General rules for treating cancer-related malnutrition

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Cancer-related malnutrition (CRM) refers to undernutrition caused by cancer, anti-cancer treatments, or cancer-related mental stress. CRM is a chronic disease–related malnutrition (cDRM) with a hyper-inflammatory state. In China, the overall prevalence of CRM among hospitalized patients is as high as 80.4%, of which 58.2% are moderately or severely malnourished.[1] Malnutrition adversely affects the clinical outcome,[2,3] extends the hospital stay, and decreases the patient’s quality of life.[4–7] Due to the detrimental effects and high prevalence of malnutrition, nutrition therapy should serve as a first-line and fundamental routine therapy for patients with cancer throughout the whole course of anti-cancer treatment. It can be administered independently or in combination with other therapies such as surgery, chemo- or radiotherapy. Cancer nutrition therapy (CNT) aims to improve the prognosis by treating the cancer, relieving its complication(s), and improving the body’s conditions with the planning, implementation, and evaluation of a nutrition intervention. CNT consists of three steps: a) nutritional diagnosis using a three-stage diagnosis model (nutrition screening, nutrition evaluation, and comprehensive evaluation)[8]; b) nutritional treatment implementation; and c) efficacy evaluation and follow-up. CNT evolves from nutrition support, whose main purpose is to provide energy and nutrients. Nutrition support becomes nutrition therapy when it is provided to treat malnutrition, regulate metabolism, and modulate the immune system rather than merely provide energy and other nutrients. Aims and strategies of CNT Cancer is a chronic, low-grade, lasting, and irreversible inflammation. The inflammatory burden is a key predictive biomarker for cancer prognosis and can be reflected by inflammatory burden index (IBI), which is calculated as follows[9]: IBI=C−reactiveprotein×neutrophillymphocyte. A higher IBI correlates with shorter survival. IBI increases as cancer progresses. The IBI ranges differ for different cancer types; hence, cancer can be categorized into high, medium, or low IBI cancers. Pancreas, lung, and biliary tract cancers are high IBI cancers, whereas breast and thyroid cancers are low IBI cancers. CRM is cachexia, a cDRM with chronic inflammation.[10] High inflammatory burden is a characteristic that separates CRM from malnutrition that caused by benign diseases. A high inflammatory burden causes malnutrition and resistance to nutrition therapy, and adversely affects the efficacy of nutrition therapy. The tumor itself is the main source for the inflammation and the root cause of malnutrition. Therefore, treatment for CRM should be approached from multiple aspects, including anti-cancer, anti-inflammation, anti-oxidant, metabolism modulation, and nutrition supplements. In this model, anti-cancer therapy is the prerequisite, standardized nutritional therapy is the fundamental, rational metabolic regulation is the core, effective inflammation modulation is the key, and moderate oxidative modification is the foundation. CNT’s fundamental purpose is to ensure efficient energy and nutrients for patient with cancer. The ultimate goal is to modulate metabolism, control cancer, maintain body function, improve quality of life, and extend survival. A well-planned nutrition intervention, coupled with rational clinical application and appropriate choice of formula, could improve malnutrition resulting from chronic catabolism, inhibit the production of inflammatory cytokines, and boost immunity. This will inhibit the proliferation of tumor cells, both directly and indirectly, and eventually improve the quality of life and survival. Principles and methods for CNT Methods Nutrition therapy consists of nutritional education and medical/artificial nutrition. Enteral and parenteral nutrition are the two main routes for medical nutrition (Figure 1). In practice, the most common method of medical nutrition is oral nutritional supplements (ONS), with partial enteral nutrition (PEN) and partial parenteral nutrition (PPN) as the two most practical modes of implementation. Implementing nutrition should follow the principle of four priorities as diet priority, nutritional education priority, oral administration priority, and enteral nutrition priority.Figure 1:: Nutrition therapy methods. EEN, exclusive enteral nutrition; NCJ tube, needle catheter jejunostomy tube; NG tube, nasogastric tube; ONS, oral nutritional supplements; PEG tube, percutaneous endoscopic gastrostomy tube; PPN, partial parenteral nutrition; TPN, total parenteral nutrition.Categories for nutrition therapy The Chinese Society of Nutritional Oncology (CSNO) has formed a clear set of clinical pathways for nutrition therapy based on a patient’s nutritional diagnosis (Figure 2). Namely, it is recommended that for patients without malnutrition, to proceed with anti-cancer treatments without nutritional intervention; for the suspect or mild malnutrition patients, to provide nutritional education while administrating anti-cancer treatments; for patients with moderate malnutrition, to administer medical nutrition (EN and/or PN) with anti-cancer treatments; and for severely malnourished patients, to implement nutrition therapy (EN and/or PN) for 1 to 2 weeks before and throughout anti-cancer treatments.Figure 2:: Clinical pathways for nutrition therapy. Nutritional education includes diet consultation and modification. Medical nutrition therapy refers to enteral nutrition, including ONS and tube feeding, and parenteral nutrition. Anti-cancer treatments include but are not limited to surgery, chemotherapy, radiotherapy, immunotherapy, etc. ONS, oral nutritional supplements.The five-level-ladder regimen for nutrition therapy The CSNO has formed a five-level-ladder regimen for nutrition therapy[11] (Figure 3). Nutrition therapy should start with diet and nutritional education whenever possible and move up along the “ladder” if the current regimen fails to meet a patient’s nutrition requirement. These steps, in ascending order, are ONSs, total enteral nutrition, PPN + PEN, and finally, total parenteral nutrition as the highest level on the “ladder.”Figure 3:: The five-level-ladder regimen for nutrition therapy.Transition in nutrition therapy Transition refers to movement from a lower step to a higher step on the nutrition therapy ladder, or vice versa. The transition from a lower ladder step to a higher step should follow what is termed the “60% principle.” Namely, if the current step fails to meet 60% of the patient’s nutrition needs, a nutrition regimen from the next higher tier should be implemented. For example, ONS should be provided if nutritional education cannot meet 60% of a patient’s nutritional needs. Likewise, when ONS cannot meet 60% of a patient’s nutritional needs, total enteral nutrition should be administrated. This principle applies to the upward transition on the ladder. The transition from a higher ladder step to a lower step should follow a 50% principle. Namely, if the nutrition support from the next lower step can provide at least 50% of the patient’s nutritional needs, the patient can wean off the current step and move to a lower step. For example, when EN can provide 50% of one’s nutritional needs and the patient is on total PN, PN can be administered in a reduced manner with increasing EN. For a patient undergoing total EN, if oral intake can meet 50% of that patient’s nutritional needs, less nutritional support via tube feeding can be given, and more can be given from oral intake. Likewise, medical nutrition can be slowly weaned off from the regimen when a regular diet can provide 50% of the nutritional needs. The timing for moving from one transitional stage to another is 3 to 5 days for general patients and 2 to 3 days for critical patients. Process of nutrition therapy Medical nutrition therapy of patient with cancer should follow a standard pathway (Figure 4). Metabolic disorders were defined as high levels of inflammatory burden and insulin resistance. An IBI >16 indicates a high inflammatory burden, and a C-reactive protein, triglycerides, and glucose index (CTI) >4.78 indicates insulin resistance. Any validated parameters of inflammatory burden and insulin resistance can be used clinically. Requirements for energy and nutrients The fundamental purpose of CNT is to meet the patient’s requirement for energy and protein intake. It has been reported that merely aiming to meet a patient’s energy requirements but not the protein requirements does not lower mortality,[12,13] yet, if a patient’s need for energy and protein is ensured, mortality drops significantly. Energy deficit from low energy intake, nitrogen deficiency from low protein intake, or high metabolic burden from excess energy and nutrition cannot benefit patient with cancer.[14] Energy Effective nutrition therapy is based on accurately estimating a patient’s total energy expenditure (TEE). TEE is the sum of resting energy expenditure (REE), physical activity level, and, for a small percentage, diet-induced thermogenesis. Cancer patients often have elevated REE because of the inflammatory response, body composition changes, brown adipose tissue activation, and weight loss. Simultaneously, their physical activity may decrease due to fatigue or other conditions, and this subsequently results in reduced energy expenditure. Taken together, the TEE of cancer patients is maintained or even decreased compared to healthy subjects. It was reported that after adjusting for physical activity, age, body composition, and weight loss, around 50% of cancer patients with weight loss had an elevated metabolism.[15] One study suggested that about 47% of newly-diagnosed patients are hyper-metabolic.[16] Meanwhile, another study found that the average step count for cancer patients was reduced by 45%, and the average sitting time increased by 2.5 hours per day.[17] The commonly used formula for TEE calculation may lead to an inaccurate result for the difference in metabolism among cancer types. The difference between the calculated result and the actual reading can be as wide as −40% to +30%. Indirect calorimetry is the most accurate way of measuring REE for cancer patients and is recommended for patients with nutrition risk.[18] If TEE or REE cannot be measured, the rule of thumb is to calculate the energy requirement using 25 to 30 kcal/kg/d.[19,20] When initiating nutrition therapy for cancer patients, it can be assumed that their energy requirement and TEE are comparable to healthy subjects. The Mifflin-St Jeor formula can be used to calculate REE. The current ESPEN and CSNO guideline recommends using 20 to 25 kcal/kg/d for bedridden patients and 25 to 30 kcal/kg/d for mobilized patients when calculating REE.[19,20] Energy requirement should be calculated differently: for PN, use 20 to 25 kcal/kg/d for calculating non-protein energy, and for EN, use 25 to 30 kcal/kg/d for calculating total energy. The minimum requirement for energy should be at least 70% of the patient’s demand. Glucose:lipid ratio It has been established that patients with insulin resistance have an impaired ability to use glucose. Cancer patients have a better capacity of digesting different lipid emulsions than healthy subjects, and they often present a normal to elevated capacity to utilize lipids.[20,21] In addition, the association between high glucose levels and a high risk of infection among non-cancer patients may also exist in cancer patients.[20] Thus, whether a cancer patient is in an insulin-resistant state affects the glucose:lipid ratio calculation. Clinical examination for insulin resistance is a complex task, and multiple formulae have been proposed to calculate insulin resistance. The CTI is considered to have the highest predictive value among the indexes. The formula for CTI is as follows[22]: C-reactiveprotein,triglycerides,glucoseindex(CTI)=0.415×ln⁡(CRPmg/L)+ln⁡(TCmg/dL×FBGmg/dL)2 (note: CTI, C-reactive protein, triglycerides, and glucose index; CRP, C-reactive protein; TC, triglycerides; FBG, fasting blood glucose). A CTI >4.78 indicates insulin resistance, and therefore the energy derived from glucose should be decreased, and that from lipids should be increased. It is recommended to assume the presence of insulin resistance if CTI cannot be obtained. Recommendations for tumor-bearing patients include administering formula with reduced energy from carbohydrates (CHO) and increasing the proportion of energy from protein and fat. The ratio of macronutrients for non-tumor-bearing patients is the same as that of healthy individuals. Under physiological conditions, the distribution of non-protein energy is generally glucose:lipid = 60% to 70%:40% to 30%. For patients with tumors, especially those with progressive tumors, it is recommended to increase the ratio of fat and decrease the ratio of CHO. The ratio of lipids to CHO can reach the level of 1:1 or even higher for energy from lipids (Table 1). Table 1 - The recommended proportion of energy from three macronutrients Non–tumor-bearing patients (%) Tumor-bearing patients (%) Enteral nutrition C:F:P =(50–55):(30–25):15 C:F:P = (30–50):(40–25):(15–30) Parenteral nutrition C:F = 70:30 C:F = (40–60):(60–40) C, carbohydrate; F, fat; P, protein. Protein One study found that muscle protein synthesis and its response to food protein stimulation were not decreased in cancer patients compared with healthy young adults.[23] However, due to the increased catabolism, cancer patients have a higher demand for protein. The protein requirement should meet 100% of the body’s requirement, which is recommended to be 1.2 to 1.5 g/kg/d.[19,20] Patients in a hyper-catabolic state, such as following major surgery, undergoing high-dose chemoradiotherapy or bone marrow transplantation, or having a high inflammatory burden or persistent fever, need more protein. Total protein intake (intravenous and oral) for cancer cachexia patients should be 1.8 to 2 g/kg/d, branched chain amino acid intake (BCAA) should be ≥0.6 g/kg/d, and essential amino acids (EAA) should be increased to ≥1.2 g/kg/d. Protein should reach 2 g/kg/d in severely malnourished patients. Protein intake should reach 1.5 g/kg/d (1.25–1.7 g/kg/d) for long-term nutritional treatment of patients with mild-to-moderate malnutrition.[24,25] A high-protein diet is beneficial for cancer patients and elderly patients, and it is recommended to eat three balanced meals a day.[24,26] Micronutrients It is essential to supply 100% of all vitamins and minerals based on recommended requirements and to adjust the dosage of some micronutrients according to the patient’s actual situation. It is not recommended to administrate large doses of vitamins and minerals as a nutritional supplement. However, in metabolic regulation therapy, the use of a high-dose of vitamin C has been reported in many cases, and its safety has been fully confirmed. It has also been shown to improve the quality of life and symptoms of patients with advanced-stage cancer, improve the effects of chemotherapy, and reduce the toxicity of chemotherapy.[27–29] One study recommended 1 to 4 g/kg, intravenously or intraperitoneally, 1 to 7 times a week for 8 to 12 weeks.[30] Our recommended usage is generally 0.5 to 1.0 g/kg, once a day, or 1 to 2 g/kg, once every 1 to 2 days. When used once a week, the dose can be increased as appropriate. Preparation selection Formula selection There are no significant differences between nutritional treatment formulas for non-tumor-bearing survivors and patients with benign diseases. The standard formula of foods for special medical purposes (FSMP) or enteral nutrition agent is preferred. For those in the tumor-bearing state, a different formula, the tumor-specific nutritional formula, could be used as priority. Fat formula Medium/long chain (MCT) fat emulsions may be more suitable for cancer patients, especially those with liver dysfunction. There is increasing evidence to support that marine omega-3 polyunsaturated fatty acids (MO3PUFAS) can inhibit the inflammatory response, reduce adverse reactions of chemotherapy, enhance the efficacy of chemotherapy, improve cognitive function, and even reduce the incidence and mortality of some tumors.[31–33] KRAS wild-type and MMR-deficient tumor types are the two types of tumors that benefit more from MO3PUFAS.[33] Omega-9 mono-unsaturated fatty acids (such as olive oil) are immunoneutral and low inflammatory and have little adverse influence on immune function and liver function. They are rich in vitamin E, which can reduce lipid peroxidation. Protein/amino acid formula The whole protein formula is suitable for the majority of patients with cancer. The short-chain polypeptide formula does not need to be digested and can be absorbed faster, which is especially beneficial for patients with impaired digestive function and elderly patients. It is widely believed that amino acid preparations with BCAA content >35% can balance aromatic amino acids, improve anorexia and early satiety, and enhance immune function.[34] Amino acid formula without antioxidants may be safer for people with a history of allergies. Whey protein can better improve the nutritional status of cancer patients and increase the levels of albumin, glutathione, and immunoglobulin G.[35,36] Pharmacological nutrition Strengthening the amounts of β-hydroxy-β-methylbutyrate (HMB),[36–38] arginine,[38,39] and omega-3 PUFA, a nucleotide in the standard formula has been shown to have positive effects on the patients with cancer, which is a current focus in nutritional cancer research. Compared with standard formulations, pharmacologically enhanced formulations can reduce infectious and non-infectious complications and shorten the length of hospital stay in patients undergoing major abdominal surgery, but fail to prolong long-term survival.[40,41] It is generally recommended that the above 3 to 4 ingredients be used in combination, and the effects on individual use remain to be confirmed. Terminal stage patients For patients approaching the end of life, there may be no more need for any form of nutritional treatment, especially those with an invasive approach, other than providing proper amounts of water and food to reduce thirsty and hunger. The majority of experts do not recommend medical nutritional therapy at this point. However, considering that nutrition therapy may improve the quality of life of some patients with end-stage cancer, we suggest making an individualized assessment, based on the formulation of reasonable programs, the selection of appropriate formulations and pathways, and the optimization of physiological or existing pathways, but do not recommend introducing new, invasive pathways. Nutritional treatment for patients with end-stage cancer is a complex social, ethical, and emotional issue rather than simply an issue of following guidelines on evidence-based medicine or health resources. Often, it is complicated by the opinions of a patient’s family members. It is recommended to listen fully and respectfully and attach great importance to the requests and suggestions of patients and their relatives, and to make detailed and clear records of these conversations and the actions are taken. Timing of nutrition therapy Traditionally, nutritional support has been administered as a passive palliative care measure after tumor-control therapy has failed. With a better understanding of nutrition therapy, it will not only become the basic treatment and first-line treatment for the patients with cancer, but it needs to develop into a full and active treatment method that should be started early (Figure 5).Figure 5:: The timing of nutrition therapy administration.From the time of cancer diagnosis, all patients can and should receive nutrition education, but not all patients should receive medical nutrition therapy (EN, PN) early. In general, medical nutrition therapy should be based on nutritional diagnosis, and it should be only after the patient is with moderate or malnutrition. However, based on the on Nutrition and Clinical of study in and a study in patients with digestive system tumors, and patients with any tumors, can start medical nutrition at the time of cancer In addition, nutritional and medical nutrition therapy can be to undergoing major surgery, especially abdominal surgery, high-dose and high-dose chemotherapy, even if the patient is not Malnutrition in patient with cancer is the result of a of intake, metabolic and increased REE are the causes of malnutrition. Compared with patients with benign the incidence of malnutrition in cancer patients is and the are more cancer patients have more and higher medical shorter and decreased and to tumor-control therapy. Therefore, patient with cancer have a need for nutrition therapy, and it should be a basic treatment and the first-line treatment for cancer. The nutrition support needs to be a of the treatment and the of cancer.