241

[45] Schaue D, Micewicz ED, Ratikan JA, Xie MW, Cheng G, McBride WH. Radiation and inflammation. Seminars in Radiation Oncology. 2015;**25**(1):4-10. DOI: 10.1016/j. semradonc.2014.07.007

[46] Lee CS, Ryan EJ, Doherty GA. Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: The role of inflammation. World Journal of Gastroenterology. 2014;**20**(14):3751- 3761. DOI: 10.3748/wjg.v20.i14.3751

[47] Cederholm T, Jensen GL, Correia MITD, Gonzalez MC, Fukushima R, Higashiguchi T, et al. GLIM Core leadership committee, GLIM working group. GLIM criteria for the diagnosis of malnutrition - a consensus report from the global clinical nutrition community. Journal of Cachexia, Sarcopenia and Muscle. 2019;**10**(1):207- 217. DOI: 10.1002/jcsm.12383

[48] Cederholm T, Barazzoni R, Austin P, et al. ESPEN guidelines on definitions and terminology of clinical nutrition. Clinical Nutrition. 2017;**36**(1):49-64. DOI: 10.1016/j.clnu.2016.09.004

[49] Soeters P, Bozzetti F, Cynober L, Elia M, Shenkin A, Sobotka L. Metaanalysis is not enough: The critical role of pathophysiology in determining optimal care in clinical nutrition. Clinical Nutrition. 2016;**35**(3):748-757. DOI: 10.1016/j.clnu.2015.08.008

[50] Engineer DR, Garcia JM. Leptin in anorexia and cachexia syndrome. International Journal of Peptide. 2012;**2012**:287457. DOI: 10.1155/2012/ 287457

[51] Diakowska D, Krzystek-Korpacka M, Markocka-Maczka K, Diakowski W, Matusiewicz M, Grabowski K. Circulating leptin and inflammatory response in esophageal cancer, esophageal cancerrelated cachexia-anorexia syndrome (CAS) and non-malignant CAS of the alimentary tract. Cytokine. 2010;**51**(2):132-137. DOI: 10.1016/j.cyto.2010.05.006

[52] Merker M, Felder M, Gueissaz L, Bolliger R, Tribolet P, Kägi-Braun N, et al. Association of Baseline Inflammation with Effectiveness of nutritional support among patients with disease-related malnutrition: A secondary analysis of a randomized clinical trial. JAMA Network Open. 2020;**3**(3):e200663. DOI: 10.1001/ jamanetworkopen.2020.0663

[53] Felder S, Braun N, Stanga Z, et al. Unraveling the link between malnutrition and adverse clinical outcomes: Association of acute and chronic malnutrition measures with blood biomarkers from different pathophysiological states. Annals of Nutrition & Metabolism. 2016;**68**(3): 164-172. DOI: 10.1159/000444096

[54] Knight K, Wade S, Balducci L. Prevalence and outcomes of anemia in cancer: A systematic reviews of the literature. The American Journal of Medicine. 2004;**116**(Suppl 7A):11S-26S. DOI: 10.1016/j.amjmed.2003.12.008

[55] http://www.who.int/vmnis/ indicators/haemoglobin.pdf. Accessed December 20, 2021.

[56] Macciò A, Madeddu C, Gramignano G, Mulas C, Tanca L, Cherchi MC, et al. The role of inflammation, iron, and nutritional status in cancer-related anemia: Results of a large, prospective, observationalstudy. Haematologica. 2015;**100**(1):124-132. DOI: 10.3324/haematol.2014.112813

[57] Akinbami A, Popoola A, Adediran A, Dosunmu A, Oshinaike O, Adebola P, et al. Full blood count pattern of prechemotherapy breast cancer patients in Lagos, Nigeria. Caspian Journal of Internal Medicine. 2013;**4**(1):574-579

[58] Waters JS, O'Brien ME, Ashley S. Management of anemia in patients receiving chemotherapy. Journal of Clinical Oncology. 2002;**20**(2):601-603. DOI: 10.1200/JCO.2002.20.2.601

[59] Madeddu C, Gramignano G, Astara G, Demontis R, Sanna E, Atzeni V, et al. Pathogenesis and treatment options of cancer related anemia: Perspective for a targeted mechanism-based approach. Frontiers in Physiology. 2018;**9**:1294. DOI: 10.3389/fphys.2018.01294

[60] Adamson JW. The anemia of inflammation/malignancy: Mechanisms and management. Hematology. American Society of Hematology. Education Program. 2008;**2008**(1):159-165. DOI: 10.1182/asheducation-2008.1.159

[61] Jain S, Narayan S, Chandra J, Sharma S, Jain S, Malhan P. Evaluation of serum transferrin receptor and sTfR ferritin indices in diagnosing and differentiating iron deficiency anemia from anemia of chronic disease. Indian Journal of Pediatrics. 2010;**77**(2):179-183. DOI: 10.1007/s12098-009-0302-z

[62] Madeddu C, Mantovani G, Gramignano G, Astara G, Macciò A. Muscle wasting as main evidence of energy impairment in cancer cachexia: Future therapeutic approaches. Future Oncology. 2015;**11**(19):2697-2710. DOI: 10.2217/fon.15.195

[63] Spivak JL. The anaemia of cancer: Death by a thousand cuts. Nature Reviews. Cancer. 2005;**5**:543-555. DOI: 10.1038/nrc1648

[64] Prince OD, Langdon JM, Layman AJ, Prince IC, Sabogal M, Mak HH, et al. Late stage erythroid precursor production is impaired in mice with chronic inflammation. Haematologica. 2012;**97**:1648-1656. DOI: 10.3324/ haematol. 2011.053397

[65] Hung SC, Tung TY, Yang CS, Tarng DC. High-calorie supplementation increases serum leptin levels and improves response to rHuEPO in longterm hemodialysis patients. American Journal of Kidney Diseases. 2005;**45**:1073- 1083. DOI: 10.1053/j.ajkd.2005.02.020

[66] Yavuzsen T, Davis MP, Walsh D, LeGrand S, Lagman R. Systematic review of the treatment of cancer-associated anorexia and weight loss. Journal of Clinical Oncology. 2005;**23**(33):8500- 8511. DOI: 10.1200/JCO.2005.01.8010

*Inflammation-Based Markers of Nutrition in Cancer Patients DOI: http://dx.doi.org/10.5772/intechopen.104428*

[67] Ezeoke CC, Morley JE. Pathophysiology of anorexia in the cancer cachexia syndrome. Journal of Cachexia, Sarcopenia and Muscle. 2015;**6**(4):287-302. DOI: 10.1002/jcsm.12059

[68] Laviano A, Inui A, Marks DL, Meguid MM, Pichard C, Rossi Fanelli F, et al. Neural control of the anorexiacachexia syndrome. American Journal of Physiology. Endocrinology and Metabolism. 2008;**295**(5):E1000-E1008. DOI: 10.1152/ajpendo.90252.2008

[69] López M, Lelliott CJ, Tovar S, Kimber W, Gallego R, Virtue S, et al. Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes. 2006;**55**(5): 1327-1336. DOI: 10.2337/db05-1356

[70] Davis MP, Dreicer R, Walsh D, Lagman R, LeGrand SB. Appetite and cancer-associated anorexia: A review. Journal of Clinical Oncology. 2004;**22**(8):1510-1517. DOI: 10.1200/ JCO.2004.03.103

[71] Noguchi Y, Yoshikawa T, Matsumoto A, Svaninger G, Gelin J. Are cytokines possible mediators of cancer cachexia? Surgery Today. 1996;**26**(7):467- 475. DOI: 10.1007/BF00311551

[72] Patra SK, Arora S. Integrative role of neuropeptides and cytokines in cancer anorexia-cachexia syndrome. Clinica Chimica Acta. 2012;**413**(13-14):1025- 1034. DOI: 10.1016/j.cca.2011.12.008

[73] Ramos EJ, Suzuki S, Marks D, Inui A, Asakawa A, Meguid MM. Cancer anorexia-cachexia syndrome: Cytokines and neuropeptides. Current Opinion in Clinical Nutrition and Metabolic Care. 2004;**7**(4):427-434. DOI: 10.1097/01. mco.0000134363.53782.cb

[74] Dinarello CA. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. The American Journal of Clinical Nutrition. 2006;**83**(2):447S-455S. DOI: 10.1093/ ajcn/83.2.447S

[75] Perboni S, Inui A. Anorexia in cancer: Role of feeding-regulatory peptides. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2006;**361**(1471):1281-1289. DOI: 10.1098/rstb.2006.1863

[76] Uehara A, Sekiya C, Takasugi Y, Namiki M, Arimura A. Anorexia induced by interleukin 1: Involvement of corticotropin-releasing factor. The American Journal of Physiology. 1989 Sep;**257**(3 Pt 2):R613-R617. DOI: 10.1152/ ajpregu.1989.257.3.R613

[77] Torelli GF, Meguid MM, Moldawer LL, Edwards CK 3rd, Kim HJ, Carter JL, et al. Use of recombinant human soluble TNF receptor in anorectic tumor-bearing rats. The American Journal of Physiology. 1999;**277**(3):R850-R855. DOI: 10.1152/ajpregu.1999.277.3.R850

[78] Michael J. Tisdale, biology of cachexia. JNCI: Journal of the National Cancer Institute. 1997;**89**(23):1763-1773. DOI: 10.1093/jnci/89.23.1763

[79] Narsale AA, Carson JA. Role of interleukin-6 in cachexia: Therapeutic implications. Current Opinion in Supportive and Palliative Care. 2014;**8**(4):321-327. DOI: 10.1097/ SPC.0000000000000091

[80] White JP. IL-6, cancer and cachexia: Metabolic dysfunction creates the perfect storm. Translational Cancer Research. 2017;**6**(Suppl 2):S280-S285. DOI: 10.21037/ tcr.2017.03.52

[81] Plata-Salamán CR. Anorexia induced by activators of the signal transducer gp

130. Neuroreport. 1996;**7**(3):841-844. DOI: 10.1097/00001756-199602290-00038

[82] Bossola M, Luciani G, Giungi S, Tazza L. Anorexia, fatigue, and plasma interleukin-6 levels in chronic hemodialysis patients. Renal Failure. 2010;**32**(9):1049-1054. DOI: 10.3109/0886022X.2010.504910

[83] Cohn SH, Gartenhaus W, Sawitsky A, Rai K, Zanzi I, Vaswani A, et al. Compartmental body composition of cancer patients by measurement of total body nitrogen, potassium, and water. Metabolism. 1981;**30**(3):222-229. DOI: 10.1016/0026-0495(81)90145-1

[84] Shinsyu A, Bamba S, Kurihara M, Matsumoto H, Sonoda A, Inatomi O, et al. Inflammatory cytokines, appetiteregulating hormones, and energy metabolism in patients with gastrointestinal cancer. Oncology Letters. 2020;**20**:1469-1479. DOI: 10.3892/ ol.2020.11662

[85] Yang W, Huang J, Wu H, Wang Y, Du Z, Ling Y, et al. Molecular mechanisms of cancer cachexia-induced muscle atrophy (review). Molecular Medicine Reports. 2020;**22**(6):4967-4980. DOI: 10.3892/mmr.2020.11608

[86] Bharadwaj S, Ginoya S, Tandon P, Gohel TD, Guirguis J, Vallabh H, et al. Malnutrition: Laboratory markers vs nutritional assessment. Gastroenterology Reports (Oxf). 2016;**4**(4):272-280. DOI: 10.1093/gastro/gow013

[87] Jabłońska B, Pawlicki K, Mrowiec S. Associations between nutritional and immune status and Clinicopathologic factors in patients with pancreatic cancer: A comprehensive analysis. Cancers (Basel). 2021;**13**(20):5041. DOI: 10.3390/ cancers13205041

[88] Izuegbuna OO, Olawumi HO, Olatoke SA, Durotoye I. An evaluation of inflammatory and nutritional status of breast cancer outpatients in a tertiary Hospital in Nigeria. Nutrition and Cancer. 2022;**74**(1):90-99. DOI: 10.1080/01635581.2020.1870703

[89] Reber E, Schönenberger KA, Vasiloglou MF, Stanga Z. Nutritional risk screening in cancer patients: The first step toward better clinical outcome. Frontiers in Nutrition. 2021;**8**:603936. DOI: 10.3389/fnut.2021.603936

[90] Nadal A, Fuentes E, Pastor J, McNaughton PA. Plasma albumin is a potent trigger of calcium signals and DNA synthesis in astrocytes. Proceedings of the National Academy of Sciences of the United States of America. 1995;**92**(5):1426-1430. DOI: 10.1073/ pnas.92.5.1426

[91] Roche M, Rondeau P, Singh NR, Tarnus E, Bourdon E. The antioxidant properties of serum albumin. FEBS Letters. 2008;**582**(13):1783-1787. DOI: 10.1016/j.febslet.2008.04.057

[92] Fruchtenicht AVG, Poziomyck AK, Reis AMD, Galia CR, Kabke GB, Moreira LF. Inflammatory and nutritional statuses of patients submitted to resection of gastrointestinal tumors. Revista do Colégio Brasileiro de Cirurgiões. 2018;**45**(2):e1614. DOI: 10.1590/0100-6991e-20181614

[93] Das U, Patel S, Dave K, Bhansali R. Assessment of nutritional status of gynecological cancer cases in India and comparison of subjective and objective nutrition assessment parameters. South Asian Journal of Cancer. 2014;**3**(1):38-42. DOI: 10.4103/2278-330X.126518

[94] Daniele A, Divella R, Abbate I, Casamassima A, Garrisi VM, Savino E, et al. Assessment of nutritional and inflammatory status to determine the prevalence of malnutrition in patients

*Inflammation-Based Markers of Nutrition in Cancer Patients DOI: http://dx.doi.org/10.5772/intechopen.104428*

undergoing surgery for colorectal carcinoma. Anticancer Research. 2017;**37**(3):1281-1287. DOI: 10.21873/ anticanres.11445

[95] Yu YL, Fan CW, Tseng WK, Chang PH, Kuo HC, Pan YP, et al. Correlation between the Glasgow prognostic score and the serum cytokine profile in Taiwanese patients with colorectal cancer. The International Journal of Biological Markers. 2021;**36**(2):40-49. DOI: 10.1177/17246008211022769

[96] Asegaonkar SB, Asegaonkar BN, Takalkar UV, Advani S, Thorat AP. C-reactive protein and breast cancer: New insights from old molecule. International Journal of Breast Cancer. 2015;**2015**:145647. DOI: 10.1155/2015/145647

[97] Costa MD, Vieira de Melo CY, Amorim AC, Cipriano Torres Dde O, Dos Santos AC. Association between nutritional status, inflammatory condition, and prognostic indexes with postoperative complications and clinical outcome of patients with gastrointestinal neoplasia. Nutrition and Cancer. 2016;**68**(7):1108-1114. DOI: 10.1080/01635581.2016.1206578

[98] Laird BJ, McMillan DC, Fayers P, et al. The systemic inflammatory response and its relationship to pain and other symptoms in advanced cancer. The Oncologist. 2013;**18**(9):1050-1055. DOI: 10.1634/theoncologist.2013-0120

[99] Yu JM, Yang M, Xu HX, Li W, Fu ZM, Lin Y, et al. Investigation on nutrition status and clinical outcome of common cancers (INSCOC) group. Association between serum C-reactive protein concentration and nutritional status of malignant tumor patients. Nutrition and Cancer. 2019;**71**(2):240-245. DOI: 10.1080/01635581.2018.1524019

[100] Read JA, Choy ST, Beale PJ, Clarke SJ. Evaluation of nutritional and inflammatory status of advanced colorectal cancer patients and its correlation with survival. Nutrition and Cancer. 2006;**55**(1):78-85. DOI: 10.1207/ s15327914nc5501\_10

[101] Liu B, Huang Y, Sun Y, Zhang J, Yao Y, Shen Z, et al. Prognostic value of inflammation-based scores in patients with osteosarcoma. Scientific Reports. 2016 Dec;**23**(6):39862. DOI: 10.1038/ srep39862

[102] Jiang Y, Xu D, Song H, et al. Inflammation and nutrition-based biomarkers in the prognosis of oesophageal cancer: A systematic review and meta-analysis. BMJ Open. 2021;**11**:e048324. DOI: 10.1136/ bmjopen-2020-048324

[103] McMillan DC. The systemic inflammation-based Glasgow prognostic score: A decade of experience in patients with cancer. Cancer Treatment Reviews. 2013 Aug;**39**(5):534-540. DOI: 10.1016/j. ctrv.2012.08.003

[104] Silva GA, d, Wiegert EVM, Calixto-Lima L, Oliveira LC. Clinical utility of the modified Glasgow prognostic score to classify cachexia in patients with advanced cancer in palliative care. Clinical Nutrition. 2020;**39**(5):1587-1592. DOI: 10.1016/j. clnu.2019.07.002

[105] da Silva JB, Maurício SF, Bering T, Correia MI. The relationship between nutritional status and the Glasgow prognostic score in patients with cancer of the esophagus and stomach. Nutrition and Cancer. 2013;**65**(1):25-33. DOI: 10.1080/01635581.2013.741755

[106] Ranzani OT, Zampieri FG, Forte DN, Azevedo LC, Park M. C-reactive protein/albumin ratio predicts 90-day mortality of septic patients. PLoS One. 2013;**8**(3):e59321. DOI: 10.1371/ journal.pone.0059321

[107] Liu Z, Shi H, Chen L. Prognostic role of pre-treatment C-reactive protein/ albumin ratio in esophageal cancer: A meta-analysis. BMC Cancer. 2019;**19**:1161. DOI: 10.1186/s12885-019-6373-y

[108] Gomes de Lima KV, Maio R. Nutritional status, systemic inflammation and prognosis of patients with gastrointestinal cancer. Nutrición Hospitalaria. 2012;**27**(3):707-714. DOI: 10.3305/nh/2012.27.3.5567

[109] Ikeguchi M, Hanaki T, Endo K, Suzuki K, Nakamura S, Sawata T, et al. C-reactive protein/albumin ratio and prognostic nutritional index are strong prognostic indicators of survival in resected pancreatic ductal adenocarcinoma. Journal of Pancreatic Cancer. 2017;**3**(1):31-36. DOI: 10.1089/ pancan.2017.0006

[110] Park HC, Kim MY, Kim CH. C-reactive protein/albumin ratio as prognostic score in oral squamous cell carcinoma. Journal of the Korean Association of Oral and Maxillofacial Surgeons. 2016;**42**(5):243-250. DOI: 10.5125/jkaoms.2016.42.5.243

[111] Feng JF, Wang L, Jiang YH, Yang X. C-reactive protein to Prealbumin ratio (CPR): A novel inflammatory-nutritional prognostic factor for predicting cancerspecific survival (CSS) and overall survival (OS) in patients with Resectable esophageal squamous cell carcinoma. Journal of Oncology. 2019;**14**:4359103. DOI: 10.1155/2019/4359103

[112] Corbeau I, Jacot W, Guiu S. Neutrophil to lymphocyte ratio as prognostic and predictive factor in breast cancer patients: A systematic review.

Cancers (Basel). 2020;**12**(4):958. 2020;13. DOI: 10.3390/cancers12040958

[113] Templeton AJ, Ace O, McNamara MG, Al-Mubarak M, Vera-Badillo FE, Hermanns T, et al. Prognostic role of platelet to lymphocyte ratio in solid tumors: A systematic review and meta-analysis. Cancer Epidemiology, Biomarkers & Prevention. 2014;**23**:1204-1212. DOI: 10.1158/1055-9965.EPI-14-0146

[114] Watt DG, Martin JC, Park JH, Horgan PG, McMillan DC. Neutrophil count is the most important prognostic component of the differential white cell count in patients undergoing elective surgery for colorectal cancer. American Journal of Surgery. 2015;**210**(1):24-30. DOI: 10.1016/j.amjsurg.2014.12.031

[115] Izuegbuna O, Olawumi HO, Olatoke SA, Agodirin OS. Haemogram pattern and Khorana score of breast cancer patients in a tertiary Centre in Nigeria. Tanzania Medical Journal. 2020;**31**(4):110-131. DOI: 10.4314/tmj. v31i4.414.g258

[116] Schlesinger M. Role of platelets and platelet receptors in cancer metastasis. Journal of Hematology & Oncology. 2018;**11**(1):125. DOI: 10.1186/ s13045-018-0669-2

[117] Siqueira JM, Soares JDP, Borges TC, et al. High neutrophil to lymphocytes ratio is associated with nutritional risk in hospitalised, unselected cancer patients: A cross-sectional study. Scientific Reports. 2021;**11**:17120. DOI: 10.1038/ s41598-021-96586-z

[118] Sato Y, Gonda K, Harada M, et al. Increased neutrophil-to-lymphocyte ratio is a novel marker for nutrition, inflammation and chemotherapy outcome in patients with locally advanced and metastatic esophageal squamous cell carcinoma. Biomedical Reports. 2017;**7**(1):79-84. DOI: 10.3892/br.2017.924

*Inflammation-Based Markers of Nutrition in Cancer Patients DOI: http://dx.doi.org/10.5772/intechopen.104428*

[119] Tan CS, Read JA, Phan VH, Beale PJ, Peat JK, Clarke SJ. The relationship between nutritional status, inflammatory markers and survival in patients with advanced cancer: A prospective cohort study. Supportive Care in Cancer. 2015;**23**(2):385-391. DOI: 10.1007/ s00520-014-2385-y

[120] Mathur K, Kurbanova N, Qayyum R. Platelet-lymphocyte ratio (PLR) and all-cause mortality in general population: Insights from national health and nutrition education survey. Platelets. 2019;**30**(8):1036-1041. DOI: 10.1080/09537104.2019.1571188

[121] Zhou X, Du Y, Huang Z, Xu J, Qiu T, Wang J, et al. Prognostic value of PLR in various cancers: A meta-analysis. PLoS One. 2014;**9**(6):e101119. DOI: 10.1371/ journal.pone.0101119

[122] Arrieta O, Michel Ortega RM, Villanueva-Rodríguez G, et al. Association of nutritional status and serum albumin levels with development of toxicity in patients with advanced non-small cell lung cancer treated with paclitaxelcisplatin chemotherapy: A prospective study. BMC Cancer. 2010;**10**:50. DOI: 10.1186/1471-2407-10-50

[123] Xu Y, Yuan X, Zhang X, Hu W, Wang Z, Yao L, et al. Prognostic value of inflammatory and nutritional markers for hepatocellular carcinoma. Medicine (Baltimore). 2021;**100**(25):e26506. DOI: 10.1097/MD.0000000000026506

[124] Lj X, Li W, Zhai J, et al. Significance of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio and prognostic nutritional index for predicting clinical outcomes in T1-2 rectal cancer. BMC Cancer. 2020;**20**:208. DOI: 10.1186/s12885-020-6698-6

[125] Hu Q, Mao W, Wu T, Xu Z, Yu J, Wang C, et al. High neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio are associated with sarcopenia risk in hospitalized renal cell carcinoma patients. Frontiers in Oncology. 2021;**11**:736640. DOI: 10.3389/ fonc.2021.736640

[126] Lin J, Zhang W, Huang Y, Chen W, Wu R, Chen X, et al. Sarcopenia is associated with the neutrophil/ lymphocyte and platelet/lymphocyte ratios in operable gastric cancer patients: A prospective study. Cancer Management and Research. 2018;**10**:4935-4944. DOI: 10.2147/CMAR.S175421

[127] Zhou X, Fragala MS, McElhaney JE, Kuchel GA. Conceptual and methodological issues relevant to cytokine and inflammatory marker measurements in clinical research. Current Opinion in Clinical Nutrition and Metabolic Care. 2010;**13**(5):541-547. DOI: 10.1097/MCO.0b013e32833cf3bc

[128] Koola MM. Methodological issues in cytokine measurement in schizophrenia. Indian Journal of Psychological Medicine. 2016;**38**(1):6-9. DOI: 10.4103/0253-7176.175086

[129] Wong HL, Pfeiffer RM, Fears TR, Vermeulen R, Ji S, Rabkin CS. Reproducibility and correlations of multiplex cytokine levels in asymptomatic persons. Cancer Epidemiology, Biomarkers & Prevention. 2008;**17**(12):3450-3456. DOI: 10.1158/1055-9965.EPI-08-0311

[130] Brenner DR, Scherer D, Muir K, Schildkraut J, Boffetta P, Spitz MR, et al. A review of the application of inflammatory biomarkers in epidemiologic cancer research. Cancer Epidemiology, Biomarkers & Prevention. 2014;**23**(9):1729-1751. DOI: 10.1158/1055- 9965.EPI-14-0064

[131] Argilés JM, López-Soriano FJ, Toledo M, Betancourt A, Serpe R, Busquets S. The cachexia score (CASCO): A new tool for staging cachectic cancer patients. Journal of Cachexia, Sarcopenia and Muscle. 2011;**2**(2):87-93. DOI: 10.1007/s13539-011-0027-5

[132] Argilés JM, Betancourt A, Guàrdia-Olmos J, Peró-Cebollero M, López-Soriano FJ, Madeddu C, et al. Validation of the CAchexia SCOre (CASCO). Staging cancer patients: The use of miniCASCO as a simplified tool. Frontiers in Physiology. 2017;**8**:92. DOI: 10.3389/fphys.2017.00092

[133] Wu J, Huang C, Xiao H, Tang Q, Cai W. Weight loss and resting energy expenditure in male patients withnewlydiagnosed esophageal cancer. Nutrition. 2013;**29**(11-12):1310-1314. DOI: 10.1016/j.nut.2013.04.010

[134] Walsh D, Mahmoud F, Barna B. Assessment of nutritional status and prognosis in advanced cancer: Interleukin-6, C-reactive protein, and the prognostic and inflammatory nutritional index. Supportive Care in Cancer. 2003;**11**(1):60-62. DOI: 10.1007/ s00520-002-0390-z

[135] Rocha NP, Fortes RC. Total lymphocyte count and serum albumin as predictors of nutritional risk in surgical patients. Arquivos Brasileiros de Cirurgia Digestiva. 2015;**28**(3):193-196. DOI: 10.1590/S0102-67202015000300012

[136] Hu Z, Tan S, Chen S, Qin S, Chen H, Qin S, et al. Diagnostic value of hematological parameters platelet to lymphocyte ratio and hemoglobin to platelet ratio in patients with colon cancer. Clinica Chimica Acta. 2020;**501**:48-52. DOI: 10.1016/j. cca.2019.11.036

## **Chapter 3**
