Relevance of Fish Oil in Gastrointestinal-Cancer-Associated Cachexia

Relevance of Fish Oil in Gastrointestinal-Cancer-Associated Cachexia: History

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Subjects: Gastroenterology & Hepatology | Oncology

Contributor:

Saunjoo L. Yoon

Oliver Grundmann

cancer cachexia
gastrointestinal cancer
dietary supplements
fish oil
PUFA

1. Introduction

Gastrointestinal (GI) cancers are among the most common cancers diagnosed (17.8%) and with the highest mortality rate (28.2%) among all cancers [1]. Involuntary weight loss is common among GI cancers [2], with advanced GI cancer patients at an increased risk of developing cancer cachexia. Cancer cachexia is commonly defined as ≥5% weight loss within a 6-month period [3]. The overall incidence of developing cancer cachexia in GI cancer patients is between 40% and 80% [4]. The risk of cancer cachexia in GI cancer patients may be as high as 90% in pancreatic cancer and as low as 15% in prostate cancer patients [5,6]. The prevalence of cachexia is inversely correlated with 5-year survival, indicating a tumor’s site-specific contribution [7]. Patients with lower body mass index (BMI) are at a higher risk of impacted quality of life and reduced survival when developing cancer cachexia compared to patients with a normal or high BMI [8].

In recent years, the early detection of cancer cachexia in patients has been of interest to improve survival and quality of life. Multiple factors contribute to a delayed diagnosis of GI cancer. Sudden and unexpected weight loss may be the first sign preceding a GI cancer diagnosis. At this point, the patient is more likely to be already pre-cachectic or in a cachectic condition and be diagnosed with an advanced GI cancer stage. Screening for colorectal and other GI cancers is based on national guidelines, with those for the United States (US) advising regular screening starting at 50 for both men and women [9]. Although most colorectal cancers are more likely to occur in ages 50 and older, the incidence among those younger than 50 accounts for about 0.5% [10]. Environmental factors contributing to the development of GI cancers, such as alcohol and tobacco use, obesity, and a diet high in fat and low in fiber, may further increase the individual risk [11].

Cancer cachexia is a multi-organ syndrome with unintentional weight loss, sarcopenia, and inflammatory processes as its hallmarks. The breakdown of lean muscle mass is often observed independent of cachexia with advanced age. Furthermore, it limits the quality of life and physical functioning and increases mortality in patients with advanced cancer. Knowing inflammatory processes accompany weight and lean muscle loss, it has been proposed that dysregulation of pro- and anti-inflammatory proteins in conjunction with metabolic hormones are causative in the development of cancer cachexia because of the tumor microenvironment [12].

Another contributing factor especially prevalent among patients with GI cancer is malnutrition, a lack of sufficient caloric intake, and/or insufficient provision of macro- and micronutrients. In the case of cancer cachexia, malnutrition as a precursor is linked to low protein intake, which is of particular concern given the already accelerated and potentially irreversible loss of lean muscle mass. Chemotherapy-related lack of appetite, nausea or vomiting, and GI upset further increase the risk of malnutrition accompanying cancer cachexia.

Because of malnutrition, GI cancer patients require an in-depth nutritional needs assessment to evaluate the risk of developing cachexia [13]. Indeed, pancreatic cancer patients with any nutritional risk have significantly lower survival than those without [14]. Specific populations, including patients with diabetes and obesity, are at an increased risk of developing cancer-associated cachexia, given their pre-existing conditions [15]. Many disease conditions are associated with increased systemic inflammation that impacts body composition. By evaluating body composition by anthropometric means and systemic inflammation biomarkers (e.g., albumin, white blood cell, neutrophile, lymphocyte, and platelet counts), the risk of cancer cachexia and need for nutritional intervention have been established [16]. A recent meta-analysis of studies evaluating the impact of nutritional supplementation on pro-inflammatory biomarkers and length of hospital stay in colorectal cancer patients demonstrated that glutamine was superior in reducing tumor-necrosis factor α (TNF-α) and shortening hospital stay, while probiotics reduced the incidence of pneumonia [17]. One intervention that has shown to be effective in reducing postoperative complications, including malnutrition and cachexia, is preoperative immunonutrition (especially those containing glutamine, arginine, and omega-3 fatty acids) [18,19].

Cancer cachexia is characterized by the co-occurrence of decreased energy intake and increased energy expenditure, leading to a negative energy balance. The primary contributors to reduced energy intake are loss of appetite (anorexia), dysphagia, pain, fatigue, and depression or anxiety [20]. Increased energy expenditure is caused by tumor metabolism, systemic inflammation, and decreased energetic efficiency due to metabolic dysregulation [20]. The negative energy balance, in turn, leads to insulin resistance and oxidative stress, which further facilitate inflammation. The primary pro-inflammatory cytokines related to the development of cancer cachexia are TNF-α, interleukin (IL)-1 beta, IL-6, epidermal growth factor (EGF), transforming growth factor (TGF)-β, and platelet-derived growth factor (PDGF) [21]. The pro-inflammatory mediators are released by the tumor microenvironment and systemically. It leads to reduced muscle protein synthesis by downregulating the mammalian Target of Rapamycin (mTOR) and increased muscle degradation by upregulating atrogin-1 and Muscle Ring-Finger Protein-1 (MuRF-1).

Current treatment of cancer cachexia remains limited to short-term prevention of progressive muscle degradation and increasing protein synthesis. As such, non-steroidal anti-inflammatory drugs (NSAIDs) are used to reduce the release of pro-inflammatory mediators and cancer-associated pain, often leading to anorexia. Steroids, in particular corticosteroids, to reduce systemic inflammation and megestrol acetate for appetite stimulation often provide short-term improvement. Similarly, anamorelin hydrochloride, an orally administered drug with ghrelin-like effects, can be used to stimulate appetite [22]. Other potential treatment options include physical exercise, targeted acupuncture, nutrition therapy, as well as enteral and parenteral nutrition.

With more than 60% of adults in the US using at least one dietary or herbal supplement [23], their use to benefit GI cancer patients and especially aid in preventing or treating GI cancer cachexia is promising, given their widespread availability and relatively low cost.

While nutritional supplementation is often incorporated into pre- and post-surgical treatment of cancer patients as the standard of care to reduce the risk of post-surgical weight loss and cachexia [24], dietary supplements cannot be used with a clinical indication or considered clinical intervention based on the US Dietary Supplement Health and Education Act (DSHEA), which prevents them from being labeled with an indication [25]. Instead, dietary supplements are regulated differently from nutritional supplements without a disease indication and are often regarded suspiciously by healthcare professionals and patients alike. Nonetheless, patients often used dietary supplements in addition to the standard of care with or without reporting to their healthcare providers [26].

2. Fish Oil

Fish oil is rich in omega-3 fatty acids, which aid in energy metabolism and utilizing fatty acids high in energy density. It has been shown to reduce levels of pro-inflammatory mediators because fish oil contains high amounts of omega-3 fatty acids, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and other polyunsaturated fatty acids (PUFAs) [28]. In a study of GI cancer patients undergoing surgical intervention, adding fish oil to arginine improved post-surgical outcomes and shortened recovery compared to no nutritional support in 305 patients [29]. Interestingly, this study found no difference in patients that were given the supplements only prior to surgery compared to those given the supplements both prior to and following surgery. This may indicate a preventive effect of fish oil on systemic inflammation. Although not statistically significant, patients given fish oil both pre- and post-surgery lost less weight compared to no supplementation or pre-surgery supplementation only. In a review on the use and effect of omega-3 fatty acids and fish oil preparation in cancer cachexia, a number of included studies reported an increase in body weight with fish oil supplementation; however, inflammatory parameters were either not impacted or the change was not uniform between different studies [30]. A clinical study in patients with breast cancer indicated lower plasma high-sensitivity C-reactive protein and maintaining CD4+ T lymphocytes in the experimental group with fish oil enriched in EPA and DHA supplementation for 30 days compared to a control group whose CD4+ lymphocytes significantly decreased [31]. However, other pro-inflammatory markers remained unchanged between the groups, supporting a differential impact of fish oil supplementation on biological markers and patient outcomes.

A placebo-controlled study in 128 GI cancer patients with cachexia indicated that fish oil-enriched nutritional support leads to lower C-reactive protein blood levels while increasing skeletal and lean muscle mass compared to the placebo group over 6 months of treatment [32]. The group receiving fish oil also showed improved chemotherapy tolerance compared to the control group, indicating a direct benefit of therapeutic outcome. The findings of this study indicated that overall survival was not significantly different between the fish oil supplement group and the placebo group [32]. However, a subgroup of patients with the modified Glasgow Prognostic Score (mGPS) of 1 or 2 benefited the most from nutritional supplementation of fish oil by significantly prolonging survival time compared to the same subgroup without the supplementation [32].

In a small clinical study of 33 patients with pancreatic cancer who had developed cachexia, fish oil and marine phospholipids were compared to examine the improvement of quality of life and weight stability [33]. Both groups received an equal amount of 0.3 g omega-3 fatty acids over a course of 6 weeks. Both groups presented with similar outcomes, indicating the benefit of omega-3 fatty acids in preventing weight loss and stabilizing lean muscle mass. In both groups, serum C-reactive protein levels were reduced by more than 50%, while high-density lipoprotein increased by 22% only in the fish oil group. Furthermore, only the fish oil supplement group showed a positive correlation with improved global quality of life as the concentration of EPA increased over the study period.

A triple-blind randomized clinical trial compared fish oil that contained 1.0 g EPA and 0.5 g DHA in 3.6 g of total supplement to olive oil without either ingredient or polyunsaturated fatty acids in 45 cachectic patients with colorectal or gastric cancer over nine weeks [34]. While the global quality of life decreased for both groups, fatigue and nausea/vomiting were significantly worse in the olive oil group compared to the fish oil group for both types of GI cancers. Appetite loss was significantly higher in the olive oil group, although it also increased in the fish oil group, albeit not clinically significant. The authors point to limitations of the study given that olive oil may also contain anti-inflammatory compounds such as oleic acid that make a definitive determination of the beneficial effects of fish oil difficult.

A clinical study of 125 advanced cancer patients with cachexia compared five study arms (medroxyprogesterone vs. EPA/DHA vs. L-carnitine vs. thalidomide vs. combination of all). Among these, the EPA/DHA arm did perform worse compared to L-carnitine, thalidomide, or combination therapy in regard to lean body mass, resting energy expenditure, and fatigue [35]. The authors concluded that combination therapy provided the greatest benefit to patients. Of note, thalidomide is not approved for the treatment of cancer cachexia, and the current evidence remains unclear as to its benefit-to-risk ratio, given its genotoxicity [36].

A randomized pilot study compared (1) the effects of enriched fish oil (30 mL/d), containing 4.9 g of EPA and 3.2 g of DHA to melatonin (18 mg/d) supplementation for four weeks, and (2) followed by combined fish oil and melatonin to all patients for the next four weeks in a small sample of 24 GI cancer patients [37]. The fish oil group (5 out of 13 patients: 38%) showed a numerically higher percentage of patients maintaining their body weight than those in the melatonin group (3 out of 11 patients: 27%), while 63% of patients after combination therapy had stable or gained weight. However, it is not clear whether a total of 8 weeks of treatment or a combination of the two results in more positive outcomes.

According to a review article on the use of fish oil in patients with advanced cancer, the evidence available as of 2012 does not clearly indicate a benefit of fish oil [38]. The authors stated that fish oil did present with a low adverse effect risk that was usually tolerable by patients. In rare instances, fish oil was discontinued if it resulted in nausea, constipation, or reduced appetite. In 2018, a systemic review of the use of omega-3 products indicated a favorable outcome for patients who took 2 g/day of EPA, resulting in lower systemic inflammation and weight stabilization or gain [39]. Although the data were not conclusive, the authors stated that future studies should consider more homogenous populations by specific cancer types and stages to distinguish beneficial effects.

The use of fish oil may benefit patients with GI cancers who are either pre-cachectic or developed cancer cachexia and abnormal CPR or albumin levels (mGPS 1 or 2), at least regarding weight maintenance with minimal potential side effects. Because of the different doses of EPA/DHA used and varying trial period lengths, it is difficult to definitively conclude what composition of fish oil over what period of time will benefit patients. At a minimum, a fish oil preparation should contain EPA and DHA in a ratio of 2:1 and a minimum dose of 2 g/day over at least a six-week period to establish a beneficial effect.

This entry is adapted from the peer-reviewed paper 10.3390/nu15153391

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