Samantha Cushen

Cancer-associated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later.

An awareness of the importance of nutritional status in hospital settings began more than 40 years ago. Much has been learned since and has altered care. For the past 40 years several large studies have shown that cancer patients are amongst the most malnourished of all patient groups. Recently, the use of gold-standard methods of body composition assessment, including computed tomography, has facilitated the understanding of the true prevalence of cancer cachexia (CC). CC remains a devastating syndrome affecting 50-80 % of cancer patients and it is responsible for the death of at least 20 %. The aetiology is multifactorial and complex; driven by pro-inflammatory cytokines and specific tumour-derived factors, which initiate an energy-intensive acute phase protein response and drive the loss of skeletal muscle even in the presence of adequate food intake and insulin. The most clinically relevant phenotypic feature of CC is muscle loss (sarcopenia), as this relates to asthenia, fatigue, impaired physical function, reduced tolerance to treatments, impaired quality of life and reduced survival. Sarcopenia is present in 20-70 % depending on the tumour type. There is mounting evidence that sarcopenia increases the risk of toxicity to many chemotherapy drugs. However, identification of patients with muscle loss has become increasingly difficult as 40-60 % of cancer patients are overweight or obese, even in the setting of metastatic disease. Further challenges exist in trying to reverse CC and sarcopenia. Future clinical trials investigating dose reductions in sarcopenic patients and dose-escalating studies based on pre-treatment body composition assessment have the potential to alter cancer treatment paradigms.

Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact

Our understanding of body composition (BC) variability in contemporary populations has significantly increased with the use of imaging techniques. Abnormal BC such as sarcopenia (low muscle mass) and obesity (excess adipose tissue) are predictors of poorer prognosis in a variety of conditions or clinical situations. As a catabolic illness, a defining feature of cancer is muscle loss. Although the conceptual model of wasting in cancer is typically conceived as involuntary weight loss leading to low body weight, recent studies have shown that both sarcopenia and cachexia can be present with obesity. The combination of low muscle and high adipose tissue (sarcopenic obesity) is an emerging abnormal BC phenotype prevalent across the body weight, and hence BMI spectra. Sarcopenia and sarcopenic obesity in cancer are in most instances occult conditions, which have been independently associated with higher incidence of chemotherapy toxicity, shorter time to tumour progression, poorer outcomes of surgery, physical impairment and shorter survival. Although the mechanisms are yet to be fully understood, the associations with poorer clinical outcomes emphasise the value of nutritional assessment as well as the need to develop appropriate interventions to countermeasure abnormal BC. Sarcopenia and sarcopenic obesity create diverse nutritional requirements, highlighting the compelling need for a more comprehensive and differentiated understanding of energy and protein requirements in this heterogeneous population.

Body Composition by Computed Tomography as a Predictor of Toxicity in Patients With Renal Cell Carcinoma Treated With Sunitinib.

Background: Sunitinib is a standard first-line option for metastatic renal cell carcinoma (mRCC). Body composition is a prognostic factor in cancer patients and patients with loss of skeletal muscle mass and fat-free mass (FFM) are prone to dose-limiting toxicity (DLT) during targeted drug therapy. We investigated whether body composition by computed tomography predicted DLT from sunitinib in mRCC. Methods: Patients with clear cell mRCC receiving sunitinib (50 mg) were included. Skeletal muscle cross-sectional area at L3 was measured by computed tomography. Sarcopenia was defined using published cutoffs. Toxicity was assessed after 4 cycles of the drug. Results: Fifty-five patients (43 male), mean age 64 years were included. Overall, 33% (N=18) of all patients were sarcopenic and of these 12.7% (N=7) were sarcopenic and overweight or obese. DLT occurred in <6 months in 53% of patients (44% male vs. 83% female) and those who experienced DLT were older (68 vs. 60 y), had a lower skeletal muscle index (51.7 vs. 59.4 cm2/m2), a lower FFM (51.4 vs. 57.7 kg), and received a higher drug dose in mg/kg FFM (0.9 vs. 0.8). Patients with the lowest compared with the highest measurements of skeletal muscle mass experienced more DLT, respectively, 92% versus 57% and experienced on average 5 toxicities versus 2. Conclusions: Sarcopenia is prevalent in patients with mRCC, is an occult condition in patients with normal/high body mass index, and is a significant predictor of DLT in patients receiving sunitinib. Our results highlight the potential use of baseline body composition to predict toxicity.

The impact of body composition parameters on ipilimumab toxicity and survival in patients with metastatic melanoma.

Background:Body composition is an important predictor of drug toxicity and outcome. Ipilimumab (Ipi), a monoclonal antibody used to treat metastatic melanoma, has specific toxicities. No validated biomarkers that predict Ipi toxicity and efficacy exist. Also, the impact of Ipi on body composition has not been established.Methods:Patients with metastatic melanoma treated with Ipi between 2009 and 2015 were included. Body composition was assessed by computed tomography at baseline and after four cycles of Ipi. Sarcopenia and low muscle attenuation (MA) were defined using published cut-points. All adverse events (AEs) and immune-related AEs (irAEs) were recorded (Common Terminology Criteria For Adverse Event V.4.0).Results:Eighty-four patients were included in this study (62% male, median age 54 years). At baseline, 24% were sarcopenic and 33% had low MA. On multivariate analysis, sarcopenia and low MA were significantly associated with high-grade AEs (OR=5.34, 95% CI: 1.15–24.88, P=0.033; OR=5.23, 95% CI: 1.41–19.30, P=0.013, respectively), and low MA was associated with high-grade irAEs (OR=3.57, 95% CI: 1.09–11.77, P=0.036). Longitudinal analysis (n=59) revealed significant reductions in skeletal muscle area (SMA), total body fat-free mass, fat mass (all P<0.001) and MA (P=0.030). Mean reduction in SMA was 3.3%/100 days (95% CI: −4.48 to −1.79%, P<0.001). A loss of SMA ⩾7.5%/100 days (highest quartile) was a significant predictor of overall survival in multivariable Cox regression analysis (HR: 2.1, 95% CI: 1.02–4.56, P=0.046).Conclusions:Patients with sarcopenia and low MA are more likely to experience severe treatment-related toxicity to Ipi. Loss of muscle during treatment was predictive of worse survival. Treatments to increase muscle mass and influence outcome warrant further investigation.

Loss of skeletal muscle during systemic chemotherapy is prognostic of poor survival in patients with foregut cancer: Muscle loss during chemotherapy is prognostic of poor survival

Malnutrition, weight loss, and muscle wasting are common in patients with foregut cancers (oesophagus, stomach, pancreas, liver, and bile ducts) and are associated with adverse clinical outcomes. However, little is known about the changes in body composition that occur in these patients during chemotherapy and its impacts clinical outcomes.

Does Prolonged Enteral Feeding With Supplemental Omega-3 Fatty Acids Impact on Recovery Post-esophagectomy: Results of a Randomized Double-Blind Trial

Objective: This randomized controlled trial (RCT) hypothesized that prolonged enteral nutrition (EN) with supplemental eicosapentanoic acid (EPA), an omega-3 fatty acid with immune and anabolic properties, may impact on clinical and nutritional outcomes. Background: Esophagectomy is associated with significant weight loss and catabolism, and negatively impacts quality of life (QL). Strategies to counter sustained catabolism have therapeutic rationale. Methods: This multicenter, double-blind, placebo-controlled RCT was powered on a 5% difference in lean body mass (LBM) at 1 month. Patients were randomly assigned to receive either EN-EPA (2.2 g EPA/day) (n = 97) or isocaloric isonitrogenous standard EN (EN-S) (n = 94), preoperatively (5 days orally), and postoperatively via a jejunostomy until 1 month postdischarge. Assessments perioperatively, and at 1, 3, and 6 months included weight, body mass index (BMI), body composition, muscle strength, cytokines, complications, and QL. Results: The median (range) nutrition support was for 51 (36 to 78) days, and overall compliance was 96%. For the entire cohort, a significant (P < 0.005) decrease in weight (−7.4 ± 6.6 kg), BMI (−2.6 ± 2.2 kg/m2), LBM (−2.5 ± 8.7 kg), and fat mass (−3.4 ± 5.8 kg) was evident from preoperatively to 6 months. The mean (±SD) loss of LBM (kg) at 1 month was −3.7 ± 8.7 in the EN-S group, compared with −5.6 ± 12.1 in the EN-EPA group (P = 0.355). Per-protocol analysis revealed no difference between the EN-EPA and EN-S in any clinical, nutritional, functional, QL or immune parameter at any time point. Conclusions: The thesis that EPA impacts on anabolism, immune function, and clinical outcomes post-esophagectomy was not supported. Compliance with home EN was excellent, but weight, muscle, and fat loss was significant in 30% of patients, highlighting the complexity of postoperative weight loss.

Computed tomography diagnosed cachexia and sarcopenia in 725 oncology patients: is nutritional screening capturing hidden malnutrition?

Nutrition screening on admission to hospital is mandated in many countries, but to date, there is no consensus on which tool is optimal in the oncology setting. Wasting conditions such as cancer cachexia (CC) and sarcopenia are common in cancer patients and negatively impact on outcomes; however, they are often masked by excessive adiposity. This study aimed to inform the application of screening in cancer populations by investigating whether commonly used nutritional screening tools are adequately capturing nutritionally vulnerable patients, including those with abnormal body composition phenotypes (CC, sarcopenia, and myosteatosis).

The Role of Inflammatory Biomarkers in the Assessment of Nutritional Status and Disease States

Biomarkers of inflammation form an important, but often overlooked, part of nutritional assessment. Recently, it has become apparent that the pathophysiology of malnutrition associated with disease or acute injury is often accompanied by acute or chronic inflammation. These inflammatory biomarkers not only shape the physiological response to infection or injury but also have notable effects on body composition, serum proteins, and morbidity and mortality in certain disease states. Their monitoring and interpretation can provide important information to practitioners in the prescription of nutrition support and can help guide expectations with respect to nutritional outcomes. The role of inflammatory biomarkers is reviewed both in the pathogenesis of chronic diseases, such as cardiovascular disease and cancer, and in the clinical setting, including interpretation of serum proteins, the etiology of disease-related malnutrition, cancer cachexia, sarcopenia of aging, as well as outcome(s) in surgery.

Body composition as a predictor of chemotherapy toxicity in patients with metastatic prostate cancer treated with docetaxel

S. J. Cushen, D. G. Power, R. McDermot, K. O’Sullivan, P. Maceneaney, L. Daly and A. M. Ryan Dept Food & Nutritional Sciences, University College Cork, Republic of Ireland, Dept Medical Oncology, Mercy & Cork University Hospitals, Cork, Republic of Ireland, Dept Statistics, University College Cork, Republic of Ireland, Dept Medical Oncology, St. Vincents University Hospital, Dublin, Republic of Ireland and Dept Radiology, Mercy University Hospital, Cork, Republic of Ireland

Changes in nutritional status after minimally invasive oesophagectomy with an enhanced recovery after surgery (ERAS) programme & aggressive nutritional intervention; Results of a prospective investigation

Oesophagectomy represents an exemplar of controlled major trauma, with marked metabolic, immunologic, and physiologic changes as well as an associated high incidence of complications. Nutritional status can be impaired post-operatively due to the hypermetabolic response to surgery and eating related symptoms such as anorexia, early satiety and acid reflux. Early aggressive nutrition support may limit catabolism but its role in an enhanced recovery after surgery (ERAS) protocol after major upper gastrointestinal surgery is unclear. The aim of this study was to examine the nutritional outcomes in a cohort of patients presenting for minimally invasive oesophagectomy (MIO) at a specialist centre from March 2012 to March 2015. All patients had histologically proven adenocarcinoma or squamous cell carcinoma of the oesophagus and were enrolled in a standardised multidisciplinary ERAS protocol including written patient education with daily treatment targets, pre-emptive analgesia, early structured mobilisation and early enteral feeding via a needle catheter jejunostomy tube which commenced on post-op day 1. Oral diet was introduced early and all patients were discharged on overnight enteral feeding for 1 month post-op. Nutritional outcomes (including body composition assessment by both computed tomography (CT) and multi-frequency bioelectrical impedance analysis (BIA)), progression to oral diet and patient-reported global quality of life (QOL) scores (EORTC QLQ-C30) were prospectively collected at baseline, and at 1, 3 and 6 months post-op. In total 54 patients gave signed informed consent. The mean age was 62 years (SD 9). There were 40 males (74 %) and 14 females (26 %). The mean percentage weight loss pre-op was 4·7 % (SD 5·3). The mean pre-op BMI was in the overweight category (28·6 kg/ m, SD 5·3), [range 16·9–43·3]. Only 15 % of patients had a BMI in the normal range, 29 (54 %) were overweight and 16 (29 %) were obese. Based on CT assessment of body composition 47 % (n = 22) met the criteria for sarcopenia pre-op. Oral diet was introduced after a mean of 4·7 days (SD 2·7) and jejunostomy feeds were switched to night time only. The mean length of stay (LOS) was 11 days (SD 13). Sarcopenic patients spent on average 5·2 days longer in hospital than non-sarcopenic (14 days (SD 19) Vs 8·8 days (SD 3·6), p = ns). On discharge 73 % were tolerating texture B (minced/mashed) half portions and 27 % were tolerating texture C (puree) half portions. Weight loss was very frequent following MIO with weight decreasing from 83 kg(SD 15) pre-op to 79·9(SD 12·6) at 1 month (p = 0·0001) and 74·2 kg(SD 11·5) by 6 months post-op. BMI dropped significantly from 28·8 kg/m (SD 5·4) pre-op to 25·5 kg/m (SD 3·4) at 6 months post-op (p = 0·0001). Based on BIA assessment of body composition the mean fat mass (kg) decreased significantly postop from 24·1 kg (SD 8·3) pre-op to 22·8 kg (SD 8·1) by 6 months (p = 0·03). Lean tissue mass decreased from 48·2 kg (SD 12) to 42·2 kg (SD 9·5) p = 0·016. There was no impact on sarcopenia on global QOL scores at 1, 3 or 6 months post-op. Global QOL decreased at 1 month post-op but returned to baseline by 3 months post-op. In conclusion: an ERAS protocol which includes early aggressive nutrition support and introduction of oral diet post MIO is associated with early discharge from hospital and return of quality of life scores by 3 months post op. There is a significant decline in nutritional status and in particular lean body mass, however this seems to stabilise at 3 months post op at which time QOL scores return to baseline. This feeding protocol (early introduction of oral diet, jejunostomy feeding and discharge on night jejunostomy feeding) is well tolerated, attenuates weight loss and assists in the post-operative recovery.