**7. Cancer-associated fatigue and other cancer-associated conditions**

The most common complaint of patients undergoing anti-neoplastic therapy is fatigue, but there are also other complaints that include: pain, nausea, vomiting, malaise, diarrhea, headaches, rashes and infections (Buckingham et al., 1997; Loke et al., 2006; Manzullo & Escalante, 2002). Other more serious problems can also occur, such as cardiomyopathy, peripheral neuropathy, hepatotoxicity, pulmonary fibrosis, mucositis and other effects (Buckingham et al., 1997; Liu et al., 2005; Loke et al., 2006; Manzullo & Escalante, 2002). Due to misconceptions among patients and their physicians, most patients feel that cancer therapy-associated fatigue is an untreatable symptom (Vogelzang et al., 1997). Although fatigue is usually the most commonly reported adverse symptom during cancer therapy, up until recently there was little effort directed at reducing fatigue before, during or after cancer therapy (Von Roenn & Paice, 2005). This has changed recently (Nicolson, 2010; Nicolson & Conklin, 2008).

Reducing cancer-associated fatigue and fatigue associated with cancer therapy are now considered important therapeutic goals. Psychological, physical, pharmaceutical and nutraceutical methods have been undertaken to reduce fatigue and improve the quality of life of cancer patients (Borneman et al., 2007; Escalante et al., 2011; Nicolson, 2010). These treatments are based on suppressing fatigue but also on controlling co-morbid or related symptoms, such as pain, anemia, cachexia, sleep disorders, depression and other symptoms (Escalante et al., 2011; Mustian et al., 2007; Nicolson, 2010; Ryan et al., 2007; Watson & Mock, 2004; Zee & Acoli-Isreal, 2009).

Unfortunately, there is no standard protocol related to treating cancer-associated fatigue and related symptoms. In reviewing the types of supportive measures used to control fatigue and related symptoms, the data suggest that graded exercise, nutritional support, treatment of psychological problems (such as depression with certain anti-depressants or psycostimulants), treatment of anemia with hematopoetic growth factors and control of insomnia with cognitive behavioral therapy or pharmacological and nonpharmacological therapies all have a role to various degrees in controlling cancer-associated fatigue

Nutritional Supplements for Cancer-Associated Fatigue and

phosphorylation (Kanno et al., 2004; Radi et al., 1994).

Ellithrope, 2006).

Cancer Therapy – A Molecular Basis for Restoring Mitochondrial Function 155

mitochondrial transmembrane potential, an essential requirement of oxidative

Lipid Replacement Therapy (Nicolson, 2003; 2005; 2010) has been used to reverse the accumulation of damaged lipids in mitochondria and other cellular membranes. Lipid Replacement Therapy plus antioxidants can reverse ROS/RNS damage and increase mitochondrial function in certain fatiguing disorders, such as chronic fatigue, chronic fatigue syndrome and fibromyalgia syndrome. Lipid Replacement Therapy has been found to be effective in preventing ROS/RNS-associated changes and reversing mitochondrial damage and loss of function (reviewed in Nicolson, 2010; Nicolson &

Lipid Replacement Therapy with unoxidized lipid and antioxidant supplements has been effective in replacement of damaged cellular and mitochondrial membrane phospholipids and other lipids that are essential structural and functional components of all biological membranes (reviewed in Nicolson, 2010; Nicolson & Ellithrope, 2003). NTFactor, a Lipid Replacement oral supplement containing phospholipids, phosphoglycolipids, cardiolipid precursors and other membrane lipids, has been used successfully in animal and clinical lipid replacement studies (Agadjanyan et al., 2003; Ellithorpe et al., 2003; Nicolson & Ellithorpe, 2006; Nicolson et al., 2010). NTFactor's encapsulated lipids are protected from oxidation in the gut and can be absorbed and transported into tissues via lipid carriers without oxidation. Once inside cells the membrane lipids naturally replace oxidized, damaged membrane lipids by natural diffusion, and carrier proteins pick up the damaged

In preclinical studies NTFactor has been used to reduce age-related functional damage. Using rodents Seidman et al. (2002) found that NTFactor prevented hearing loss associated with aging and shifted the threshold hearing from 35-40 dB in control, aged rodents to 13-17 dB. They also found that NTFactor preserved cochlear mitochondrial function and prevented aging-related mitochondrial DNA deletions found in the cochlear. Thus NTFactor was successful in preventing age-associated hearing loss and reducing mitochondrial

In clinical studies Lipid Replacement Therapy has been used to reduce fatigue and protect cellular and mitochondrial membranes from oxidative damage by ROS/RNS (reviewed in Nicolson, 2003; 2005; 2010). A vitamin supplement mixture containing NTFactor was by used by Ellithorpe et al. (2003) in a study of patients with severe chronic fatigue and was found to reduce their fatigue by approximately 40.5% in 8 weeks. In these studies fatigue was monitored by use of the Piper Fatigue Scale to measure clinical fatigue and quality of life (Piper et al., 1987). In addition, in a subsequent study we examined the effects of NTFactor on fatigue and mitochondrial function in patients with chronic fatigue (Agadjanyan et al., 2003). Oral administration of NTFactor for 12 weeks resulted in a 35.5% reduction in fatigue and 26.8% increase in mitochondrial function; whereas after a 12-week wash-out period fatigue increased and mitochondrial function decreased back towards control levels (Agadjanyan et al., 2003). Thus in fatigued subjects dietary Lipid Replacement Therapy can significantly improve and even restore mitochondrial function and significantly decrease fatigue. Similar findings were observed in chronic fatigue syndrome and fibromyalgia syndrome patients (Nicolson & Ellithorpe, 2003). Recently a new formulation of NTFactor plus vitamins, minerals and other supplements resulted in a 36.8%

lipids for degradation, transport and excretion (Mansbach & Dowell, 2000).

damage and DNA deletions in rodents (Seidman et al. 2002).

reduction in fatigue within one week (Nicolson et al., 2010) (Table 1).

(Escalante et al., 2011; Mustian et al., 2007; Nicolson, 2010; Ryan et al., 2007; Watson & Mock, 2004; Zee & Acoli-Isreal, 2009). Some of these approaches using pharmacological drugs and growth factors have been systematically analyzed in 27 studies (meta-analysis) by Milton et al. (2008). In this limited analysis, only a psycostimulant (methylphenidate) and hematopoetic growth factors (erythropoietin and darbopeitin) were more effective than placebo treatments. Other treatments were no better than placebo in the treatment of cancerrelated fatigue (Milton et al., 2008).
