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Malnutrition, anorexia and cachexia in cancer patients: A mini-review on pathogenesis and treatment

Biomedicine & Pharmacotherapy, 8, 67, pages 807 - 817

Abstract

Malnutrition, anorexia and cachexia are a common finding in cancer patients. They become more evident with tumor growth and spread. However, the mechanisms by which they are sustained often arise early in the history of cancer. For malnutrition, these mechanisms can involve primary tumor or damage by specific treatment such as anticancer therapies (surgery, chemotherapy, radiotherapy) also in cancers that usually are not directly responsible for nutritional and metabolic status alterations (i.e. bone tumors). For anorexia, meal-related neural or hormonal signals and humoral signals related to body fat or energy storage and the interaction of these signals with the hypothalamus or the hypothalamic inappropriate response play a pathogenetic role. Some cytokines are probably involved in these mechanisms. For cachexia, the production of proinflammatory cytokines by tumour cells is the initial mechanism; the main biochemical mechanisms involved include the ubiquitine proteasome-dependent proteolysis and heat shock proteins. Treatment includes pharmaceutical and nutritional interventions.

Keywords: Cancer, Malnutrition, Anorexia, Cachexia, Treatment.

1. Introduction

Nutritional assessment is an essential step in the global management of all cancer patients, in order to distinguish malnourished and non-malnourished patients [1]. The American Society for Parenteral and Enteral Nutrition guidelines defined malnutrition as an acute, subacute or chronic state of nutrition, in which a combination of varying degrees of overnutrition or undernutrition with or without inflammatory activity have led to a change in body composition and diminished function [2].

The European guidelines for surgical patients suggest a systematic screening of malnourished patients [3]. Malnutrition in cancer patients is associated with increased morbidity, including a higher rate of toxicities during chemotherapy and radiotherapy, increased hospital length of stay, increased treatment costs, decreased performance status and altered quality of life [1]. While anorexia is defined as the loss of the desire to eat, which frequently leads to reduced food intake, cachexia is a multi-organ syndrome, characterized by weight loss (at least 5%), muscle and adipose tissue wasting and inflammation. Metabolic abnormalities in carbohydrate, lipid and protein metabolism are thought to be caused by tumor-induced production of humoral inflammatory mediators (such as cytokines) or other mediators produced directly by the tumor [4].

The complex syndrome of cancer cachexia is a pathological state where loss of muscle (skeletal and visceral) or muscle and fat occurs, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system and metabolic dysfunction. Cancer cachexia occurs in 50% to 80% of the cancer patients and identified as an independent predictor of shorter survival and increases the risk of treatment failure and toxicity in this population. It reduces the quality of life and accounts for more than 20% of all cancer-related deaths [5] and [6].

This review focuses on pathogenesis and clinical aspects of both malnutrition, anorexia and cachexia with principles of treatment.

2. Etiology of malnutrition in individuals with cancer

Malnutrition is more common in gastrointestinal (GI), head and neck and lung than in other types of cancer and it is associated with a poor prognosis [7], [8], [9], [10], and [11]. The underlying etiology of malnutrition in cancer patients is multifactorial and includes abnormalities in GI function. These GI abnormalities can be due to tumour-related mechanisms or anticancer therapies in addition to tumor-induced metabolic abnormalities [12].

Obstruction, metabolic abnormalities and functionality changes are more common tumor-related mechanisms for malnutrition. Head and neck cancer may cause dysphagia and odynophagia; more than 50% of the patients with advanced head and neck cancer have a markedly impaired nutrition and a significant involuntary weight loss at the time of diagnosis [13]. These patients may have underlying chronic malnutrition at presentation due to alchool, tobacco abuse and unhealthy dietary habit [13] and [14]. Primary mediastinal tumors, such as lymphoma as well as metastatic tumors, such as lung or breast tumors may provoke dysphagia due to esophageal involvement [15]. Esophageal cancer typically causes progressive dysphagia, odynophagia and rigurgitation [16]. Common presenting symptoms of gastric cancer include loss of appetite, early satiety, abdominal discomfort [17]. Leukemias and lymphomas, when disseminated to the small bowel, can provoke malabsorption by direct infiltration of the enteric wall or by massive infiltration of lymphatic structures. Bowel tumors can present with obstructive symptoms [18] and [19]. Extensive liver infiltration by primary or secondary tumor may have important metabolic consequences, first of all hypo-albuminemia, reduction in protein and fat synthesis and sometimes hypoglycemia. The presenting symptoms of pancreatic cancer can include pain, loss of appetite, steatorrhea, dyspepsia [20]. Among neuro-endocrine gastro-enteropancreatic tumors [21], carcinoid tumors may cause diarrhoea related to increased gut motility, due to abnormal hormone production (serotonin) [22]; in patients with gastrinoma, an intermittent diarrhoea, often with steatorrhea may be present as a result of digestive enzyme inactivation in the small intestine by unbuffered gastric acid [23]. Treatment with somatostatin analogues has proved effective in the control of diarrhoea following the production and release of serotonin and vasoactive intestinal peptide (VIP) [21].

2.2. Anticancer therapies

Surgery, chemotherapy and radiotherapy can induce or worsen malnutrition. However, in our experience, an oncologic effective treatment, except for GI cancers or in patients after receiving several lines of chemotherapy, rarely causes an uncontrolled malnutrition. On the other hand, a treatment with low toxicity and limited antitumoral efficacy can favor a malnutritional status induced by the tumor progression [24].

2.2.1. Surgery
2.2.1.1. Laryngectomy, pharyngolaryngectomy, esophagectomy

Digestive tract surgery can interfere with nutrition by effects on swallowing and gastrointestinal motility, or more often by malabsorption [24]. Common nutritional consequences of the surgical resection of the larynx and digestive organs are shown in Table 1. The most common complications after oral cancer surgery are alterations in swallowing and mastication, that may continue for up to a year after treatment in up to 50% of the patients [25] and [26]. Three years after surgery, 42% of laryngectomy and 50% of pharyngolaryngectomy patients experienced long-term dysphagia leading to nutritional deficits and requiring a modification of their diet or tube feeding [26] and [27]; chronic xerostomia, that also impairs swallowing, can occur in patients up to 5-years after treatment [28]. In neurogenic dysphagia, there are different levels of severity so, it is possible to distinguish two different types of diets, one for liquids and one for patients with pharyngeal problems concerning the bolus formation [29]. Dysphagia, heartburn, hoaresness, reflux, abnormal gastric emptying, dumping syndrome (diarrhoea, abdominal cramps, nausea, dizziness, diaphoresis), increased stool frequency are frequently reported after esophagectomy; 80–90% of the patients experience early satiety, about 75% suffer from post-prandial dumping syndrome, 50–60% have reflux of food/fluid and absence of hunger in the first postoperative year. Weight loss is common after esophagectomy, and the majority of patients are unable to return to their preoperative weight [30].

Table 1 Common unfavourable nutritional consequences following resection of larynx and digestive organs.

Resected organ Impact on nutrition
Oral cavity, larynx, pharynx Dysphagia
Thoracic esophagus Dysphagia, reflux, pain during alimentation, early satiety, dumping syndrome
Stomach Anorexia, early satiety, reflux, epigastric pain, dumping syndrome, malabsorption (fat, iron, calcium, vitamin B12)
Small intestine Bacterial overgrowth, malabsorption, diarrhoea
Colon (total or subtotal resection) Water and electrolyte loss
Pancreas Malabsorption, steatorrhea, nausea, vomiting, diabetes
Liver Transitory hypo-albuminemia
2.2.1.2. Gastrectomy

Total gastrectomy has a profound effect on nutritional status, including weight loss, malabsorption, maldigestion, shortened intestinal transit time and bacterial overgrowth. This surgical intervention, by reducing the reservoir into which patients can eat and by altering the physiology of digestion produces malnutrition in approximately 80% of the patients [31] and [32]. Diarrhoea usually occurs within 1–2h after eating, and is probably partly caused by vagotomy, lack of gastric hormones, and defective fat absorption due to pancreatic insufficiency [33]. Factors increasing malabsorption include defective stimulation of biliary and pancreatic secretions by ingested food by-passing the duodenum, and inadequate mixing of biliary and pancreatic secretions with food. Malabsorption of dietary fat has been proposed as a major contributor to weight loss. Malabsorption of aminoacids has also been reported, resulting in a state of persistent proteolysis for long periods after surgery [31]. Loss of gastric and duodenal absorptive surface causes malabsorption of iron, vitamin B12, calcium, fat and carotene; stasis in the afferent loop can lead to bacterial overgrowth and abnormalities in bile salt metabolism.

2.2.1.3. Pancreaticoduodenectomy

The degree of pancreatic function impairment is related to the extent of parenchyma resection and the functional state of the residual pancreas [34] and [35]. Accordingly with what was just previously mentioned, another contributing factor for malnutrition is disease progression. One year after curative resection, the malnutrition status is maintained as well as many gastrointestinal symptoms [36]. After a follow-up longer at least one year, more than 50% of the patients submitted to pancreaticoduodenectomy have been reported to develop a pancreatic exocrine insufficiency. Pancreatic exocrine insufficiency is caused by a loss of enzymatic activity in the intestinal lumen, in particular lipase, with consequent malabsorption of fat, protein, starch, and fat-soluble vitamins, such as A, D E and K [37]. Therapy is based on the oral administration of pancreatic enzymes aiming at providing the duodenal lumen with sufficient active lipase at the time of gastric emptying of nutrients [38]. Foods containing long chain triglycerides (LCT) may be replaced by the recruitment of medium chain triglycerides (MCT) that are more rapidly hydrolyzed and absorbed. MCT should be given in four daily doses of about 15mL, while higher doses are not recommended for the possible induction of diarrhea [39]; there can be loss of endocrine function too, and when glucose is not well controlled, there will be weight loss.

2.2.2. Chemotherapy

Chemotherapy can induce nausea, vomiting, mucositis, diarrhoea, dysgeusia. Also, biological therapies can induce low-moderate nausea and/or vomiting (interferons and monoclonal antibodies, such as bevacizumab, cetuximab) or diarrhoea (timidine kinase inhibitors, such as lapatinib). Some drugs, as alkylating agents (i.e. cyclofosfamide, ifosfamide, etc), methotrexate, fluorouracil, actinomycin-D, cisplatin, vincristin, doxorubicin, etc, can cause malabsorption by inducing direct mucosal and metabolic alterations [24] and [40].

2.2.3. Radiotherapy

Malnutrition and weight loss occur in about 90% of the patients submitted to intensive radiotherapy for head and neck, thoracic, abdominal and pelvic tumors. Irradiation of head and neck and thorax can cause malnutrition by xerostomia, mucositis, pain, hypophagia; abdominal irradiation also causes malabsorption [24]. Radiation-induced emesis occurs acutely in more than 90% of the patients receiving total body irradiation. Emesis develops in about 50% of patients receiving upper abdominal irradiation, in a median time of three days after RT [41] and [42]. The mechanism of radiation-induced emesis seems to be linked to the release of serotonin from gastrointestinal enterochromaffin cells. Most of the antiemetic agents active against chemotherapy-induced emesis have some activity against radiation-induced emesis (5-HT3 plus dexamethasone) [43]. Radiation therapy to the oral cavity frequently causes oral complications, including mucositis, xerostomia, tissue ulceration and taste alterations. Symptoms are typically maximal the week following the completion of radiation therapy, then, they usually plateau and may even diminish [44]. The intense pain may substantially limit adequate hydration and nutrition [45]. There is no sufficient evidence that non-absorbable antibiotics or antimicrobial mouthwashes are useful in this setting [46] and [47]. Analgesics and local anesthetics are used with mixed results [43], [48], and [49]. Acute esophagitis is a common adverse event (up to 30%) in the radiotherapy of intrathoracic neoplasms, and it is even more common for doses exceeding 50Gy and after chemo-radiation treatment [50]. Symptoms are dysphagia and thoracic pain. In the acute phase, therapy consists in nutritional support [29], amifostine, sucralfate, ranitidine and antifungal drugs; in the chronic phase, when a stenosis occurs, the most common intervention is the initiation of enteral nutrition; otherwise, esophageal dilation and stent placement are necessary [51].

2.3. Common GI abnormalities in individuals with cancer

Common general symptoms from abnormalities in GI function due to the primary tumor or the treatment of the tumor and affecting the nutritional status are: nausea, vomiting, malaise, anorexia, diarrhea, mechanic obstruction. Pain, fatigue and depression, that are common in cancer patients, also have an impact on nutrient intake [52].

2.4. Specific topics

2.4.1. Dysphagia

It can occur in patients with head, neck, esophageal and mediastinal tumors. Moreover, mechanical dysphagia may occur from obstructive tumors. As to diet, specific recommendations are reported [29]. The meat should be well cooked and cut into small pieces before being minced or homogenized: it is necessary to filter smoothies food to remove frustules. The liquid should be added gradually, the excess can alter the flavor and texture of foods. The use of whole milk improves the texture of smoothies foods. It is recommended to use thickeners (jellies, potato starch), lubricants (oil, butter, sauces, such as mayonnaise, white sauce), diluents (broths, vegetable juices or fruit, milk) to change the food consistence. The oil also considerably increase the calory intake of food without increasing the volume. The early start of enteral nutrition (EN) prevents deterioration of the nutritional status and the quality of life in mechanical dysphagia. In a non-randomized clinical trial performed in patients with esophageal cancer, EN allowed the planned cancer treatment in dysphagic patients with therapeutic response similar to non-dysphagic patients. The parenteral nutrition (PN) does not prevent the side effects of dysphagia and does not improve survival [53]. Neurogenic dysphagia may be caused by surgical ablation of muscular and nervous structures; the severity of swallowing deficit is dependent on the size and location of the lesion, the degree and extent of surgical excision and the association of chemo- or radiotherapy [54] and [55].

2.4.2. Dumping syndrome

This syndrome mainly occurs after gastrectomy and esophagectomy. It is commonly defined as a rapid gastric emptying characterized by GI and vasomotor symptoms appearing after ingestion of meals, particularly as a response to simple carbohydrates. It includes early and late syndromes. The early dumping syndrome occurs 15 to 30min after the meal, especially if rich in simple carbohydrates. The rapid abdominal distension and the activation of autonomic reflection with the release of vasoactive substances, such as serotonin and bradykinin, are responsible for the symptoms. The late dumping syndrome appears 2 or 3h after a meal due to a post-prandial hypoglycemia crisis that develops after too rapid influx of glucose in the blood and consequent hyperinsulinemia. The use of mixed meals can help in preventing dumping syndrome. In the early dumping syndrome, it is recommended to eat small and frequent meals, to separate the solid food ingestion from drinks about 40min, to avoid all carbohydrates or to prefer complex carbohydrates rich also in fiber, and finally to increase protein consumption. Supplementation with dietary fiber, including pectin, guar gum, and glucomannan has proven to be effective in the treatment of hypoglycemic episodes [56]. These dietary fibers form gels with carbohydrates, resulting in delayed glucose absorption and prolongation of bowel transit time. In the late syndrome, it is recommended to avoid sugar drinks, alcohol and to consume soluble fiber during each meal [29] and [39]. Subtotal gastrectomy, if possible, is generally preferred, because of a less effect on nutritional status. The nutritional status of patients submitted to subtotal gastrectomy has been found stabilized 6 months after surgery, but total gastrectomy patients have a reduced nutritional status, in terms of body weight, body mass index and anthropometric measurements, up to 12months after surgery [32].

Acute nausea and vomiting occur within 24h from chemotherapy administration and are often mediated by activation of serotonine type 3 receptors in the gastrointestinal tract by serotonin (5-HT) released by the enterochromaffin cells [41]. Delayed nausea and vomiting appear more than 24h after treatment and can persist until 7days after chemotherapy [41]; they are more common with cisplatin, carboplatin, oxaliplatin, doxorubicin, cyclophosphamide than with other antiblastics; the mechanisms underlying this complications are various and involve substance P, brain barrier and gastrointestinal motility disruption, adrenal hormones. Anticipatory nausea and vomiting can occur before or during chemotherapy administration, and are correlated to a previous experience of chemotherapy with poor control of emesis; certain associations with chemotherapy administration, such as the hospital environment or the oncologist's office, taste, smell, viewing, thoughts might trigger the onset of emesis [41], [51], [57], and [58]. The management of chemotherapy induced nausea and vomiting is standardized, and the antiemetic guidelines are based on the intrinsic emetic risk of each drug and/or their combination [43], [57], [59], [60], [61], [62], and [63]. Emetogenic potential of some commons chemotherapeutic agents is shown in Table 2A and Table 2B.

Table 2A Emetogenic potential of intravenous antineoplastic agents. source: Adapted from: National Comprehensive Cancer Network Guidelines version 1.2012, 2011. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

High emetic risk (> 90%)
Carmustine>250mg/m2, cisplatin ≥50mg/m2, cyclophosphamide>1500mg/m2, dacarbazine, doxorubicin>60mg/m2, epirubicin>90mg/m2, ifosfamide10g/m2, mechloretamine, streptozocine
Moderate emetic risk (30–90%)
Aldesleukin>12–15 miu/m2, amifostine>300mg/m2, carmustine>250mg/m2, busulfan, carboplatin, carmustine250mg/m2, cisplatin<50mg/m2, cyclophosphamide1500mg/m, daunorubicin, doxorubicin60mg/m2, epirubicin90mg/m2, idarubicin, ifosfamide<10g/m2, interferon-alpha10 miu/m2, irinotecan, melphalan, methotrexate250mg/m2, oxaliplatin, temozolomide
Low emetic risk (10–30%)
Amifostine300mg/m2, aldesleukin12–15 miu/m2, cabazitaxel, docetaxel, doxorubicin (liposomal), eribulin, etoposide, 5-fluorouracil, gemcitabine, interferon-alpha>5<10 miu/m2, methotrexate>50<250mg/m2, mitomycin, mitoxantrone, paclitaxel, pemetrexed, pentostatin, topotecan
Minimum (< 10%)
Bevacizumab, bleomycin, bortezomib, cetuximab, cladribine, fludarabine, interferon-alpha<5 miu/m2, methotrexate<50mg/m2, panitumumab, rituximab, temsirolimus, trastuzumab, vincristine, vinblastine, vinorelbine

Table 2B Emetogenic potential of oral antineoplastic agents.

Moderate to high
Busulfan4mg/day, cyclophosphamide100mg/m2/day, estramustine, etoposide, lomustine single day, procarbazine, temozolomide (>75mg/m2/day)
Minimal to low risk
Bexarotene, busulfan<4mg/day, capecitabine, chlorambucil, cyclophosphamide<100mg/m2/day, dasatinib, erlotinib, everolimus, flodarabine, gefitinib, imatinib, lapatinib, lenalidomide, melphalan, mercaptopurine, methotrexate, pazopanib, sorafenib, sunitinib, temozolomide (≤75mg/m2/day), thalidomide, topotecan, tretinoin, vandetanib, vorinostat
2.4.4. Mucositis

Cytotoxic chemotherapy and radiotherapy cause oxidative stress and injury leading to inflammation. Concomitant treatment-induced myelosuppression may favour secondary infections by bacteria, viruses and fungi [45]. Mucositis can involve the entire alimentary tract (stomatitis, esophagitis, gastritis, enteritis, colitis, proctitis) with ulceration, pain, bleeding, dysphagia, with significant morbidity and decline in the quality of life [45]. The principal risk factors include the type of chemotherapeutic agents, dose, route and frequency of administration, monotherapy or combination therapy, concomitant radiotherapy, neutropenia, corticosteroids, poor oral hygiene, smoke, alcohol intake. The drugs most specifically associated with mucositis are antimetabolites (i.e. 5-fluorouracil), antitumor antibiotics, taxanes, cisplatin, etoposide, cyclophosphamide, irinotecan [64] and [65]. As to prophylactic measures, oral hygiene protocols are recommended. Supportive measures may be considered to be the basis of care. A detailed review of guidelines for the care of patients with oral mucositis has been published by the Multinational Association of Supportive Care in Cancer (MASCC) and the Cochrane Group [66] and [67]. An accurate dental examination to identify and remove infections, preventive protocols that include education regarding oral hygiene, and the frequent use of bland oral rinses are considered basic care in patients at risk for mucositis. Oral rinses without alcohol, such as baking soda and salt solutions, may improve oral comfort [68]. Cryotherapy is the most conventional preventive method, at least for 5-fluorouracil-based therapy. Patients are instructed to suck on ice chips or rinse with ice-cold water during the administration of chemotherapy. Cryotherapy causes local vasoconstriction, the blood flow to the oral mucosa slows down and the distribution of the drug among the cells decreases, reducing incidence and severity of oral mucositis [69], [70], [71], [72], [73], [74], and [75]. Systemic analgesic therapy is recommended; antibiotics and/or antifungal medications should be given to patients with evidence of infection. Various mouthwashes containing diphenydramine, lidocaine, nystatin, corticosteroids can be used in clinical practice [43], [70], [71], [72], [73], [74], and [75].

2.4.5. Diarrhoea and radiation enteritis

Acute diarrhoea is a common effect, more often in patients submitted to regimens containing antimetabolites, platinum-derived drugs, thymidylate synthetase inhibitors, camptothecin and epidermal growth factor receptor (EGFR) inhibitors. Uncomplicated acute diarrhoea may be treated with loperamide and adequate fluid intake; water soluble fiber supplements and anti-diarrheal agents together can also help to combat diarrhea. In case of severe diarrhoea, intravenous fluids, antibiotics, electrolyte correction, somatostatin analogues may be necessary [76], [77], [78], [79], and [80]. Dietary modifications are commonly implemented to stop or lessen the severity of cancer treatment-related diarrhea. It is recommended to eat small, frequent meals and to avoid lactose-containing food until the cause of the diarrhea is known, spicy foods, alcohol, caffeine-containing foods and beverages, certain fruit juices, gas-forming foods and beverages, high-fiber foods, and high-fat foods. Finally, patients should be encouraged to increase clear liquid intake to at least 3L per day, room-temperature fluids may be better tolerated [43] and [81]. Abdominal or pelvic radiotherapy can induce an acute enteritis; the onset of this syndrome is shortly after a course of radiotherapy, and usually symptom resolution occurs within 3months. This syndrome usually occurs at doses higher than 10Gy [82] and serious enteritis is rare with doses less than 50Gy [83]. Chronic radiation enteritis typically develops between 18 months and 6 years after radiotherapy has been completed, and occurs in more than one-fifth of patients receiving radiotherapy [84], [85], and [86]. About one-third of patients with chronic enteritis will be operated during the follow-up, for intestinal obstruction, fistula or perforation [86] and [87]. Treatment factors that may increase the risk of developing radiation enteritis are: the amount of small intestine included in the radiation field, radiation dose, fractionation and technique, and the concomitant administration of chemotherapy. Treatment includes diet, anti-diarrhoeals, such as loperamide, anti-inflammatory agents, such as sulfasalazine, antibiotics, colestyramine, octreotide, lactobacillus rhamnosus [51] and [83]. Radiation enteritis can lead to intestinal failure, which affects the nutritional status and survival expectance [88]. Injury to the rectum can induce a proctitis, that often is moderate-severe and frequently requires intervention; important lesions occur when the dose is major of 60Gy. Toxicity is more frequent when radiotherapy, as usually, is administered 4–6 weeks after surgery concomitant with chemotherapy. Therefore, the current practice is to wait 6–8 weeks. Early and late nutritional consequences of radiotherapy are briefly summarized in Table 3.

Table 3 Radiotherapy: unfavorable consequences with impact on nutrition.

Site Early consequences Late consequences References
NCS, total body Nausea and/or vomiting   [24]
Head and neck Odynofagia, dysphagia, xerostomia, mucositis, anorexia, dysgeusia dysosmia Tissue ulceration, xerostomia, dental caries, bone necrosis, trismus, dysgeusia [24], [27], [44], and [45]
Esophagus Dysphagia, odynophagia Fibrosis, stenosis, fistula [24] and [50]
Lung Anorexia, odynophagia, nausea Fibrosis [24] and [50]
Abdomen and pelvis Anorexia, nausea, vomiting, diarrhoea, acute enteritis, colitis Ulcer, malabsorption, diarrhoea, chronic enteritis, colitis [41], [42], [82], [83], [84], [85], [86], [87], and [88]

NCS: nervous central system.

2.4.6. Alterations in taste and smell

Cisplatin, carboplatin, 5-FU, methotrexate and many other drugs as well as radiotherapy can affect the taste sensation, with hypogeusia or dysgeusia; some patients complain of a bitter taste during the administration of cytotoxic drugs; 77% of the patients treated with cisplatin experience a metallic taste [89]. Altered smell (dysosmia) during or after the administration of antineoplastic drugs may also occur [90]. As for diet, specific recommendations are reported. In particular, dietary approaches involving taste enhancement and food flavoring may be successful interventions. Patients’ self-management reccomendations comprise increased use of seasonings and spice, eating cold meals, and avoiding foods with strong smells [81] and [91].

3.1. Pathogenesis of anorexia

3.1.1. Short-term acting mediators

The prevalence of anorexia in cancer patients is highly variable [92]. Factors other than treatment-induced abnormalities, such as pain and depression, may contribute to decreased food intake [93]. The pathogenesis of cancer anorexia is multifactorial and is associated with disturbances of the central physiological mechanisms controlling food intake [94] and [95]. Food intake is regulated by long- and short-term acting mediators [96], [97], [98], and [99], involving complicated associations between neuropeptides and other neurotransmitters in the central nervous system (CNS) [100], [101], [102], [103], and [104]. The disturbances of these neuroendocrine pathways could be responsible for symptoms as refusal to eat, denial of hunger, irritability. Short-term acting mediators are peptides produced by enteroendocrine cells interspersed among the gastrointestinal tract; they act through the bloodstream or the vagus nerve on the CNS and account for satiety signals. These satiety signals are meal-related and are effective in maintaining adequate meal size according to the energy expenditure and long-term maintenance of body weight. The incretin hormones glucagon-like-peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and potentially oxyntomodulin (OXM) do improve the response of the endocrine pancreas to nutrients. GLP-1 and OXM also reduce food intake. Ghrelin is released by the stomach and stimulates appetite. Gut hormones promoting satiety include cholecystokinin (CCK), peptide tyrosine–Tyrosine (PYY), as well as OXM, and pancreatic polypeptide (PP).

3.1.2. Long-term acting mediators

Long-term acting mediators are hormonal signals [105] produced by the pancreas, such as insulin, as well as by the adipose tissue, like leptin and adiponectin, all communicating with the brain concerning body fat and energy storage [106], [107], and [108]. These hormones do participate in the long-term regulation of energy homeostasis and body weight maintenance. Insulin is vital for regulating the storage of absorbed nutrients, also acting as an adiposity signal to the brain for the regulation of energy balance. Leptin is an adipocyte-derived factor, or adipokine, that is the dominant long-term signal informing the brain of adipose energy reserves [109]. Similar to insulin, leptin is transported across the blood-brain barrier, where it binds to specific receptors on appetite-modulating neurons, most notably but not exclusively in the arcuate nucleus [109]. Low leptin levels in the brain increase the activity of the hypothalamic orexigenic signals that stimulate feeding and suppress energy expenditure, and decrease the activity of anorexigenic signals that suppress appetite and increase energy expenditure [110].

3.1.3. The hypothalamic arcuate nucleus

The hypothalamic arcuate nucleus (ARC) seems to play a crucial role in receiving and integrating these signals, it is incompletely isolated from the general circulation by the blood–brain barrier, allowing direct access of circulating factors to ARC neurones. One food intake regulatory pathway consists of neurons co-expressing neuropeptide Y (NPY) and agouti-related protein (AgRP), both potent stimulators of food intake, and an adjacent set of ARC neurons co-express proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), which suppress food intake [111]. POMC is a precursor molecule that stimulates the anorectic peptide α-melanocyte-stimulating hormone (α-MSH), an agonist at the melanocortin-3 (MC3) and melanocortin-4 (MC4) receptors [112]. AgRP is the endogenous antagonist of the MC3 and MC4 receptors, and central injection of AgRP dramatically increases food intake [113]. Neuropeptide Y is also a potent orexigenic agent, though its effects are shorter lived than AgRP. It stimulates feeding, possibly via the Y1 and Y5 receptors [114]. Hypothalamic neurons respond to peripheral long- and short-term signals by modifying the synthesis of the neuropeptides described above. Leptin signals the status of energy stores and activating POMC/CART neurons and inhibiting NPY/AgRP neurons, resulting in inhibition of feeding and an increase in energy expenditure. Ghrelin activates NPY/AgRP neurons by stimulating feeding and decreasing energy expenditure [115] (Fig. 1). In the presence of the anorexia-cachexia syndrome, leptin levels are decreased [116] whereas ghrelin is normal or elevated [117]. Nevertheless, energy intake is not increased as expected. The hypothalamic inappropriate response to these peripheral signals appears to be mediated by the persistent activation of POMC neurons. Consistent evidence indicates that the melanocortin system is active in the cancer-induced cachexia. Central melanocortin receptor blockade by AGRP or other antagonists reversed anorexia and cachexia in the animal models, suggesting a pathogenetic role for this system [118] and [119]. Previous studies demonstrated that NPY feeding systems are dysfunctional in anorectic tumor-bearing rats. IL-1β administered directly into cerebral ventricles antagonizes NPY-induced feeding in rats at a dose that yields estimated pathophysiological concentrations in the cerebrospinal fluid, such as those observed in anorectic tumor-bearing rats [120] and [121]. IL-1β decreases hypothalamic NPY mRNA levels that are specific to and not associated with a generalized reduction in the brain levels. The hypothalamic NPY system is thus one of the key neural pathways disrupted in anorexia induced by IL-1β and other cytokines. However, no change or even increase in NPY mRNA levels have been reported in the hypothalamus of tumor-bearing rats [122], thus suggesting the involvement of other orexigenic and/or anorexigenic signals in anorexia and body weight loss.

gr1

Fig. 1 Neuroendocrine regulation of food intake. Peripheral long term (insulin, leptin) and short term (PYY, ghrelin) signals modulate the ARC synthesis of hunger (AGRP, NPY) and satiety (POMC) neuropeptides acting on PVN neurons to regulate food intake (also see text). ARC: hypotalamic arcuate nucleus; PVN: paraventricular nucleus; NPY: neuropeptide Y; MCR-4: melanocortin-4 receptor; AGRP: agouti-related peptide; POMC: pro-opiomelanocortin; α-MSH: alpha-melanocyte-stimulating hormone; PYY: peptide tyrosine-tyrosine. Interrupted arrows: activated POMC neurons inhibit AGRP/NPY neurons and vice-versa.

3.1.4. Serotonin

Serotonin is a neurotransmitter that contributes to the regulation of numerous behavioural and physiologic functions, like satiety regulation. The hypothalamic serotonin is synthesized from tryptophan and there is no negative feedback that regulates its synthesis, so, more tryptophan goes to the brain, more serotonin is produced. In the course of neoplastic disease, plasma and cerebrospinal fluid levels of tryptophan are greatly increased in anorectic patients [123]. Peripheral infusion of IL-1 induces anorexia and raises brain tryptophan levels, thereby, suggesting increased serotonin synthesis [124]. Further, IL-1 intra-hypothalamic injection depresses food intake and increases the serotonin release [125]. These data indicate that during catabolic state increased hypothalamic expression of IL-1 occurs in conjunction with increased serotonin release. Serotonin and IL-1 interact within the ARC nucleus to influence the activity of the melanocortin system, yielding and maintaining the inhibition of NPY/AgRP neuronal activity and the suppression of the inhibition of POMC neurons. These biochemical events facilitate the release of the α-MSH, endogenous MC4R agonist, and suppress the release of the AgRP, endogenous MC4R antagonist, thus resulting in dysfunction of the melanocortin system.

3.1.5. Circulating factors

Cancer-induced anorexia may result from circulating factors produced by the tumor or by the host in response to the tumor. Many cytokines, including IL-1-α, IL-1-β, IL-6, IL-8, TNF-alpha have an effect on appetite [126], [127], and [128]. Chronic administration of these cytokines, either alone or in combination, can reduce food intake and reproduce the distinct features of the cancer anorexia–cachexia syndrome [129] and [130]. These cytokines may produce long-term inhibition of feeding by stimulating the expression and release of leptin and/or by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, thus leading to the prevention of the normal compensatory mechanisms in the face of both decreased food intake and body weight [131]. A TGF-beta superfamily member, MIC-1, has recently been implicated in anorexia and weight loss in cancer patients through central mechanisms [132].

3.2. Pathogenesis of cachexia

The pathogenesis of cancer cachexia is multifactorial and includes alterations in energy and substrate metabolism (Table 4). A principal initial mechanism is the production by tumor cells of proinflammatory cytokines (interleukins, interferon-γ, TFNα, NFkβ). These cytokines impair muscle and fat metabolism. The presence of the cancer results in profound changes in the protein, lipid and glucose metabolism, which in turn account for the loss of energy taken with food and an inefficient use of energy and plastic substrates. Also, the “theft” of nutrients by tumor cells in active replication at the expense of the tissues of the host organism contributes to the onset of cachexia. In addition to controlling food intake, the metabolic disturbances associated with tumor burden contribute most importantly to the appearance of cachexia [133]. Most solid tumors produce a variety of changes in the energy and nutrients metabolism regardless of their origin [134].

Table 4 Principal mediators and mechanisms of anorexia and cachexia.

Syndrome Mediator Mechanism Reference
Anorexia IL-1-alpha, IL-1-beta, IL-6, IL-8, TNF-alpha, MIC-1, serotonin Imbalance between NPY (orexigenic) and melanocortin (anorexigenic) signals in the hypotalamus [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], and [132]
Cachexia Low oxygen tension in tumor Activation of Cori cycle [135]
  LMF/ZAG, TNF-alpha, IL-1, IFN-gamma Increased lipolysis in adipose tissue [136] and [137]
  TNF-alpha, IL-1, IL-6, IFN-gamma Suppression of lipoprotein-lipase in adipose tissue [138]
  PIF, Angiotensin-II, TNF-alpha Depression in protein synthesis

Increase in protein degradation via ubiquitin-proteasome pathway
[136], [137], and [142]
  IL-6 Induction of lysosomal and non-lysosomal proteolytic pathways

Hepatic production of acute phase proteins
[131]

IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; LMF: lipid mobilizing factor; ZAG: zinc-alpha-2-glycoprotein; PIF: proteolysis-inducing factor; NPY: neuropeptide-Y.

3.2.1. Carbohydrate metabolism

As for the carbohydrate metabolism, the most important changes are glucose intolerance, insulin resistance, increased gluconeogenesis from amino acids and lactate (Cori cycle), since many solid tumors produce a large amounts of lactate. Hepatic gluconeogenesis from lactate and amino acids is markedly increased in the course of cancer and is insensitive to physiological stimuli inhibitors, such as the administration of glucose. Gluconeogenesis from lactate uses adenosine triphosphate (ATP) molecules and it is very energy inefficient for the host, so, this cycle may be considered one of the main determinants of the increased energy expenditure observed in cancer patients [135].

3.2.2. Lipid metabolism

The lipid metabolism is also affected by tumor. Exogenous lipid hydrolysis by lipoprotein lipase is reduced but mainly the fat deposits are consumed as a result of increased mobilization and oxidation of lipids. Fatty acid oxidation does not stop with the glucose administration, and this contributes to increase the energy resting expenditure. Increased lipid mobilization in cancer cachexia can be attributed to a tumor catabolic factor named lipid mobilizing factor (LMF), which acts directly on adipose tissue with the release of free fatty acids (FFA) and glycerol. LMF has been isolated from a cachexia-inducing murine tumor and from the urine of weight-losing cancer patients [136]. The LMF showed an apparent molecular weight of 43kDa and was homologous with the plasma protein zinc-α-2-glycoprotein (ZAG) in amino acid sequence. Studies in animal models suggested that the production of LMF by cachexia-inducing tumors may account for the loss of body fat and the increase in energy expenditure, but not for anorexia [136]. LMF acts directly on adipose tissue with the release of free fatty acids and glycerol through an elevation of cyclic AMP [137]. Also, TNF-alpha can induce lipid depletion, either through inhibition of lipoprotein lipase or by stimulation of lipolysis, although its role in cancer anorexia–cachexia syndrome is still controversial [138]; moreover, IL-1, IL-6, TNF-γ and IFN-γ have been shown to inhibit expression of lipoprotein lipase mRNA; IL-1 and IFN-gamma have been shown to directly stimulate lipolysis [138]. Alterations in fat metabolism lead to decreased fat storage and severe cachexia in animal models and humans [136], especially when combined with decreased food intake.

3.2.3. Protein metabolism

Alterations of the plasma amino acid profile are another important aspect of the disorder of intermediary metabolism in the course of cancer. These changes are a direct consequence of the energy metabolism disorder as well of the liver and muscle protein turnover disorder. Many studies did show a reduction in plasma concentration of gluconeogenetic amino acids in cancer patients sustained by an increased liver gluconeogenesis. In contrast, the branched chain amino acids which are quickly consumed during simple malnutrition, have physiological levels in cancer patients. These are the important pathogenetic differences between simple malnutrition and cancer cachexia [138]. During starvation, glucose utilization by the brain is normally replaced by ketone bodies derived from fat, leading to decreased glucogenesis from amino acids by the liver and conservation of muscle mass [138]. In cancer cachexia, however, amino acids are not spared and there is depletion of lean body mass. This characteristic is thought to be responsible for the reduced survival time of cachectic cancer patients [139] and [140]. The body protein turnover is increased because of the augmented hepatic synthesis as well of the increased degradation of the muscle tissue, whereas the protein synthesis is normal or slightly reduced. Both protein synthesis and degradation have been reported respectively in biopsies of skeletal muscle from cachectic cancer patients [139]. Whole body protein turnover is significantly increased in weight-losing cancer patients because of the reprioritization of liver protein synthesis, commonly known as the acute-phase reactant response [138]. Loss of skeletal muscle mass in both cachectic mice and cancer patients has been shown to correlate with the presence of the serum of a proteolysis-inducing factor (PIF), which induces protein degradation as well as inhibits protein synthesis in isolated skeletal muscle [136], [137], [138], and [141]. PIF is excreted in the urine of patients with cancer cachexia, not in those with similar tumors without cachexia [142]. Likely, PIF induces catabolism in skeletal muscle upregulating the ATP-ubiquitin-dependent proteolytic pathway, as reported in mice gastrocnemius exposed to PIF [142]. TNF-α, IL-1, IL-6 play a crucial role in the ATP-ubiquitin-dependent proteolytic pathways activation, and thus in the development of hypotrophy. Further, IL-6 can play a role in the loss of the lean body mass in cachectic mice bearing the colon-26 adenocarcinoma, by inducing both lysosomal (cathepsin) and non-lysosomal (proteasome) proteolytic pathways [128]. The ubiquitin-proteasome-dependent proteolysis is the most important mechanism of muscle protein loss in cahexia derived from several diseases, including cancer [143]. In patients with chronic heart failure and cardiac cachexia systemic inflammation and more elevated levels of circulating Hsp70 have been observed. In general, the heat shock proteins (HSPs) are constitutively expressed, but the pathophysiological stress upregulates them. Heat shock protein 70, known as chaperone, prevents protein aggregation, contributing to the refolding of stress-damaged proteins. Hsp70 has been proposed as a cytoprotective therapeutic agent for disease severity and survival [144]. Indeed, the protective role of heat shock protein, in response to many harmful stimuli, has been suggested by Luo [145]: in particular, it has been highlighted how dexamethasone (and the glucocorticoids) stimulate the muscle cachexia in various catabolic conditions. The ubiquitin-proteasome proteolytic pathway is normally inhibited by the transcription factor NF-kB, which is in turn inhibited by glucocorticoids. Therefore, the heat shock proteins may have a protective role as to protein degradation, blocking the glucocorticoid effects.

3.2.4. Anticancer drugs

Contradictory data exist regarding the possible direct effect of anticancer drugs on developing of cachexia. Five-days continuous infusion of 5-fluorouracil is associated with protein synthesis inhibition [24]. In tumor-bearing mice, taxanes induce prolonged weight loss; paclitaxel also increases the expression of cachectic cytokines in cultured murine cells; however, in clinical use, taxanes have not been reported to cause cachexia; in contrast, 5-deoxy-5-fluorouridine (5-DFUR) administered in cachectic mice reduces weight loss even at doses at which tumor still grows or does not significantly shrink [146] and [147]. Also capecitabine, a derivative of 5-DFUDR, may have anticachectic effects [148].

The clinical issue of cachexia includes a cachexia spectrum – early to late cachexia. If treatment-related nutrition impact symptoms are identified and treated, the patient may not progress to severe cachexia. Furthermore, in the clinical evaluation of cachexia, the loss of lean body mass should be differentiated from the weight loss [6] and [149].

4. Treatment

4.1. Pharmaceutical

The best management of cancer cachexia is to cure the cancer, as this will completely reverse the cachexia syndrome. Unfortunately, this remains an infrequent achievement in advanced solid tumors [149]. The pathogenesis of cancer cachexia is multifactorial and includes anorexia, inflammation, metabolic disturbances and enhanced muscle proteolysis, and each of these is a potential therapeutic target. Initial studies concentrated on the treatment of anorexia, but now the principal aim is to attenuate inflammation or muscle proteolysis, or to use different drugs in combination so as to treat several aspects of cachexia simultaneously [5]. When treating weight loss associated with cachexia, two targets have to be considered. Firstly, contributing factors to decrease food intake could be assessed and treated. Secondly, neutralizing the metabolic alterations which include abnormal carbohydrate metabolism, lipid mobilization, hepatic protein metabolism and, above all, alterations in the rate of skeletal muscle protein breakdown is of paramount importance. In order to reverse metabolic disturbances, many drugs have been proposed and used in clinical trials, while others are still under investigation using experimental animals. Among appetite stimulants, progesterone derivatives, cannabinoids, corticosteroids and cyproheptadine are commonly used (Table 5). The best treatment of the cachectic syndrome is most likely a multifactorial approach. A combination of nutritional support and nutraceuticals with specific drugs may lead to optimal results [4] and [150].

Table 5 Anti-cachexia treatments.

Drug Experimental animals Humans
Progesterone derivatives ++ ++
Cannabinoids ++ +
Cyproheptadine + +
Corticosteroids
Ghrelin ++ ++
Pentoxyfilline ++ ND
Anabolic steroids ++ ++
Omega-3 fatty acids ++ ++
Erythropoietin ND ++
ATP, Creatine ND +
Amino acids ND +
Thalidomide +
Anti-cytokines antibodies and receptors ++
Anti-inflammatory cytokines ++ ND
Beta-2 agonists ++ ND
Prostaglandin inhibitors ++ +
ACE inhibitors ++ ND
Proteasome inhibitors ND ND

– no effect;+slight effect; ++: good results; ND: no data available.

4.2. Nutritional

In the modern approach to the cancer patient, the nutritional intervention should be done as soon as possible in order to prevent or delay the onset of anorexia–cachexia syndrome. The calculation of nutritional requirements is strictly dependent on the identification of nutritional status, metabolic state, the underlying disease and its treatment. In 2009, the American Society for Parenteral & Enteral Nutrition (ASPEN) and the European Society for Clinical Nutrition and Metabolism (ESPEN) convened an International Consensus Guideline Committee to develop an etiology-based approach to the diagnosis of adult malnutrition in clinical settings. The malnutrition is defined as starvation related when inflammation is not present; the malnutrition is related to chronic disease when inflammation is mild to moderate degree and it is related to acute disease when there is a marked inflammatory response. Because no single parameter is definitive for adult malnutrition, the identification of two or more of the following characteristics is recommended for diagnosis: insufficient energy intake, weight loss, loss of muscle mass, loss of subcutaneous fat, localized or generalized fluid accumulation that may sometimes mask weight loss, diminished functional status as measured by hand-grip strength. The characteristics distinguish between severe and non-severe malnutrition [151]. If the malnourished subject succeeds to satisfy his nutritional need, it is recommended to prepare a personalized diet in accordance with the patient preferences. The nutritional regime should provide 30–35kcal/kg/day and 1 to 1.2g protein/kg/day, with a share of fat that can cover 30 to 50% of the non-protein calories [152] and [153]. Nutrition support intervention in patients identified by screening and assessment as at risk for malnutrition or malnourished may improve clinical outcomes [154]. In patients with chronic illnesses, oral nutritional supplementation has been shown to be beneficial in terms of physical function and weight gain.

The nutrition support is indicated in the following case:severe or moderate malnutrition (weight loss>10% in the last 6 months) with food intake planned or estimated as low (<50% of requirements) for a period longer than five days;normal nutritional status but clear nutritional risk, or estimate of insufficient oral nutrition for at least 10 days, or hypercatabolism severe (loss of nitrogen >15g/day);moderate hypercatabolism (including nitrogen loss between 11 and 15g/day) with anticipation of insufficient oral nutrition for more than 7 days or disorders of absorption, intestinal transit or digestion of food, serious and not rapidly reversible (within 10days).

The nutrition support, however, is not considered appropriate when the expected duration is less than 5 days, or when, in a well-fed patient, the period of provided inadequate food intake is less than 10 days. The nutrition intervention may occur at various levels with EN and PN that do not exclude each other. EN must be preferred to PN when the functional integrity of the gastro-intestinal tract is preserved in a partial or total way. Contraindications to EN as well the absolute indications for total PN (TPN) are represented by a lack of proper bowel function or an impaired intestinal transit, or finally by the denial of consent by the patient or tutor [155] and [156].

Anyway, the efficacy of this strategy may be largely influenced by the duration of adequate support, intrinsic biological aggressiveness of the tumor and the availability of an effective cancer treatment.

5. Conclusion

In cancer patients malnutrition, anorexia and cachexia increase morbidity and mortality. While the pathogenesis of malnutrition recognizes multiple mechanisms originated by the primary tumor or a specific treatment, that of anorexia includes the hypothalamic dysfunction as the principal player. The pathogenesis of cachexia is under investigation and some cytokines appear important. Treatment includes pharmaceutical and nutritional interventions.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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Footnotes

a Unit of Oncology 1, Department of Oncology, Transplants and New Technologies in Medicine, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy Unit of Oncology 1, Department of Oncology, Transplants and New Technologies in Medicine, Azienda Ospedaliera Universitaria Pisana, Via Roma 67, Pisa, 56126, Italy

b Department of Internal Medicine, University of Pisa, Pisa, Italy Department of Internal Medicine, University of Pisa, Pisa, Italy

c Laboratory of Preclinical and Surgical Studies, Istituto Ortopedico Rizzoli, Bologna, Italy Laboratory of Preclinical and Surgical Studies, Istituto Ortopedico Rizzoli, Bologna, Italy

d Department of Reproduction and Ageing, University of Pisa, Pisa, Italy Department of Reproduction and Ageing, University of Pisa, Pisa, Italy

lowast Corresponding author. Tel.: +39 050 992141; fax: +39 050 993002.


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Cancer cachexia: mechanisms and progress in treatment

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