The use of omega-3 fatty acids in the management of cancer cachexia. Rhys White Principal Oncology Dietitian Guys and St Thomas NHS Foundation Trust

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1 The use of omega-3 fatty acids in the management of cancer cachexia Rhys White Principal Oncology Dietitian Guys and St Thomas NHS Foundation Trust

2 Overview Cancer cachexia Clinical features Pathogenesis Prevalence Diagnosis and classification Brief introduction to n-3 fatty acids and their mechanism of action in cancer cachexia Overview of the literature Current thinking

3 Clinical Features of Cancer Cachexia Cancer related weight loss cannot simply be defined as malnutrition Comprises: Skeletal and adipose tissue loss Anorexia Hyper-metabolic state where the metabolic responses occur as a combination of the hosttumour interaction resistant to standard nutritional support

4 Pathogenesis of Cancer Cachexia (Skipworth et al (2007) Clin Nutr, 26 p.667)

5 Prevalence of Cancer Cachexia Occurs in approximately 50-80% of cancer patients Most common in solid tumour cancers and in particular in those of the upper gastrointestinal (UGI) tract and lung. Up to 20% of all cancer related deaths are thought to be directly related to cachexia (Argiles et al (2014) Nat Rev Cancer;14, p.754)

6 Definition and classification of cancer cachexia: an international consensus (Fearon et al (2011) Lancet Onc, 12, p.489)

7 Why do we care about cachexia? Negative impact on outcomes including: Survival and prognosis Function Performance status and fitness for treatment Treatment toxicity/complications Quality of life Length of stay

8 Omega 3 fish oils (n-3 PUFA- EPA/DHA) EPA = Eicosapentaenoic acid DHA = Docosahexaenoic acid

9 n-3 Fatty Acids an overview n-3 is a structural descriptor for a family of polyunsaturated fatty acid (PUFA) In n-3 fatty acids the first double bond is on carbon 3 of the acyl chain Have anti-inflammatory properties (Calder (2012) Br J Clin Pharmacol, 75, p645) Oily fish are the best dietary source of very long chain n-3 FA s (EPA and DHA) e.g g per portion but depends on metabolic characteristics of the fish, their diet, water temperature and the season

10 Mechanism n-6 series n-3 series IL-6, CRP

11 History of clinical trials assessing n-3 PUFA in cancer cachexia

12 Early positive findings Barber et al (1999) Br J Cancer, 81, p80 Evaluated the effect of EPA enriched supplement drinks on weight loss in 20 patients with advanced pancreatic cancer. Patients experienced weight gain, increased performance status and increased appetite after 3 weeks. Wigmore et al (2000) Nutr and Cancer, 36, p177 Evaluated the effect of EPA capsules over 12 weeks in 26 advanced pancreatic patients. 0.5kg weight gain at 1 month which remained stable at 12 weeks However, these studies were small, non-randomised and un-controlled

13 Fearon et al (2003) Gut, 52, p1479 RCT with 200 pancreatic patients who had lost more than 5% of pre-illness weight Randomised to receive either: oral nutritional supplement containing 2.2g EPA identical standard nutritional supplement with no EPA Patients in both arms of the 8 week study had a statistically significant increase in weight gain no benefit of EPA over standard supplementation Post-hoc analysis: significant positive correlation in the EPA arm between daily supplement intake and increase in body weight (but not in the control arm)

14 Relationship between oral supplement intake, with or without n-3 fatty acids, and weight (A, B) or lean body mass (C, D) of patients with pancreatic cancer cachexia after eight weeks of supplementation. K C H Fearon et al. Gut 2003;52: Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

15 Effect of intake of protein and calorie dense oral supplement with n-3 fatty acids on change in weight and lean body mass at eight weeks in patients with pancreatic cancer cachexia. K C H Fearon et al. Gut 2003;52: Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

16 Less positive outcomes followed.. Jatoi et al (2004) J Clin Oncol, 22, p2469 Randomised 421 patients with incurable cancers, including lung, into a double blind placebo controlled trial. Showed that the EPA supplement alone does not improve weight or appetite. Fearon et al (2006) J Clin Oncol, 24, p3401 Investigated 518 patients of mixed tumours, randomly assigned to either 2g or 4g of EPA or placebo. There were no statistical significant improvements in survival or weight. Systematic reviews 3 systematic reviews in 2007, 2009 and 2012 concluded that there was insufficient evidence to support a recommendation for n-3 PUFA to treat cancer cachexia Dewey at al (2007) Cochrane Database Syst Rev, 24,1 Mazzotta et al (2009) J Pain Symptom Manage 37, p 1069 Ries et al (2012) Palliat Med 26, p294

17 Recent findings Van der Meij (2010) J Nutr 140, p1774 & (2012) EJCN, 66p. 399 Randomised, double blind placebo controlled trial 40 locally advanced lung cancer patients received EPA-ONS v isocaloric non-epa ONS EPA group: better weight and fat free mass maintenance greater energy and protein intake improved global quality of life Improved performance status and physical activity

18 Recent findings Sanchez-Lara (2014) Clin Nutr, 33, p patients with advanced lung Ca given standardised menu + Prosure bd (2.2g EPA/day) vs isocaloric diet EPA group improved weight and body composition decreased fatigue, loss of appetite and neuropathy

19 Effect on chemotherapy DHA/EPA have been shown to promote cytotoxic effects of several anti-cancer drugs improving cancer treatment outcome Non-randomised controlled studies have shown improved responses to chemotherapy in patients supplemented with fish oils (Murphy et al (2011) Cancer, 117 p.3774) BUT Pre-clinical models indicate n-3 FA s may enhance tumour cell proliferation and induce chemo resistance (Murphy et al (2013) Clin Nutr, 32 p.466)

20 ESPEN guidelines on nutrition in cancer patients (2016) B5-7 N-3 Fatty acids to improve appetite and body weight Strength of recommendation WEAK Level of evidence In patients with advanced cancer undergoing chemotherapy and at risk of weight loss or malnourished, we suggest to use supplementation of long-chain N-3 fatty acids or fish oil to stabilise or improve appetite, food intake, lean body mass and body weight Low No convincingly serious safety issues

21 Multimodal interventions

22 Primary objective To establish whether a multimodal intervention is effective in treating cachexia. This will be assessed after 2 cycles of chemotherapy (study endpoint -between 6-9 weeks) by measuring weight. Secondary objectives To examine the effect of a multimodal intervention for cancer cachexia on muscle mass (CT at L3) and physical activity (ActivPAL). Patients Diagnosis of lung cancer, pancreatic cancer or cholangiocarcinoma Due to commence anti-cancer therapy Patients and recruitment A total of 240 patients will be recruited from out-patient oncology clinics at multiple sites in Europe, Canada and Australia.

23 Objective: Whether multi-targeted approach is acceptable to NSCLC patients experiencing cancer cachexia

24 Key thoughts and findings Anorexia, inflammation and increased energy expenditure, associated with cancer cachexia, have a negative impact on weight and muscle mass which contributes to poorer clinical outcomes Weak evidence base for routine use of n-3 fatty acids in the management of cancer cachexia Given the complex multifactorial nature of cachexia effective management is likely to involve multi-modal interventions including exercise, nutrition and drugs