Tora S. Solheim

ESPEN guidelines on nutrition in cancer patients

Cancers are among the leading causes of morbidity and mortality worldwide, and the number of new cases is expected to rise significantly over the next decades. At the same time, all types of cancer treatment, such as surgery, radiation therapy, and pharmacological therapies are improving in sophistication, precision and in the power to target specific characteristics of individual cancers. Thus, while many cancers may still not be cured they may be converted to chronic diseases. All of these treatments, however, are impeded or precluded by the frequent development of malnutrition and metabolic derangements in cancer patients, induced by the tumor or by its treatment. These evidence-based guidelines were developed to translate current best evidence and expert opinion into recommendations for multi-disciplinary teams responsible for identification, prevention, and treatment of reversible elements of malnutrition in adult cancer patients. The guidelines were commissioned and financially supported by ESPEN and by the European Partnership for Action Against Cancer (EPAAC), an EU level initiative. Members of the guideline group were selected by ESPEN to include a range of professions and fields of expertise. We searched for meta-analyses, systematic reviews and comparative studies based on clinical questions according to the PICO format. The evidence was evaluated and merged to develop clinical recommendations using the GRADE method. Due to the deficits in the available evidence, relevant still open questions were listed and should be addressed by future studies. Malnutrition and a loss of muscle mass are frequent in cancer patients and have a negative effect on clinical outcome. They may be driven by inadequate food intake, decreased physical activity and catabolic metabolic derangements. To screen for, prevent, assess in detail, monitor and treat malnutrition standard operating procedures, responsibilities and a quality control process should be established at each institution involved in treating cancer patients. All cancer patients should be screened regularly for the risk or the presence of malnutrition. In all patients - with the exception of end of life care - energy and substrate requirements should be met by offering in a step-wise manner nutritional interventions from counseling to parenteral nutrition. However, benefits and risks of nutritional interventions have to be balanced with special consideration in patients with advanced disease. Nutritional care should always be accompanied by exercise training. To counter malnutrition in patients with advanced cancer there are few pharmacological agents and pharmaconutrients with only limited effects. Cancer survivors should engage in regular physical activity and adopt a prudent diet.

Cancer cachexia: A systematic literature review of items and domains associated with involuntary weight loss in cancer

BACKGROUND The concept of cancer-related anorexia/cachexia is evolving as its mechanisms are better understood. To support consensus processes towards an updated definition and classification system, we systematically reviewed the literature for items and domains associated with involuntary weight loss in cancer. METHODS Two search strings (cachexia, cancer) explored five databases from 1976 to 2007. Citations, abstracts and papers were included if they were original work, in English/German language, and explored an item to distinguish advanced cancer patients with variable degrees of involuntary weight loss. The items were grouped into the 5 domains proposed by formal expert meetings. RESULTS Of 14,344 citations, 1275 abstracts and 585 papers reviewed, 71 papers were included (6325 patients; 40-50% gastrointestinal, 10-20% lung cancer). No single domain or item could consistently distinguish cancer patients with or without weight loss or having various degrees of weight loss. Anorexia and decreased nutritional intake were unexpectedly weakly related with weight loss. Explanations for this could be the imprecise measurement methods for nutritional intake, symptom interactions, and the importance of systemic inflammation as a catabolic drive. Data on muscle mass and strength is scarce and the impact of cachexia on physical and psychosocial function has not been widely assessed. CONCLUSIONS Current data support a modular concept of cancer cachexia with a variable combination of reduced nutritional intake and catabolic/hyper-metabolic changes. The heterogeneity in the literature revealed by this review underlines the importance of an agreed definition and classification of cancer cachexia.

Validation of the Consensus-Definition for Cancer Cachexia and evaluation of a classification model—a study based on data from an international multicentre project (EPCRC-CSA)

BACKGROUND Weight loss limits cancer therapy, quality of life and survival. Common diagnostic criteria and a framework for a classification system for cancer cachexia were recently agreed upon by international consensus. Specific assessment domains (stores, intake, catabolism and function) were proposed. The aim of this study is to validate this diagnostic criteria (two groups: model 1) and examine a four-group (model 2) classification system regarding these domains as well as survival. PATIENTS AND METHODS Data from an international patient sample with advanced cancer (N = 1070) were analysed. In model 1, the diagnostic criteria for cancer cachexia [weight loss/body mass index (BMI)] were used. Model 2 classified patients into four groups 0-III, according to weight loss/BMI as a framework for cachexia stages. The cachexia domains, survival and sociodemographic/medical variables were compared across models. RESULTS Eight hundred and sixty-one patients were included. Model 1 consisted of 399 cachectic and 462 non-cachectic patients. Cachectic patients had significantly higher levels of inflammation, lower nutritional intake and performance status and shorter survival. In model 2, differences were not consistent; appetite loss did not differ between group III and IV, and performance status not between group 0 and I. Survival was shorter in group II and III compared with other groups. By adding other cachexia domains to the model, survival differences were demonstrated. CONCLUSION The diagnostic criteria based on weight loss and BMI distinguish between cachectic and non-cachectic patients concerning all domains (intake, catabolism and function) and is associated with survival. In order to guide cachexia treatment a four-group classification model needs additional domains to discriminate between cachexia stages.

Non-steroidal anti-inflammatory treatment in cancer cachexia: a systematic literature review.

Abstract Background. There are no established treatments for cachexia. Recently it has been suggested that the evidence for non-steroidal anti-inflammatory (NSAID) treatment is sufficient to support its regular clinical use. Primary objective in this systematic review was to assess efficacy and safety of NSAID treatment in improving body weight and muscle mass in patients with cancer cachexia. Secondary objectives were to assess whether this treatment could improve other cachexia domains such as anorexia and food intake, catabolic drive and function. Material and methods. A systematic literature review of PubMed, EMBASE and Cochrane Central register of controlled trials database was carried out using both text words and MeSH/EMTREE terms. Results. Thirteen studies were included; all but two trials showed either improvement or stabilization in weight or lean body mass. Seven studies were without a comparator. Studies are generally small and a few are methodologically flawed, often due to multiple outcomes with excess risk of false positives. Conclusion. NSAIDs may improve weight in cancer patients with cachexia, and there is some evidence on effect on physical performance, self-reported quality of life and inflammatory parameters. Evidence is too frail to recommend NSAID for cachexia outside clinical trials. This is supported by the known side effects of NSAIDs, even though the reviewed literature report almost negligible toxicity.

Dietary treatment of weight loss in patients with advanced cancer and cachexia: A systematic literature review

PURPOSE A systematical literature review evaluating the effect of dietary counseling in treating weight loss and improving energy intake in patients with advanced cancer with different stages of cachexia. PRINCIPAL RESULTS Five publications were retrieved, of which three were randomized. Two out of five studies showed less weight loss with dietary counseling (+1% weight gain vs. -1.5% weight loss, p=0.03, 1.4kg vs. -2kg, p<0.05), two presented positive effect on energy intake (92% of total caloric need vs. 73%, p<0.01, 1865±317kcal vs. 1556±497kcal, ns). CONCLUSION Dietary counseling can effect energy intake and body weight, however, apparent heterogeneity between studies is present. Based on these results there is not enough proof of evidence that dietary counseling given to patients with cancer is beneficial for improving weight or energy balance in the different cachexia stages. Nutrition is an essential part of cachexia treatment as it is not considered possible to increase or stabilize weight if nutritional needs are not met.

Evidence base for multimodal therapy in cachexia.

Purpose of reviewThe lack of success of unimodal treatment studies in cachexia and the growing awareness that multiple components are responsible for the development of cachexia have led to the view that cachexia intervention should include multimodal treatment. The aim of this article is to examine the evidence for multimodal treatment in the management of cancer cachexia. Recent findingsThere are some studies involving multimodal treatment that indicate significant effects on cachexia outcomes. There are, however, no randomized controlled trials to date that incorporate fully a structured exercise program, nutrition, good symptom treatment as well as drug treatment, to counteract the effects of altered metabolism. SummaryThe effectiveness of any drug intervention for cancer cachexia probably will only be maximized if incorporated into multimodal treatment. Further, cachexia treatment trials should also aim to include patients at an early phase in their cachexia trajectory and use validated outcome measures.

Weight loss, appetite loss and food intake in cancer patients with cancer cachexia: Three peas in a pod? – analysis from a multicenter cross sectional study

Abstract Background. How to assess cachexia is a barrier both in research and in clinical practice. This study examines the need for assessing both reduced food intake and loss of appetite, to see if these variables can be used interchangeably. A secondary aim is to assess the variance explained by food intake, appetite and weight loss by using tumor-related factors, symptoms and biological markers as explanatory variables. Material and methods. One thousand and seventy patients with incurable cancer were registered in an observational, cross sectional multicenter study. A total of 885 patients that had complete data on food intake (PG-SGA), appetite (EORTC QLQ-C30) and weight loss were included in the present analysis. The association between reduced food intake and appetite loss was assessed using Spearmans correlation. To find the explained variance of the three symptoms a multivariate analysis was performed. Results. The mean age was 62 years with a mean survival of 247 days and a mean Karnofsky performance status of 72. Thirteen percent of the patients who reported eating less than normal had good appetite and 25% who had unchanged or increased food intake had reduced appetite. Correlation between appetite loss and food intake was 0.50. Explained variance for the regression models was 44% for appetite loss, 27% for food intake and only 13% for weight loss. Conclusion. Both appetite loss and food intake should be assessed in cachectic patients since conscious control of eating may sometimes overcome appetite loss. The low explained variance for weight loss is probably caused by the need for more knowledge about metabolism and inflammation, and is consistent with the cancer cachexia definition that claims that in cachexia weight loss is not caused by reduced food intake alone. The questions concerning appetite loss from EORTC-QLQ C30 and food intake from PG-SGA seem practical and informative when dealing with advanced cancer patients.

P‐selectin genotype is associated with the development of cancer cachexia

The variable predisposition to cachexia may, in part, be due to the interaction of host genotype. We analyzed 129 single nucleotide polymorphisms (SNPs) in 80 genes for association with cachexia based on degree of weight loss (>5, >10, >15%) as well as weight loss in the presence of systemic inflammation (C‐reactive protein, >10 mg/l). 775 cancer patients were studied with a validation association study performed on an independently recruited cohort (n = 101) of cancer patients. The C allele (minor allele frequency 10.7%) of the rs6136 (SELP) SNP was found to be associated with weight loss >10% both in the discovery study (odds ratio (OR) 0.52; 95% confidence intervals (CI), 0.29–0.93; p = 0.026) and the validation study (OR 0.09, 95% CI 0.01–0.98, p = 0.035). In separate studies, induction of muscle atrophy gene expression was investigated using qPCR following either tumour‐induced cachexia in rats or intra‐peritoneal injection of lipopolysaccharide in mice. P‐selectin was found to be significantly upregulated in muscle in both models. Identification of P‐selectin as relevant in both animal models and in cachectic cancer patients supports this as a risk factor/potential mediator in cachexia.

Prognosis in advanced lung cancer - A prospective study examining key clinicopathological factors

OBJECTIVES In patients with advanced incurable lung cancer deciding as to the most appropriate treatment (e.g., chemotherapy or supportive care only) is challenging. In such patients the TNM classification system has reached its ceiling therefore other factors are used to assess prognosis and as such, guide treatment. Performance status (PS), weight loss and inflammatory biomarkers (Glasgow Prognostic Score (mGPS)) predict survival in advanced lung cancer however these have not been compared. This study compares key prognostic factors in advanced lung cancer. MATERIALS AND METHODS Patients with newly diagnosed advanced lung cancer were recruited and demographics, weight loss, other prognostic factors (mGPS, PS) were collected. Kaplan-Meier and Cox regression methods were used to compare these prognostic factors. RESULTS 390 patients with advanced incurable lung cancer were recruited; 341 were male, median age was 66 years (IQR 59-73) and patients had stage IV non-small cell (n=288) (73.8%) or extensive stage small cell lung cancer (n=102) (26.2%). The median survival was 7.8 months. On multivariate analysis only performance status (HR 1.74 CI 1.50-2.02) and mGPS (HR 1.67, CI 1.40-2.00) predicted survival (p<0.001). Survival at 3 months ranged from 99% (ECOG 0-1) to 74% (ECOG 2) and using mGPS, from 99% (mGPS0) to 71% (mGPS2). In combination, survival ranged from 99% (mGPS 0, ECOG 0-1) to 33% (mGPS2, ECOG 3). CONCLUSION Performance status and the mGPS are superior prognostic factors in advanced lung cancer. In combination, these improved survival prediction compared with either alone.

A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer

Cancer cachexia is a syndrome of weight loss (including muscle and fat), anorexia, and decreased physical function. It has been suggested that the optimal treatment for cachexia should be a multimodal intervention. The primary aim of this study was to examine the feasibility and safety of a multimodal intervention (n‐3 polyunsaturated fatty acid nutritional supplements, exercise, and anti‐inflammatory medication: celecoxib) for cancer cachexia in patients with incurable lung or pancreatic cancer, undergoing chemotherapy.