Dietary Supplements in People with Metastatic Cancer Who Are Experiencing Malnutrition, Cachexia, Sarcopenia, and Frailty: A Scoping Review

Cancer-associated malnutrition, or cachexia, stemming from cancer or its treatments, is particularly prevalent in metastatic cancers, and is often interrelated with sarcopenia and frailty. Evidence suggests that dietary supplements play a role in managing these conditions. As metastatic cancer cells are associated with notable genomic and phenotypic alterations, response to dietary supplements may differ between metastatic and non-metastatic cancers. However, research in this area is lacking. This scoping review aims to identify the dietary supplements that have been studied in patients with metastatic cancers and malnutrition-related conditions, along with their proposed effects, mechanisms, outcome measures, and tools used. A systematic search was conducted across databases, including MEDLINE, EMBASE, CINAHL, and clinical trial registries. Of the initial 6535 records screened, a total of 48 studies were included, covering a range of dietary supplements—vitamins, minerals, antioxidants, proteins, amino acids, fatty acids, fiber, and others. While the types of dietary supplements included varied across cancer types, omega-3 and carnitine were investigated most often. Proposed relevant attributes of dietary supplements included their antioxidant, anti-inflammatory, anti-cancer, and immunomodulatory properties. Overall, there was a paucity of interventional studies, and more randomized controlled trials are warranted.


Introduction
Cancer treatments have significantly improved over time, leading to a prolonged survival time after a diagnosis of metastatic cancer, and consequently an increased number of advanced cancer survivors [1]. Advanced cancer survivors experience a range of Table 1. List of inclusion and exclusion criteria.

Inclusion Criteria
Additional Operational Information Human studies -Primary, quantitative studies, or systematic reviews Systematic reviews are defined as reviews with a comprehensive search strategy, methods section, and critical appraisal of included studies Studies investigating the effects of dietary supplements (vitamins, minerals, proteins or amino acids, fatty acids, prebiotics or fiber, probiotics, and plant or herbal extracts) whether in isolation or in combination with other dietary supplements or interventions This includes studies where dietary supplements were not the intervention of interest or all study groups received the same dietary supplements, as intra-group comparisons may have been made, which can provide information on the effects of dietary supplements. Studies conducted among people with metastatic cancer (defined as Stage IV) This is further defined by the following cut-off values: for primary trials, at least 50% metastatic; for systematic reviews, at least 50% included papers conducted in solely metastatic populations; for studies yet to be completed, only those that set out to recruit solely patients with metastatic cancers. Studies including people with malnutrition cachexia or anorexia, sarcopenia, frailty, or weight loss Studies that consisted of a subset of patients (any proportion) with these conditions were included. Nutrient deficiencies were also considered a form of malnutrition. If the nutrition status of study participants was not specified, articles were considered to meet the inclusion criteria regarding malnutrition-related conditions as long as they meet the earlier criteria of metastatic cancer, as it has been established in the literature that malnutrition is prevalent in people with advanced cancer [32].

Exclusion Criteria
Animal or laboratory studies Qualitative studies or narrative/literature reviews Studies investigating the effects of drugs or traditional medicine (e.g., Chinese herbal therapies) Supplements administered via intravenous or intramuscular routes (e.g., intravenous ascorbic acid infusion) Studies investigating the effect of oral nutritional supplements alone, which have not been enhanced with dietary supplement(s) of interest (e.g., unfortified standard formulations of commercial milk-based supplements, such as Ensure ® ) Where there was missing information that precluded a decision on the inclusion or exclusion of the article, corresponding authors of the article were emailed to retrieve more information. Data extraction was performed jointly by two authors (JJ and CH) using a data extraction form (Supplementary File S3) that was developed by the team and pilot tested by the same two authors (JJ and CH) prior to use to ensure all relevant results were extracted. Extracted data were subsequently reviewed by another author (RJ). Data extraction included information on the dietary supplements that have been investigated in the target population, as well as their hypothesized effects and proposed mechanisms, and outcome measures that have been assessed. In line with the purpose of scoping reviews outlined in the literature, the present scoping review was intended to map and summarize available evidence, without investigating effectiveness or formulating recommendations for clinical practice [33]. Hence, findings on the actual outcomes of the included studies were not analyzed. Findings of interest to the present scoping review (supplement types, hypothesized effects, proposed mechanisms, and outcome measures used) were narratively synthesized.

Search Results
The initial search yielded 8070 records from the databases, 227 records from the clinical trial registries, and 3 records from other sources ( Figure 1). After removal of duplicates, 6535 records remained, of which 6286 were excluded following title and abstract screening. Of the 248 full-text articles assessed for eligibility, 200 were excluded. A total of 48 articles met the criteria and were included in narrative synthesis.

Types of Dietary Supplements
A variety of dietary supplements were investigated across studies and were grouped into the following categories: vitamins (n = 13), minerals (n = 5), antioxidants (apart from vitamins and minerals) (n = 7), proteins (n = 3), amino acids (n = 14), fatty acids (n = 18), fiber (n = 1), and others (n = 5). Dietary supplements were provided orally in all except three studies [36,67,71], where they were administered enterally. Table 3 shows the types of dietary supplements, cancers, and malnutrition-related conditions in each of the different studies.
The three antioxidant vitamins-Vitamins A, C, and E-were administered concomitantly as part of antioxidant treatments with the same dosages (Vitamin A 30,000 IU daily; Vitamin C 500 mg daily; Vitamin E 400 mg daily) in two studies (an RCT [44] and a quasiexperimental single-group trial [54]) that investigated the efficacy of combined treatments and also included other dietary supplements, such as quercetin, carbocysteine, lipioic acid, eicosapentaenoic acid (EPA), and/or carnitine. In the RCT, all five study arms were given the vitamins [44]. Vitamin E was additionally included in one other RCT, where it was given to the intervention group which received fish oil as the main intervention [39].
Vitamins B1 (thiamine) and B6 (pyridoxine) were included in a quasi-experimental trial, in the form of Aminotrofic ® sachets, which mainly consisted of amino acids [76]. Vitamin B6 was additionally included in a case study as a replacement therapy in doses of 150 mg daily [70]. Vitamin B9 (folate) was administered in an RCT [46], two quasiexperimental trials [60,61], and an observational study [68], of which all also involved concomitant vitamin B12 administration and pemetrexed therapy. In the RCT, where the main aim was to test the efficacy of different doses of pemetrexed, Vitamin B9 was administered to both study groups via a daily multivitamin containing 500 mg folic acid, along with regular intramuscular vitamin B12 [46]. In one of the quasi-experimental trials, where the aim of the study was to test if the lead-in time for vitamin B supplementation prior to cisplatin-pemetrexed therapy could be shortened, vitamin B9 supplementation in doses of 350-500 µg daily were administered, along with intramuscular vitamin B12 [61]. In the other quasi-experimental trial, where the aim was to evaluate the safety of oral administration of vitamin B12, vitamin B9 (500 µg daily) was administered along with vitamin B12 in patients receiving pemetrexed [60]. In the observational study, vitamin B9 was administered in doses of either 400 µg, 700 µg, or 1000 µg once daily depending on the individual's baseline total plasma homocysteine level, along with regular oral iron and intramuscular vitamin B12 [68]. The latter study aimed to assess the prevalence of elevated total plasma homocysteine levels at baseline and following pemetrexed treatment, as well as the association between folic acid supplementation and hematological toxicity [68].
In an observational study, iron was administered in the form of ferrous sulphate 200 mg twice daily at the initiation of chemotherapy as per clinic protocol, along with oral vitamin B9 and vitamin B12 injection [68]. In a case report, iron was administered in the form of 30 mg sucrosomial iron daily as a supportive intervention to radiation therapy in a patient with sideropenic anemia [79]. Selenium was investigated in only one study (a quasi-experimental trial) and was given in the form of seleno-L-methionine in doses of 2500, 3000, or 4000 µg twice daily for 14 days followed by once daily, in combination with axitinib [75].
In terms of antioxidants other than vitamins and minerals, carbocysteine and lipoic acid were administered concomitantly in three RCTs [42,44,74] and one quasi-experimental trial [54]. A combination of carbocysteine and lipoic acid was administered in two RCTs (that likely shared overlapping participants) as part of an antioxidant treatment (dosage specified as 2.7 g carbocysteine daily and 600 mg lipoic acid daily in one of the RCTs) along with dietary supplement carnitine [42,74]. In the remaining RCT and quasi-experimental trial, carbocysteine (2.7 g daily) and lipoic acid (300 mg daily) were administered in combination with quercetin, as well as EPA and the antioxidant vitamins A, C, E [44,54], and either with or without additional carnitine in the RCT [44].
Curcumin was investigated as the sole dietary supplement in a quasi-experimental trial in doses of 2 g daily (equivalent to 400 mg daily of active curcuminoids extract) [77]. In an RCT, curcumin was administered as part of a combined treatment including other dietary supplements (carnitine and lactoferrin) at a dose of 4 g daily [73]. Lycopene was investigated in only one study (quasi-experimental trial), where it was given at a dose of 30 mg daily in people receiving concomitant docetaxel therapy [66].

Proteins and Amino Acids
Protein supplements were investigated in three RCTs. Types of protein supplements included in studies were whey protein isolate (n = 1) [38] and lactoferrin (n = 2) [43,73]. Whey protein isolate was administered in the form of two sachets of cysteine-rich lipid-and lactose-free cow milk whey protein (Prother ® ) consisting of 20 g protein [38]. Lactoferrin was administered as two tablets daily (equivalent to 200 mg daily), along with recombinant human erythropoietin, to people with anemia [43]. In another RCT, the same dose of lactoferrin (200 mg daily) was administered along with carnitine and curcumin, as part of a combined treatment, in people with cancer-related anemia and cachexia [73].
For amino acids, carnitine, an amino acid derivative, was the most investigated and was included in seven studies, including five RCTs [41,42,44,73,74] and two quasiexperimental trials [53,56]. It was the sole dietary supplement investigated in two studies [41,53] and part of a combined treatment with other dietary supplements (EPA, branched chain amino acids, coenzyme Q10, lipoic acid, carbocysteine, curcumin, lactoferrin, quercetin, and/or vitamins A, C, and E) in five studies [42,44,56,73,74]. Carnitine was given as L-carnitine and in doses of 50 mg, 2 g, 4 g, or 6 g daily in included studies.
Arginine was the second most commonly investigated amino acid. Arginine was the main dietary supplement investigated in an RCT where it was administered in the form of a specially formulated enteral formula and replaced 41% of casein [36], as well as in an observational study where it was given in the form of an immunonutrition enteral formula (Impact ® ) containing 12.5 g/L L-arginine, dietary nucleotides, EPA, and docosahexaenoic acid (DHA) [67]. Arginine was investigated as part of a combined treatment with glutamine (amino acid) and β-hydroxyl β-methyl butyrate (HMB) (amino acid metabolite) in three studies (two RCTs [35,45] and one quasi-experimental trial [57]), which were also the only studies where glutamine or HMB were included. Daily doses were in the following ranges: 14-28 g arginine, 14-28 g glutamine, and 2.4-6 g HMB daily [35,45,57].
Branched chain amino acids (BCAA) were investigated in a quasi-experimental trial, where they were administered in the form of an enriched ONS (Inner Power ® ), which consists of 2500 mg BCAA per pack, along with coenzyme Q10 and carnitine, with one pack given daily [56]. Two studies, an RCT [72] and a quasi-experimental trial [76], included all the essential amino acids. In the RCT, a 4 g essential amino acid powder was the sole intervention and was given thrice daily (equivalent to 12 g amino acids daily) [72]. In the quasi-experimental trial, essential amino acids were given in the form of two sachets of Aminotrific ® supplement, which also consisted of vitamins B1 and B6 [76].

Fiber
Fiber was only included in one case study where omega-3 fatty acids were the main dietary supplement of interest [69]. The participant consumed one serving of fortified ONS (Forticare Nutricia) daily, which contains both EPA and fiber and provides 2.6 g fiber daily.

Others
Other dietary supplements that were investigated were β-hydroxybutyrate (BHB) [81], coenzyme Q10 [56], muscadine grape extract [52], dietary nucleotides [67], and royal jelly [34]. The supplement BHB was included in a quasi-experimental trial that has not started recruitment yet and will be administered in the form of liquid ketone supplement, two tablespoons three times daily (providing 1 g/kg body weight daily of BHB) [81]. Coenzyme Q10 was administered in a quasi-experimental trial in the form of one pack of enriched ONS (Inner Power ® which contains BCAA, carnitine, and 30 mg coenzyme Q10 per pack) daily [56]. Muscadine grape extract was investigated in a quasi-experimental trial in the form of capsules that were taken twice daily (each capsule containing~160 mg phenolics) in five dose levels of 320 to 1600 mg total phenolics [52]. Royal jelly was administered in the form of 800 mg capsules three times daily (equivalent to 2400 mg daily), as per figures published in the erratum [82].
In studies with concomitant interventions, dietary supplements were administered with ONS in 12 studies and were used to fortify/enrich ONS in some studies. Oral nutritional supplements were the only other intervention in three studies [36,49,51], while different types of dietary supplements were used as a combination (i.e., omega-3 and arginine) in addition to ONS in two studies [67,71]. In the remaining studies with ONS, dietary supplements were also used in conjunction with nutritional counseling [58,80], prescribed diet [48], drug [37], or a combination of drug, nutritional counseling, and exercise (home-based aerobic and resistance training) [50], or were part of a combination of dietary supplements and drugs [44,54]. In the 17 studies with concomitant interventions but without ONS, dietary supplements were delivered concurrently with drugs [43] or nutritional counseling [38], or as part of a combination with other dietary supplements [35,39,45,46,60,61,68,76] that were accompanied by drugs [42,73,74], or in-person structured nutrition, exercise, and symptom advice via the Macmillan Durham Cachexia Pack [57], or in-person individualized nutritional and exercise counseling along with prescription of individualized home-based resistance training [56].
Reduces proinflammatory cytokines to improve oxidative stress and CACS symptoms, as part of a combination of antioxidants, ONS, and drugs [44,54].

Vitamin B1
Contributes to prevention of anorexia and cachexia along with Vitamin B6 and amino acids during chemotherapy [76].
Useful in muscle trophism, along with Vitamin B6 and amino acids [76].
Nutritional status, clinical status, QoL, adherence to chemotherapy.

Vitamin B6
Oral replacement therapy corrects neutropenia that stems from Vitamin B6 deficiency [70]. Contributes to prevention of anorexia and cachexia along with Vitamin B1 and amino acids during chemotherapy [76].
Oral replacement therapy corrects Vitamin B6 deficiency and its associated neutropenia [70]. Useful in muscle trophism, along with Vitamin B1 and amino acids [76].
Nutritional status; vitamin B6 and neutrophil levels; clinical status; QoL, regression of cervical adenopathy; adherence to chemotherapy.
Total plasma homocysteine levels, QoL, relative dose intensity, tumor response, survival, adverse events (including neutropenia grade and other toxicities).

Vitamin B12
Oral vitamin B12 is an alternative to intramuscular vitamin B12 for purposes of reducing pemetrexed-associated adverse events, when used along with Vitamin B9 [60].
Oral administration of vitamin B12 is capable of correcting vitamin B12 deficiency and is, thus, an alternative to intramuscular injection [60].
Total plasma homocysteine levels, tumor response, survival, adverse events (including neutropenia grade and other toxicities).

Vitamin C
Functions as an antioxidant agent to improve CACS as part of an integrated treatment [44,54].
Reduces proinflammatory cytokines to improve oxidative stress and CACS symptoms, as part of a combination of antioxidants, ONS, and drugs [44,54].
Vitamin D Improves survival in metastatic colorectal cancer [40]. Replacement therapy improves muscle strength and pain associated with prostate cancer bone metastasis [64]. 1α-OHD3 along with calcium supplementation prevents bone mass loss in men with prostate cancer treated with complete androgenic blockade [62]. Improves symptom burden in women with estrogen receptive-positive metastatic breast cancer [59].
Exerts anti-cancer effects when converted to calcitriol in the body, by regulating cancer-related genes [40]. Inhibits growth of prostate cancer cells [64]. 1α-OH vitamin D3, along with calcium, prevents bone mass loss [62].

Calcium
Prevents bone mass loss in men treated with complete androgenic blockade, along with 1α-OHD3 [62].
Calcium, along with 1α-OH vitamin D3, prevents bone mass loss, which people with advanced prostate cancer receiving complete androgenic blockade are more susceptible to [62].

Iron
Improves sideropenic anemia when administered in the form of sucrosomial iron, as a supportive therapy alongside radiation therapy [79].
As radiation therapy can lead to side-effects such as mucositis and dysphagia resulting in malnutrition and subsequent onset of sideropenic anemia, sucrosomial iron improves sideropenic anemia when given concomitantly with radiation therapy [79].

Selenium
Improves axitinib therapy response when administered in the form of seleno-L-methionine [75].
Seleno-L-methionine stabilizes tumor vasculature and reduces risks of angiogenesis, tumor metastasis and treatment resistance when given in combination with chemotherapeutic and vascular endothelial growth factor-targeted agents [75].

Carbocysteine
Functions as an antioxidant agent to improve cancer cachexia symptoms as part of an integrated treatment [42,44,54,74].
Reduces proinflammatory cytokines to improve oxidative stress and CACS symptoms, as part of a combination of antioxidants, ONS, and drugs [44,54]. Important precursor of cell-reduced glutathione and counteracts oxidative stress [42].

Curcumin
Improves nutritional and immunometabolic alterations of cachexia and cancer-related anemia as part of a combined treatment also consisting of L-carnitine, lactoferrin and celecoxib [73]. Exerts antioxidant and anti-inflammatory effects in advanced cancer cachexia [77].
Possesses anti-inflammatory and antioxidant effects to mitigate inflammation and oxidative stress in cachexia [73,77].

Lipoic acid
Functions as an antioxidant agent to improve cancer cachexia symptoms as part of an integrated treatment [42,44,54,74].
Reduces proinflammatory cytokines to improve oxidative stress and CACS symptoms as part of a combination of antioxidants, ONS, and drugs [44,54]. Important precursor of cell-reduced glutathione and counteracts oxidative stress [42].

Lycopene
Concomitant administration with docetaxel is an effective treatment for prostate cancer [66].
Possesses antioxidant properties and has chemo preventive effects in prostate cancer; inhibits antiapoptotic protein, and improves antitumor efficacy of docetaxel [66].
Prostate specific antigen response, survival, adverse events.

Quercetin
Functions as an antioxidant agent to improve CACS as part of an integrated treatment [44,54].
Reduces proinflammatory cytokines to improve oxidative stress and CACS symptoms when used in a combination of antioxidants, ONS, and drugs [44,54].

Proteins and amino acids
Lactoferrin Improves nutritional and immunometabolic alterations of cachexia and cancer-related anemia as part of a combined treatment with L-carnitine, curcumin and celecoxib [73]. An alternative to intravenous iron supplementation when combined with recombinant human erythropoietin, in the treatment of anemia in advanced cancer during chemotherapy [43].
Key in host defense against infection and excessive inflammation [43]. As patients with cancer anemia may have low or normal serum iron levels, yet increased ferritin levels and rich bone marrow iron reserves, it is suggested that cancer anemia is associated with flaws in iron use rather than iron shortage [43]. Lactoferrin, which is involved in iron transport mechanisms, can thus treat this form of iron-related anemia [43,73] [38].
Possesses immune-enhancing factors and contains cysteine (a limiting amino acid in the glutathione production), where glutathione protects cells from free radicals and carcinogens. Induces more muscle protein synthesis, being more rapidly digested than other protein sources [38].

All essential amino acids
Counter wasting processes associated with cancer cachexia [72]. Prevents anorexia and cachexia in cancer during chemotherapy, along with vitamins B1 and B6 [76].
Weight, body composition, nutritional status, clinical status, muscle strength, exercise capacity, QoL, adherence to chemotherapy.

Arginine
Prevents cancer recurrence following surgical removal of malignant tumors, especially when administered perioperatively [36]. Improves postoperative recovery as part of an immunonutrition enteral formula in head and neck cancer [67]. Prevents LBM loss and reverses cancer cachexia, as part of a mixture with HMB and glutamine [35,45]. Delays cachexia onset in advanced lung cancer [57].
Conditionally essential amino acid that acts as a substrate for nitric oxide synthesis (which is potentially toxic to cancer cells), improves immune function [36,45,67], modulates protein turnover [45], fights remnant cancer cells following surgical removal of malignant tumors [36], and improves wound healing [35,67]. Works in synergy with HMB to mitigate muscle loss, and with both HMB and glutamine to reduce muscle damage from ROS and proinflammatory cytokines [57].
Weight; body composition; LBM; grip strength; energy and protein intake; liver function; renal function; total protein, prealbumin, albumin, globulin, retinol-binding protein, total cholesterol, and triglycerides levels; fatigue; QoL; need for parenteral nutrition during hospital admission; duration of tube feeding; length of hospital stay; fistula incidence after surgery; readmission rates; treatment success; cancer recurrence; metastases or second primary tumors occurrence; survival.
Branched chain amino acids (BCAA) Improves physical function in elderly patients with advanced lung or pancreatic cancer as part of a multimodal intervention with coQ10 and L-carnitine [56].

Not specified
Weight, BMI, LBM, nutritional status, food intake, physical function/muscle strength, physical activity levels.
Carnitine Improves cancer cachexia in pancreatic cancer [41], and improves fatigue and ROS levels in advanced cancer [53]. As part of a combined treatment, improves cancer cachexia symptoms [42,44,73,74], cancer-related anemia [73], and physical function in elderly patients with advanced lung or pancreatic cancer [56].

Glutamine
As part of a mixture with arginine and HMB, prevents LBM loss and reverses cancer cachexia [35,45] or delays cachexia onset in advanced lung cancer [57].
Regulates muscle protein synthesis or turnover [35,57] and exerts immune stimulatory effects [45]. Works with both HMB and arginine to reduce muscle damage from ROS and pro-inflammatory cytokines [57].

HMB
As part of a mixture with arginine and glutamine, prevents LBM loss and reverses cancer cachexia [35,45] or delays cachexia onset in advanced lung cancer [57].
Modulates protein turnover [45,57] and works in synergy with arginine to mitigate muscle loss [57]. Improves nitrogen balance, inhibits proteolysis-inducing factor [35], and works with arginine and glutamine to reduce muscle damage from ROS and pro-inflammatory cytokines [57].
Weight; body composition; LBM; grip strength; calorie and protein intake; liver function; renal function; total protein, albumin, globulin and prealbumin levels; triglyceries and total cholesterol levels; fatigue; QoL; treatment success. Fatty Acids Modifies membrane composition of neutrophils to reduce inflammation and wasting in advanced cancer [47], improves T-cell subsets and cytokine production when used along with vitamin E [39], and improves SIMS symptoms [37]. Omega-3or EPA-containing ONS improves nutritional, clinical and inflammatory parameters, and health-related QoL in advanced lung cancer [48]; improves prognosis in advanced gastrointestinal cancer [49] and hypopharyngeal cancer among patients on induction chemotherapy [71]; and improves cachexia during gemcitabine therapy [51]. Improves postoperative recovery in head and neck cancer, as part of an immunonutrition formula [67]. Omega-3-containing ONS as part of a multimodal intervention improves clinical outcomes in cancer [69] and attenuates cachexia in incurable lung or pancreatic cancer [50] or advanced cancer with CACS [44,54]. Marine phospholipids (with >50% phospholipid-bound fatty acids as EPA and DHA) aid in cancer cachexia management [63]. Omega-3 fatty acids (EPA and DHA) in krill oil improve lipid profile disorder and inflammatory processes associated with cachexia [78]. A more purified EPA + DHA supplement is more reliable than fish oil supplements [69]. EPA is a biologically active component of fish oil responsible for anticachectic activity [65].

CoQ10
Improves physical function in elderly patients with advanced lung or pancreatic cancer as part of a multimodal intervention [56].

Not reported
Weight, BMI, skeletal muscle analysis, grip strength, food intake, nutritional status, nutrition impact symptoms, physical function, physical activity levels.

Muscadine grape extract (MGE)
Improves cancer outcomes by reducing symptom burden and is tolerated and safe for use in patients with metastatic solid tumors who have failed standard therapies [52].
Muscadine grape contains a high concentration of anthocyanin, ellagic acid, gallic acid, and flavonols and has antioxidant properties. It inhibits tumor cell growth and induces apoptosis, while also reducing systemic inflammation [52].

Dietary nucleotides
Improves postoperative recovery in head and neck cancer as part of an immunonutrition enteral formula [67].
Weight, energy and protein intake, albumin levels, retinol binding protein levels, duration of tube feeding, need for parenteral nutrition during admission, fistula incidence after surgery, length of hospital stay, readmission rates, mortality.

Royal jelly
Protects from toxicities induced by tyrosine kinase inhibitors in renal cancer [34].
Possesses anti-inflammatory and antioxidative effects, influences immune system, and protects from adverse events such as inflammation, oxidative stress and immune system dysfunction induced by anticancer agents [34].

Tools Used in Outcome Measurements
The tools that were used to assess each of the different outcome measures, where specified, are presented in Table 5.

Discussion
This scoping review summarized the types of dietary supplements used in studies involving metastatic cancer patients with malnutrition-related conditions. Thirty-one supplements were identified, which varied across different cancer types. Dietary supplements were investigated as part of combined treatments in most of the studies, where they could be administered as single (i.e., omega-3) or multiple types (i.e., omega-3 + arginine), or along with ONS, other dietary supplements, counseling, exercise, and/or drugs. Omega-3 and L-carnitine were the top two most predominantly investigated supplements-omega-3 for its anti-inflammatory [37,44,49,51,63,71], antioxidant [49,63,71], and immunomodulatory [49,63,65,71] properties, and carnitine for its suggested benefits in the modulation of inflammatory response mechanisms that have been associated with cancer cachexia [41] and role in metabolism [42,44,53,73]. To combat oxidative stress and manage the complexity of cancer-related malnutrition, multimodal treatments were considered necessary to reduce proinflammatory cytokines [44,54]. Metastasis itself is a complex challenge that necessitates multimodal therapeutic agents for effective inhibition [2] and managing its associated syndromes. While multimodal interventions may confer benefits over single interventions, it is challenging to identify the individual contribution of dietary supplements to any beneficial effects seen. Hence, it might be worthwhile investigating this with multi-arm RCTs, including both single and combined interventions which are compared to controls in future studies.
Overall, the included studies consistently reported positive effects for multimodal treatments as well as omega-3 supplements. Evidence for vitamins, minerals, and amino acids was less consistent. While antioxidants and other dietary supplements were reported by studies to exert positive effects, the number of studies that they have been included in were scant. As the present scoping review was, however, not designed to investigate effectiveness, critical appraisal and synthesis of outcome findings of the included studies were not carried out, and recommendations regarding their use cannot be made within the scope of this review.
Cancer-related malnutrition is a complex condition attributable to the imbalance of in vivo redox systems (including antioxidant enzymes and antioxidants) and upregulation of proinflammatory cytokines [44,54]. Omega-3 has the ability to inhibit the production of proinflammatory cytokines [48,49,63,65,71], and thus holds promise in its potential to manage this syndrome [44,51,63,65]. Two previous systematic reviews (one in adults with cancer undergoing chemotherapy and/or radiotherapy [84] and the other in adults with cancer cachexia who were not undergoing cancer treatment during the study period [85]) indicated beneficial effects (e.g., improvements in body composition, weight, appetite, QoL) of omega-3 fatty acid supplements (EPA; DHA). However, a systematic review in patients with advanced cancer (which included locally recurrent cancers in definition) [86] did not find sufficient evidence to support the superiority of omega-3 fatty acid supplements (specifically EPA) over placebo. As the Cochrane review was conducted over 15 years ago, it may be useful to conduct an updated review focusing on patients with metastatic cancer, as more primary studies become available. This can also help identify the effectiveness of dietary supplements in managing cancer-related malnutrition and address the lack of Level 1 evidence in this population.
Overall, more primary studies are warranted for the dietary supplements elucidated in this review. For example, carnitine was investigated in seven studies, of which only two studies [41,53] investigated it as the sole intervention. Additionally, the present review has mapped the types of dietary supplements to their proposed usefulness for particular cancer types (i.e., vitamin D for prostate cancer). This may provide some indication to researchers regarding the potentially efficacious dietary supplements that can be investigated in studies for specific cancer types.
The strengths of this review include its methodological rigor in line with standards and guidance for scoping review conduct and reporting, the dual approach to screening and extraction to reduce error, and the comprehensive search strategy. Additionally, a wide scope of all available evidence at varying levels on the evidence hierarchy was included. The limitations of the present review include the exclusion of studies where dietary factors (e.g., vitamins, minerals, fatty acids) were administered via the intramuscular and intravenous routes. These were excluded as they were technically not dietary supplements [87]; however, they might have otherwise provided additional useful information. Additionally, while efforts were made to contact study authors where missing information precludes the inclusion of a paper, only a small number of replies (5/38) were received. Lastly, as none of the included studies specified the inclusion of children, sarcopenic, or frail populations, the present review is unable to provide information on these population groups.

Implications for Research
With the identified dietary supplements and their noteworthy mechanisms and rationale for use in patients with metastatic cancers, particularly for omega-3, vitamin D, and amino acids (arginine, carnitine, glutamine, and HMB), future research in this area is required to assess efficacy on patient outcomes. Future studies should consider conducting fully powered RCTs to increase the reliability of the results. With most of the existing studies having been conducted among mixed or unspecified cancer populations, it would be worthwhile to investigate the efficacy of dietary supplements in specific cancer types, particularly in cancers where malnutrition-related issues are more prevalent (e.g., head and neck cancers). As the forms of dietary supplements were considered to make a difference in some cases (i.e., purported superiority of phospholipids-bound omega-3 over triacylglycerols-bound), researchers may consider the merit of the different forms of dietary supplements when designing future studies. There is also a need to report malnutrition with validated nutritional assessment tools (e.g., PG-SGA) in specific cancer cohorts (e.g., breast, lung, brain).

Conclusions
Dietary supplements investigated in studies conducted among patients with metastatic cancers were multifarious and differed across cancer types. With plausible effects and mechanisms proposed in relation to their role in managing malnutrition-related conditions in this population group, future studies assessing the efficacy of dietary supplements on patient outcomes are needed. As primary trials are still lacking for most of the dietary supplements, future RCTs can be considered, along with a consideration of the forms of dietary supplements to be tested, concomitant interventions to be employed (if any), and the relevance of dietary supplements to the specific cancer type of interest.