Cancer cachexia is a paraneoplastic disorder whose distinctive features are alterations in body compositions, involuntary loss of skeletal muscle mass with or without adipose tissue wasting, owing to the altered metabolism and deregulated homeostasis of protein [1] [2]. Cancer patients with cachexia inevitably evince hypermetabolism with diminished energy intake and enhanced energy expenditure and an aberrant proteostasis associated with the higher proteolysis and lower protein synthesis [3] [4] [5] [6]. Different from starvation and normal malnutrition, it manifests few salient tumors as well as systemic inflammation driven characteristics which finally leads to escalating functional damage, post-treatment complications, impaired Quality of Life (QoL) and the malady-induced human demise [7]. It is worth mentioning that half of all the cancer-related mortalities (~8 million per year) are attributed to cancer cachexia—mostly occurring in cancers of GI tract and in head and neck, lung cancer, etc. Cachexia is heterogeneously spread across cancer patients with varying tumor type, stage and therapeutic modalities. Advanced stage of disease and its effects on intake, digestion and assimilation of nutrients are important determinants of cancer cachexia [8].

Undernutrition is vastly prevalent in cachectic cancer patients as a result of diminished food intake, vitiated quality of diet and catabolism [9]. While tumor-associated mechanical interference affects the dietary ingestion and absorption and tumor-produced catabolic factors (such as Activins, Myostatin, Parathyroid hormone-related protein, HSP70, HSP90, etc.) evoke catabolism, several inflammatory cytokines (such as TNF-α, IL-1, IL-6, IL-17, IFN-γ, etc.) derived from tumor-immune system crosstalk impede the appetite signals within the CNS [10] [11] [12]. Undernutrition inexorably affects the macro and micronutrients status of the patients [13]. As such, there exist no curative modalities for cancer cachexia but nutritional care remains the mainstay of a multimodal therapy. Standardized optimum nutritional intervention can target different pathways causing chronic inflammation and metabolic perturbations to mitigate and partially reverse the propagation of the disease. The general validity of such notions can be established and supported by an array of scientific investigations both in preclinical and clinical settings [14]. Yet, optimized nutritional formulations are lacking to address all the issues mentioned above.

Herein, we report the anti-cachexia effects of an optimal clinical nutrition formulation developed and marketed by Esperer Onco Nutrition. In a phase IV post marketing surveillance (PMS) study with 63 patients from various hospitals across India, the safety and efficacy of EON Therapy (Es-Invigour plus Es-Fortitude-Protect) was recently evaluated. This multi-nutrient and multi-targeted nutritional intervention, being concurrent with mainstream therapy, has a potential to ameliorate the cachectic condition and overall QoL of the patients involved. We are now performing extensive molecular analysis on the same and envisioning more rigorous outcomes of our future studies.

Informed consent was obtained from 91 patients for enrolment in the study of which 63 volunteers were recruited for the study post screening using predefined inclusion and exclusion criteria (Table 1). The recruited patients included both males (42) and females (21) with age varying between 19 - 60 years. All the patients were on curative therapy with most of the patients taking one or more chemotherapeutic agents. Detailed baseline demographic data of recruited patients is presented in Table 2. Patients were administered enteral nutritional supplements (Es-Invigour and Es-Fortitude Protect). The composition of both the supplements is presented in Table 3 and Table 4.

Cancer cachexia is a multi-factorial, multi-organ devitalizing, intimidating condition in patients mostly with advanced cancer whose eruption is symptomized by massive loss of lean body mass, anorexia, altered protein and energy metabolism, and chronic inflammation [17] [18]. Besides being an undeviating cause of 20% of all cancer related demise, cachexia makes the patients more intolerant towards mainstream chemotherapy and radiotherapy thereby, exhibiting diminished response to therapy and restricting recourses of therapeutic modalities [19] [20]. Although cachexia (anorexia) demonstrates an entirely disparate way of tissue wasting by targeting skeletal muscle compared to starvation which largely impacts fat tissues, it is not limited to the muscle-waste, rather strikes multiple other organs such as heart, liver, brain and fat tissue [21]. It is, thus, important to have an insight related to the molecular and metabolic factors for tissue wasting taking into account the role of every contributing organs as well as proliferating, high energy-demanding tumor tissue. As an inevitable consequence of the interplay, cancer patients with cachexia manifest a negative energy balance with nutrients unleashed into the bloodstream which again promotes the neoplastic growth [22].

Cancer cells inevitably commandeer the immune system towards exuding certain cytokines which aid in tumor growth and propagation [23]. Chronic local inflammation, described as one of the hallmarks of cancer, provides a microenvironment which, in turn, reinforces malignant growth [24] [25] [26]. Chronic inflammatory state is associated with excess fuel consumption which affects several tissues, promotes catabolism and induces cachexia [27] [28]. Therefore, one established mechanism of cancer cachexia is inflammation-driven well-orchestrated physiological response of substrate mobilization, an adaptive response towards accessing protein and energy stored in body [29] [30]. It turns out that, during disease progression, pro-inflammatory cytokine activity gets elevated which is indicated by the production of acute-phase response (APR) proteins, viz., C-reactive protein (CRP) and fibrinogen. Cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, and interferon-gamma (IFN-γ) have shown to play roles in cancer cachexia [31]. To elaborate a little more, many biological processes are critically dependent on skeletal muscle homeostasis which is regulated by an intricate balance between protein synthesis and proteolysis which is again governed by complex hormonal network of several catabolic (such as Activins, Myostatin, Parathyroid hormone-related protein, etc.) and anabolic (such as IGF-1) factors. Cancer progression is known to be deeply associated with the disruption of this balance [32]. Mechanistically, ubiquitin-proteasome pathway, calpains (Calcium activated proteases) and autophagy are involved in degradation of protein in skeletal muscle [33].

It is, therefore, coherent and counter-intuitive from the above discussion that hindering inflammatory responses and restoring protein balance to protect the loss of skeletal muscle mass—is the goal of cachexia therapy. It turns out that cachexia is partially reversible in both the arms. In this regard, understanding the management of specific inflammatory signaling is very important. Several arsenals, both pharmaceutical and nutraceutical, with anti-inflammatory potential have demonstrated beneficial outcomes against cachexia—such as, medroxyprogesterone, megestrol acetate, ghrelin, cannabinoids, melanocortin antagonists, thalidomide, etanercept, omega-3 fatty acids (eicosapentaenoic acid), herbal medicine (kampo), cortico-steroids, non-steroidal anti-inflammatory drugs, β 2-adrenergic agonists, erythropoietin, etc. [31]. There is no denying the fact that assessment of nutritional and metabolic status, evaluation of malnutrition and thorough counselling have become a part of the zeitgeist. Enriching food, oral nutritional supplements, enteral tube feeding and parenteral nutrition have also gained significant attention. A personalized multimodal combinatorial therapy approach with mutual interactions between multi-target interventions and multi-nutrient interventions has been reckoned as best provision to handle cancer cachexia where nutritional intervention is endorsed as an integral part [34] [35]. Nutrition is equally important for tissue rebuilding and energy supply in patients with cachexia. Recommended protein intake to circumvent anabolic resistance in patients with cancer cachexia is 1.0 - 2.0 g/Kg per day, food energy intake being increased by 300 - 400 Kcal per day [35] [36]. With the advent of this combinatorial multimodal intervention, a new level of nutritional and metabolic patient care where commonality in definitions and grading systems is being established towards efficient treatment with nutritional intervention along with adequate medical resources.

In our clinical validation study performed on many patients across India, nutritional intervention named as EON Therapy (here, Es-Invigour along with Es-Fortitude Protect) is administered concurrently with different stages and cycles of cancer medication [37]. Much to our intrigue, they are showing very promising results in terms of improving quality of life and body weight gain in all the patients enrolled for the treatment. This can be attributed to the ingredients we are using in our formula. It turns out that plant polyphenols are efficacious due to their ability to sensitize drug-resistant cancer cells towards chemotherapeutics as well as protect non-target tissues from damage owing to their antioxidant and anti-inflammatory properties. The most popular among these polyphenols is, indubitably, curcumin—which is extracted from the rhizomes of Curcuma longa (known as turmeric) and has a multitude of therapeutic effects in various cancers [38]. It turns out that β-carotene, a polyene dietary carotenoids acts as an immune modulator with a potential to quench singlet oxygen, scavenge free radicals (ROS) at lower partial oxy-gen pressures, provide photoprotection to photosynthetic organisms and prevent cancer, heart diseases, and age-related macular degeneration [39]. The anti-inflammatory activity it exerts can be attributed to the upregulation of Heme oxygenase 1 (Hmox1) mRNA expression. Using lipopolysaccharide (LPS) stimulated RAW 264.7 macrophages, anti-inflammatory property of the branched chain amino acids (BCAAs) was evaluated where BCAA diminished NO production, down regulated iNOS, COX-2, IL-6 mRNA expression [40]. Many proteins involved in DNA damage, signalling and repair, replicative enzymes and transcription factors, need Zinc (Zn), a first transition Group IIB element and an essential mineral, for proper functioning. Zinc deficiency has also been shown to impair the DNA binding abilities of p53, nuclear factor κB (NFκB), and AP-1 transcription factors in rat glioma C6 cells. Few in vivo studies showed an effect of Zn in altering antioxidant status in colonic histoarchitecture of rats [41]. Importantly, a wide range of functions are carried out by probiotics, live beneficial organisms, including direct interactions with the gut luminal microbiota, metabolic outcomes, effects on barrier function, and crosstalk with the central nervous system and enteric immunity. They also have shown their potential in the management of Gastroesophageal reflux disease (GERD), an upper digestive tract disorder, often associated with occurrence of cancer [42]. Mechanistically, nutraceuticals mentioned above have exerted their anti-inflammatory properties against cachexia causing local inflammation counter-balancing the negative protein and energy metabolism. Also, concurrent with the mainstream therapy, copious food intake in the form of nutritional supplementation has properly managed cachexia causing reduced food intake. Thus, in both the arms, cancer cachexia is well addressed with nutritional intervention EON Therapy.

EON Therapy, administered along with mainstream chemo and radiotherapy, demonstrated its anti-cachexia efficacy in terms of ameliorating malnutrition and inhibiting weight loss in 63 cancer patients. Simultaneous betterment in several biochemical and QoL parameters further emphasizes its effect on general wellness of patients. Prompted by this clinical outcome, more in-depth mechanistic investigations of the anti-cachexia properties of the ingredients have already been undertaken and will come in public domain soon. Of course, clinical validation studies with larger cohorts of patients and control arms are being investigated to corroborate the initial findings. This study strongly suggests that extensive research should be performed towards developing and marketing nutritional supplements specifically for cachectic cancer patients for better management and prognosis.

We acknowledge authorities of all the hospital sites for providing us with the volunteers required for the study.

The authors declare no conflicts of interest regarding the publication of this paper.

Kumar, A., Sharma, J., Chattopadhyay, R., Charde, S. and Mukherjee, A. (2022) EON Therapy Ameliorates Cachexia and Quality of Life in Cancer Patients. Journal of Cancer Therapy, 13, 379-396. https://doi.org/10.4236/jct.2022.137033