Evidence based practice guidelines for the nutritional management of cancer cachexia

Abstract

The purpose of these guidelines is to provide dietitians in Australia with a user-friendly summary of the evidence to support the nutritional management of adult patients with cancer cachexia. This best available evidence is presented and used as a basis for providing recommendations about clinical practice. The clinical questions were as follows: How should patients be identified for referral to the dietitian in order to maximise nutritional intervention opportunities? How should nutritional status be assessed? What are the goals of nutrition intervention for patients with cancer cachexia? What is the nutrition prescription to achieve these goals? Should eicosapentaenoic acid be included in the prescription? What are effective methods of implementation to ensure positive outcomes? Does nutrition intervention improve outcomes in patients with cancer cachexia? This document is a general guide to appropriate practice to be followed only subject to the dietitian’s judgement in each individual case. The guidelines are designed to provide information to assist decision-making and are based on the best information available at the date of compilation. The guidelines recommend intensive nutrition therapy. This has potential resource implications that may include additional staff, change to staff roles and increased use of high/protein energy supplements if they are considered. Therefore, in applying the guidelines these potential organisational and cost barriers need to be considered. These guidelines for practice are provided with the express understanding that they do not establish or specify particular standards of care, whether legal, medical or other. A Steering Committee of dietitians with research expertise in nutritional management of cancer cachexia and evidence based guideline development produced the first draft of the clinical practice guidelines. Initial members of the guideline development team convened in December 2003 were Dr Judy Bauer (Chairperson—The Wesley Hospital, Brisbane), A/Prof Susan Ash (Queensland University of Technology, Brisbane) and Ms Wendy Davidson (Princess Alexandra Hospital, Brisbane). This group developed the initial draft and workshop presentation. Additional members of the team from August 2004 were Ms Jan Hill (Royal Brisbane & Women’s Hospital, Brisbane), Ms Teresa Stock (Royal Brisbane & Women’s Hospital, Brisbane), Dr Elisabeth Isenring (Flinders University, Adelaide) and Dr Marina Reeves (Queensland Cancer Fund, Brisbane). The draft was modelled on other guidelines developed for the nutritional management of disease. A workshop of dietitians was convened at the 22nd National Conference of the Dietitians Association of Australia in May 2004 to consider the draft guidelines and provide peer review. Participants evaluated the guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument (The AGREE Collaboration).1 Participant feedback from the workshop was incorporated into a second draft. The second draft of the guidelines was presented at a workshop for dietitians in Perth in November 2004, where again evaluation was completed using the AGREE tool. Participant feedback from the workshop was incorporated into the third draft. At both workshops case studies were presented to demonstrate the use of the guidelines. A statistician was consulted to clarify issues related to levels of evidence and incorporation of evidence from post –hoc analyses of randomised trials. The relevant articles were identified by electronic database searches (up to and including April 2005). The reference lists of relevant articles were also hand searched for any additional studies. In areas where cachexia-specific data was lacking, results from studies of other groups of patients with cancer have been included, and identified as such. The following search strategies were used for the electronic databases listed below. Details of the search results were retained by the guideline development team. Term 1 Cancer or neoplasm or carcinoma or tumo?r Cancer* or neoplasm* or carcinoma or tumour Term 2 Cachexia or cachectic or weight loss or malnourished or wasting Cachex* or cachect* or (weight los*) or malnourished or wast* Term 3 Nutrition or diet Nutrition* or diet* Search = Terms 1 and 2 and 3 Limited to adult humans Search updated with databases available April 2005 Electronic databases The Cochrane Database of Systematic Reviews The Cochrane Central Register of Controlled Trials (CENTRAL) Medline Advanced 1950–2005/01 PubMed (to include early 2005 publications)—Cancerlit CINAHL (1982–current) Web of Science EMBASE Health Source: Nursing/Academic Edition Cancernet Cancer Spectrum Australasian Medical Index (AMI) The strength of the evidence was assessed using the level of evidence rating system recommended by the National Health and Medical Research Council (NHMRC) publication A Guide to the Development, Implementation and Evaluation of Clinical Practice Guidelines.2 A table was developed to collate the evidence for screening, assessment, intervention and monitoring and evaluation against key outcome indicators. Levels of evidence, quality of study design, the strength of the effect and relevance to practice were considered in ranking the evidence. The evidence rating system used in the guidelines is as follows: Level I Evidence obtained from a systematic review of all relevant randomised controlled trials Level II Evidence obtained from at least one properly designed randomised controlled trial Level III-1 Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method) Level III-2 Evidence obtained from comparative studies with concurrent control and allocation not randomised (cohort studies), case-control studies, or interrupted time series with a control group Level III-3 Evidence obtained from comparative studies with historical control, two or more single arm studies, or interrupted time series without a parallel group Level IV Evidence obtained from case studies, either post-test or pre- and post-test.2 For intervention studies, Level I is recommended as the gold standard. It was felt that clinical nutrition studies are difficult to complete in a blinded fashion and often the group most likely to benefit from the intervention is excluded for ethical reasons. For these reasons, recommendations based on lower levels of evidence but with strong quality of design, strength of effect and relevance has been included. The guideline development team also used the NHMRC additional levels of evidence and grades for recommendations for developers of guidelines—Pilot Program.3 This grading system for recommendations has been developed as an interim measure to assist guideline developers in assessing the entire body of evidence and indicating the strength of each guideline recommendation. The grades of recommendation are: Level A Body of evidence can be trusted to guide practice Level B Body of evidence can be trusted to guide practice in most situations Level C Body of evidence provides some support for recommendation(s) but care should be taken in its application Level D Body of evidence is weak and recommendation must be applied with caution.3 The five components that are considered in judging the body of evidence are the volume of evidence, consistency of the results, potential clinical impact of the proposed recommendation, the generalisability of the body of evidence to the target population of the guideline and the applicability of the body of evidence to the Australian healthcare context. A recommendation cannot be graded as A or B unless the volume and consistency of the evidence components are both graded A or B. The third draft underwent additional peer, expert and consumer review. It was distributed to previous workshop participants, DAA oncology experts, DAA oncology interest groups, international dietitians who had expressed an interest in participation, oncologists, nurses, other professionals working in the area of cancer and consumers for additional comment. Participant feedback was incorporated into a final draft, which was endorsed by the DAA Practice Advisory Committee (September 2005) and the DAA Board (November 2005). The guidelines should be reviewed every three years to ensure they remain current. Responsibility for review lies with the guideline development team. Next Review Date: 2008. A number of workshops were held during the development stage to identify the applicability of the guidelines for dietitians in the practice area of cancer. These workshops included: the 22nd National Conference of the Dietitians Association of Australia in May 2004; and in Perth in November 2004. Once the guidelines had been endorsed a further workshop was held in Queensland in March 2006, sponsored by Queensland Health, for dietitians to apply the guidelines to particular case studies. Evaluation from all three workshops indicated that the guidelines were applicable for dietetic practice. The guidelines were developed without the assistance of external funding. Where guideline development team members were authors of a published article, other members of the guideline development team evaluated the article for levels of evidence. Guideline development team conflict of interest declarations are: off label research support (Abbott: J, Bauer, S. Ash, W. Davidson) and support for conference attendance (Abbott: J, Bauer, S. Ash, W. Davidson; Novartis: J. Bauer, E. Isenring). The workshops conducted in 2004 at the DAA Conference in Melbourne and Perth were externally sponsored. The views or interests of the workshop sponsors have not influenced the final recommendations. The framework for evidence-based practice for the nutritional management of cancer cachexia is presented in Figure 1. Framework for the development of evidence based practice guidelines for the nutritional management of cancer cachexia (adapted from Hakel-Smith & Lewis,4 and Splett5). The evidence based statements are listed under headings based on the nutrition care process. Clinical question How should patients be identified for referral to the dietitian in order to maximise nutritional intervention opportunities? Evidence statement Level of evidence The Malnutrition Screening Tool (MST) is an effective screening tool for identifying nutritional risk in cancer patients Level III-36 Clinical question How should nutritional status be assessed? Evidence statement Level of evidence Subjective Global Assessment (SGA) is a valid method of assessing nutritional status in patients with cancer cachexia IV7 The scored Patient-Generated Subjective Global Assessment (PG-SGA) is a valid method of assessing nutritional status in patients with cancer cachexia III-37, 8 Bioelectrical impedance analysis is not suitable for body composition measurement in individual patients with cancer cachexia III-39, 10 Clinical question What are the goals of nutrition intervention for patients with cancer cachexia? Evidence statement Level of evidence Weight-losing patients with cancer cachexia who stabilise their weight have greater quality of life and survival duration than those who continue to lose weight III-211 Clinical question What is the nutrition prescription to achieve these goals? Evidence statement Level of evidence Energy and protein requirements for weight stabilisation are approximately 120 kJ/kg/d and 1.4 g protein/kg/d in patients with cancer cachexia receiving supportive care III-211 Energy and protein requirements for weight stabilisation are approximately 120 kJ/kg/d and 1.4 g protein/kg/d in patients with cancer cachexia receiving chemotherapy IV7 Weight stable patients have higher energy intake than weight losing patients in patients with cancer cachexia receiving supportive care III-211 Well-nourished patients with advanced cancer have higher energy and protein intakes compared to malnourished patients with advanced cancer IV12 Clinical question Should EPA be included in the prescription in patients with cancer cachexia? Evidence statement Level of evidence The prescription of EPA improves outcomes in patients with cancer cachexia Level C7, 11, 13-20 Body of evidence provides some support for recommendation but care should be taken in its application Clinical question What are effective methods of implementation to ensure positive outcomes? Evidence statement Level of evidence Compliance with a nutrition prescription of 1.5 cans/d of a high protein energy supplement ± EPA does not reduce total food intake in patients with cancer cachexia receiving supportive care III-220 Consumption of a high protein energy supplement enriched with EPA does not reduce total food intake in patients with cancer cachexia receiving chemotherapy IV7 Frequent clinician contact (minimum fortnightly) improves clinical outcomes in patients with cancer cachexia III-37, 18 Clinical question Does nutrition intervention improve outcomes in patients with cancer cachexia? Evidence statement Level of evidence Nutrition intervention improves outcomes in patients with cancer cachexia Level C7, 11, 13-20 Body of evidence provides some support for recommendation but care should be taken in its application A summary of recommendations for the nutritional management of cancer cachexia is presented in Table 1. The majority of cancer patients experience weight loss as their disease progresses and in general, weight loss is a major prognostic indicator of poor survival and impaired response to cancer treatment.21 The incidence of malnutrition amongst patients with cancer has been estimated at between 40% and 80%.22, 23 The prevalence of malnutrition depends on the tumour type, location, stage and treatment.24 The consequences of malnutrition may include an increased risk of complications, decreased response and tolerance to treatment, a lower quality of life, reduced survival and higher health-care costs.25-27 Cancer cachexia has been implicated in the deaths of 30–50% of all cancer patients, as many die from the wasting associated with the condition.28 The causes of weight loss in patients with cancer are multifactorial and may be due to symptoms reducing intake, treatment related or mechanical obstruction, or cachexia. Symptoms such as anorexia, depression, anxiety, fatigue, early satiety and pain can result in a decreased appetite and food intake. Cancer treatment may result in weight loss, for example surgery (malabsorption), radiotherapy (nausea, pain, diarrhoea, mucositis), and chemotherapy (nausea, vomiting, diarrhoea, mucositis). Weight loss may be due to mechanical obstruction caused by the cancer itself, such as obstruction of the oesophagus causing swallowing problems and reduced intake. Appropriate nutrition support provided during radiotherapy can help to overcome some of the nutrition impact symptoms and help patients to maintain weight compared with standard practice where patients continued to lose weight during radiotherapy treatment.29 However if the weight loss is due to cachexia, it may not be reversible because host intermediary metabolism (carbohydrate, protein and lipid metabolism) is abnormal, limiting the success of nutrition intervention.30 Numerous drug therapies (e.g. megestrol, steroids) have been trialled in patients with cancer cachexia to stimulate appetite or attenuate metabolic changes. Several trials with synthetic progesterone agents have demonstrated a beneficial influence on weight, however, this is largely due to an increase in fat mass.31-33 Evaluation of pharmacotherapies is beyond the scope of these guidelines. The term cancer cachexia is derived from the Greek words kakos and hexis meaning poor condition. Cachexia has been defined as a syndrome characterised by the progressive loss of lean tissue and body fat, and losses are often in excess to that explained by the associated anorexia. There are often additional metabolic derangements, including anaemia, acute phase protein response and alterations in plasma lipid profile.34 The development of cachexia is common in people with solid tumours such as pancreatic, lung, gastric and colorectal cancer. Weight loss in cancer cachexia is different from the weight loss of starvation or anorexia. This is due to accelerated loss of skeletal muscle in relation to adipose tissue, presence of pro-inflammatory cytokines and prolonged acute phase protein response (APPR) that contributes to increased resting energy expenditure and weight loss.35 Patients with cancer cachexia experience anorexia, early satiety, weakness, muscle wasting, fatigue, anaemia and severe weight loss. In starvation more than three-quarters of the weight lost is from body fat and only a small amount from muscle. In cancer cachexia, weight loss arises equally from loss of muscle and fat.36 There are no definitive methods for diagnosis of cancer cachexia. Clinical signs of anorexia, muscle wasting and weight loss of ≥ 5% over 6 months in patients diagnosed with cancer would be expected but clinical judgement is required. Weight loss due to mechanical obstruction, treatment or side-effects, which would be expected to resolve once the obstruction is bypassed/removed or treatment ceased should not be classified as cachexia. These patients still require nutrition intervention but the focus of these guidelines is on cancer cachexia. The patient target group encompasses any adult patient with cancer fulfilling the diagnostic criteria for cachexia. In Australia, hospital inpatients are generally seen by dietitians as a result of referrals by medical or nursing staff.37 Studies have found the prevalence of malnutrition to be similar between those patients who were referred to a dietitian by medical staff and those who were not referred.38, 39 It is recommended that in addition to referrals by medical staff, nutrition screening be performed on admission to hospital or in the outpatient setting during the planning stages of commencing anticancer therapies. Nutrition screening is the process of identifying patients with characteristics commonly associated with nutrition problems that may require comprehensive nutrition assessment (American Dietetic Association (ADA).40 The purpose of nutrition screening is to quickly identify clients who are malnourished or at risk of becoming malnourished who would benefit from nutrition support and prioritise resources to those clients who most need nutrition support. According to the ADA,40 an effective nutrition screening tool should be: Simple, quick, reliable, valid and inexpensive Easily administered with minimal nutritional expertise Applicable to most patients and designed to incorporate only routine data and tests available on admission Many nutrition screening tools have been developed to identify clients at risk of malnutrition in the acute care setting and the community. Problems identified with numerous published nutrition screening tools include requiring specialised nutrition knowledge, biochemical parameters that may not be immediately available, requiring complex calculations or not being evaluated in terms of reliability or validity.37, 41 A number of reliable and valid nutrition screening tools have been recently published: Malnutrition Screening Tool6, 42 Malnutrition Universal Screening Tool43 Mini Nutrition Assessment-Short Form44 Nutrition Risk Screening45 When selecting an appropriate nutrition screening tool, it is imperative that the tool has been validated in the client population in which it is to be applied. The Malnutrition Screening Tool (MST) is a valid screening tool for identifying nutrition risk in patients with cancer (Appendix II)6, 42 No studies have been identified that report nutrition screening in patients with cancer cachexia. Clinical question How should patients be identified for referral to the dietitian in order to maximise nutritional intervention opportunities? The Malnutrition Screening Tool (MST) is an effective screening tool for identifying nutritional risk in patients with cancer Level III-36 Practice Recommendation Identify ‘at risk’ patients in oncology wards and outpatient clinics using a nutrition screening tool such as the Malnutrition Screening Tool that has been validated for oncology patients Practice Tips: Nutrition assistants, administration or nursing staff may implement the MST. The MST can be incorporated into admission forms or patient information sheets. Repeat nutrition screening during treatment at least fortnightly for patients initially screened at low risk. If a patient has been referred to the dietitian by other methods, e.g. direct referral from medical oncologist, nutrition screening is unnecessary—proceed to nutrition assessment. Nutrition assessment is a comprehensive approach to defining nutritional status using medical, nutrition and medication histories, physical examination, anthropometric measurements and laboratory data.40 Nutrition assessment parameters may be affected by non-nutritional factors resulting in poor sensitivity and specificity.46 No single parameter is sufficiently sensitive and specific to determine nutritional status and a combination of parameters should be used.47 Several nutrition assessment tools have been published which use a combination of parameters. Subjective global assessment (SGA) determines nutritional status on the basis of a medical history (weight change, dietary intake change, presence of gastrointestinal symptoms that have persisted for greater than two weeks, functional capacity) and physical assessment (evidence of loss of subcutaneous fat, muscle wasting, oedema or ascites). The features are combined subjectively into an overall or global assessment where patients are rated as being well nourished (SGA A), moderately or suspected of being malnourished (SGA B) or severely malnourished (SGA C).48 The scored Patient-Generated Subjective Global Assessment (PG-SGA) is an adaptation of SGA specifically developed for use in the cancer population (Appendix III).49 It contains additional questions regarding short-term weight loss, a more extensive range of nutrition impact symptoms and for each component of the PG-SGA, points (0–4) are awarded depending on the impact on nutritional status. Typical scores range from 0 to 47 with a higher score reflecting a greater risk of malnutrition. The PG-SGA score has been correlated with a number of objective parameters (% weight loss, body mass index (BMI)), measures of morbidity (survival, length of stay, quality of life), has a high degree of interrater reproducibility and high sensitivity and specificity when compared with other validated nutritional assessment tools.8, 26,50-53 A change in score of approximately nine points is required to move one global rating category.53 The PG-SGA score may be more sensitive than the global rating to demonstrate improvement or deterioration in nutritional status.52 The scored PG-SGA has been recommended as the nutrition assessment tool for patients with cancer by the Oncology Nutrition Dietetic practice group of the American Dietetic Association.54 In patients with cancer cachexia, two studies report nutritional status based on the global categorisation and the PG-SGA score.7, 8 Biochemistry may be influenced by disease and treatment and therefore it is important to use clinical judgement when interpreting values. For example, serum albumin may be low due to the acute phase protein response. However, serum albumin has been shown to be an independent prognostic variable for survival in patients with cancer.55 Patients with raised serum C-reactive protein levels have lower energy intake than those with normal levels56 and there is some evidence that resting energy expenditure may be increased in these patients.57 A variety of techniques are available to measure body composition such as Dual Energy X-ray Absortiometry (DEXA), anthropometric measurements (e.g. triceps skinfold thickness (TSF); corrected arm muscle area (CAMA)), deuterium and bioelectrical impedance analysis (BIA). DEXA and deuterium are expensive methods that are impractical in the clinical setting but may be of use in research studies. Serial anthropometric measurements may be useful to monitor change however, accredited training in anthropometry is recommended. BIA measures tissue conductivity and can be used to assess total body water (TBW) from which fat free mass (FFM) can be calculated. It is important that a BIA prediction equation is used that has been validated in the population under study.58 Studies examining the validation of BIA in cancer patients are limited9, 10,59-62 and no equation has been developed or validated in patients with cancer cachexia. At a group level, these equations are suitable to predict TBW in patients with cancer cachexia but for an individual, they are unsuitable for use.10 Tools used to assess functional status include Karnofsky Performance Status and Eastern Cooperative Oncology Group (ECOG). A variety of tools have been developed and validated to measure quality of life such as the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30,63 Functional Assessment of Cancer Therapy (FACT)64 and the Short Form Health Survey (SF 36).65 In patients with cancer, the PG-SGA score has been shown to be associated with quality of life (EORTC-QLQC30), and therefore can be used to predict the direction and magnitude of change in quality of life.53 Clinical question How should nutritional status be assessed? Evidence statement Level of evidence Subjective Global Assessment (SGA) is a valid method of assessing nutritional status in patients with cancer cachexia IV7 The scored Patient-Generated Subjective Global Assessment (PG-SGA) is a valid method of assessing nutritional status in patients with cancer cachexia III-37, 8 Bioelectrical impedance analysis is not suitable for body composition measurement in individual patients with cancer cachexia III-39, 10 Practice Recommendation Use the scored Patient Generated—Subjective Global Assessment (PG-SGA) as the nutrition assessment tool in patients with cancer cachexia. Practice Tips: A summary of nutrition assessment practice tips are contained in Table 2. Nutrition intervention is the second stage of the clinical judgements made in the nutrition care process. The key aspects of intervention are establishing the goals of treatment, determining the nutrition prescription and the implementation of the nutrition care. The success or otherwise of nutrition intervention depends equally on these components.66 Having identified the nutrition problem by assessing and interpreting the evidence and data collected about the patient, a judgement about the goals of treatment must be made. Established goals provide the criteria to be measured in the outcome evaluation step, where effectiveness of the nutrition intervention is evaluated.1 When discussing nutrition intervention options with patients and carers, it is important to present realistic potential outcomes. The goals and outcomes of nutrition intervention will be dependent on patient’s diagnosis and prognosis. If goal requirements cannot be achieved with oral intake, alternative means of nutrition support should be considered. Refer to guidelines for the use of parenteral and enteral nutrition in adult and paediatric patients from the American Society of Parenteral and Enteral Nutrition.67 Traditionally, treatment has focused on weight gain as the goal of nutrition intervention. Some studies have failed to show a positive effect of nutrition intervention when weight gain was the outcome.16, 17,55 Other studies using weight stabilisation as an outcome of nutrition intervention have shown positive effects. Weight losing patients with advanced gastrointestinal and non-small cell lung cancer whose weight stabilises have a longer survival and improved quality of life than those who continue to lose weight.11, 68,69 Weight stabilisation is an appropriate goal for weight losing cancer patients provided that life expectancy is at least two months.11 Continue to reassess stage of treatment and disease, and whether any change to palliative care status. Determine level of support from the patients General Practitioner, carer and palliative care team. When a patient is having palliative treatment or palliative supportive care at end stage of disease, intensity of dietary intervention may need to be adapted. Liaise with patient/family/carers and medical team to determine level of intervention required. Unnecessary dietary restrictions can be relaxed (e.g. cholesterol lowering modifications). Discuss treatment with patient for indication of satisfaction with intensity of care. If end stage, the dietitian may advocate for patient with carer or family to reduce intensity of dietary treatment. The desired outcomes are maximising patient comfort and maintaining quality of life. In many cases this may mean a patient will not meet full nutrition requirements, for example if tube feeding is refused or supplement drinks are not liked. Each case should be assessed individually and with full discussion with the team to determine new goals of care. Patients in the final weeks of life are unlikely to be able to maintain their lean body mass. Any weight gain that does occur at this time is likely to be due to fluid retention. For comfort measures refer to DAA paper: Nutrition priorities in palliative care of oncology patients.70 Clinical question What are the goals of nutrition intervention for patients with can