Vitamin/Mineral Supplement Evaluation Assignment Help

There was a time in the not-too-distant past when hay and oats or sweet feed were the basis of most working horses’ diets.

In recent years, sweet feed has fallen out of fashion as horse owners have realized that it is often loaded with sugar and starch. Oats are a good source of energy, but they aren't balanced in calcium and phosphorus; they are also very low in minerals and vitamins.

If your horse is receiving adequate amounts of quality forage and a feed ration that complements that forage and your horse’s particular stage in life, does he need a nutritional supplement? Good question, but there’s not just one answer.

Starting Point

Before you start adding vitamins, minerals and other supplements to your horse’s feed, do your homework. In many cases, supplementation is unnecessary. If you're feeding your horse the proper amount of forage and using a good-quality, mixed feed containing added nutrients and fed according to directions, supplementation may be needed depending on the individual horse.

“The only way to determine if a supplement is needed in addition to the regular diet is to calculate the amount of each nutrient provided by each feed, sum the parts and compare the sum to the requirements of the horse in question,” Lawrence points out.

Let’s say you have an “easy keeper” who doesn’t require much, if any, grain. The potential issue here is that forage alone may supply the calories and protein he needs, but not all the vitamins and minerals.

This horse could benefit from a supplement or a ration balancer, sometimes referred to as a “balancer pellet.” This is a concentrated feed with a lower recommended feeding rate. It supplies necessary protein, vitamins and minerals, without adding unnecessary calories. You may only need to feed a cup or two per day, depending on your horse’s specific needs.

Forage should always be the foundation of your feeding program.

When you read the directions, you’ll see that most balanced commercial equine feeds are formulated so that the horse needs to eat a specific amount daily to get the required vitamins and minerals on the label.

If you do feed a grain ration, but your horse only gets a small amount per day, you might consider switching to a ration balancer instead. By feeding a ration balancer, you’re sure the horse is getting all the required nutrients without having to feed unnecessary calories from extra grain.

Always remember: feeding according to directions is critical in order to get the most benefit out of your feed.

Additional Needs

So your horse is getting good forage and either a commercial diet or a ration balancer. Is that enough? This is when you need to take a hard look at your horse’s overall health.

Is his hair coat soft and shiny, even in winter? Does he have good hooves or are they brittle, soft and easily broken? Does he have enough energy for his work? Is he hauled for competition or work regularly? Is he under stress from travel or heavy training? Does he spend most of his time in a stall? Has he recently had health problems? Does he frequently have digestive issues? Is your mare in late-stage gestation or nursing a foal? Is the horse in question young and growing?

If you answered “yes” to one or more of these questions, your horse is likely a candidate for supplementation. You can ask your veterinarian or an equine nutritionist for recommendations and do your own research on products that may be helpful.

If your horse has poor quality hooves, for example, choose a supplement designed to support normal hoof health. You’ll need to be patient. Hoof growth is very slow, it can take six to nine months for the entire hoof wall to be replaced. You’ll want to continue using the supplement to maintain the benefits.

Horses who spend most of the day in a stall may need supplemental vitamin D, since this vitamin is usually provided through exposure to direct sunlight.

In cases where a horse is under stress, his immune and digestive systems may need specific supplementation.

An iron supplement may help in specific cases when a horse needs additional support, but it is not typically recommended for permanent use. “It would be good for an owner to discuss the need for an iron supplement with their veterinarian before supplementing,” notes Lawrence.

Hardworking horses or those living in hot, humid regions usually need more salts than what is provided in a commercial concentrate. In these situations, electrolytes should be supplemented. Electrolytes can also benefit horses year-round by encouraging adequate water consumption, which is vital for proper digestive function and overall health.

Horses under stress, competition or heavy workloads may benefit from supplementation of B-complex vitamins, which are helpful for energy metabolism.

Getting Results

The time it takes to see results from supplementation will vary, sometimes significantly.

“It depends entirely on the nutrient and the response you are looking for,” says Lawrence. “Changing hoof quality will take a long time because the hoof grows slowly. If you are trying to change antioxidant status by supplementing with vitamin E, that could occur in a few weeks or days.”

Quality can vary dramatically between supplements marketed for the same issue, so you can’t go by price alone. Compare product ingredients and percentages carefully.

When choosing a supplement, look for the National Animal Supplement Council (NASC) quality seal on the label or check with the manufacturer directly. This guarantees the product is made by a member of the NASC, which has undergone a scrupulous independent quality audit and adheres to stringent guidelines for manufacturing, labeling and adverse event reporting.

Don’t Overdo It!

When it comes to supplements, there is such a thing as “too much,” and it’s not good. For example, some minerals can cause more harm than benefit when used incorrectly. Certain fat-soluble vitamins, such as A and D, can build to toxic levels if severely overfed.

If you are feeding two supplements, read both labels carefully and check to see if any ingredients are duplicated. You don’t want to over-supplement or use supplements haphazardly.

“There are two main problems associated with over-supplementation. The first is that it can result in an unbalanced diet. The second is that it wastes money,” explains Lawrence. “There is a third problem that is often ignored and that is the excretion of excess nutrients into the environment.”

The bottom line is that if your horse is fed a balanced diet, one that fully meets his nutritional requirements for his age and the job he’s doing, adding supplements won’t help and can even unbalance the diet. But if his ration is in some way deficient for his needs, there are a number of excellent supplements on the market that can fill the nutritional gap.


Cachexia is often seen in cancer patients in advanced stages of the disease. The European Palliative Care Research Collaborative has defined cancer-related cachexia as follows: ‘Cancer cachexia is a multi-factorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. The pathophysiology is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism’.[1] With regard to the underlying causes, there is an interplay between systemic inflammation and hypermetabolism due to neoplasma, nutritional and/or intake factors related to tumour or treatment induced anorexia, changes in physiological uptake and/or storage and biopsychosocial aspects of functional impairment.[2]

The aetiology of micronutrient deficiency is multifaceted. Cancer may impede the usual intake of micronutrients. In addition, inflammatory activity and gastrointestinal symptoms of the cancer itself or the catabolic effect of the anti-neoplastic therapy may result in malnutrition, which also reduces micronutrient intake.[3] Lack of dietary supplements[4, 5] may also play a role in cancer aetiology, and supplementation with these elements has been put forward as a preventive measure. Against this backdrop, there is an ongoing discussion on the need for dietary supplementation with micronutrients such as vitamins, minerals, proteins, or certain trace elements.[6] However, there is no clear indication for the importance of these substances for treatment of cachexia or cachexia-related symptoms. Therefore, expert guidelines from the American Cancer Society, the World Cancer Research Fund, and the American Institute for Cancer Research advise patients with cancer against the use of food supplements and advocate obtaining nutrients from normal food intake whenever possible.[7, 8] Nevertheless, the American Cancer Society guide for informed choices describes a probable benefit when taking a standardized food supplement containing multiple vitamins and minerals during and after cancer treatment in order to cover the daily demand, even though the daily requirement of micronutrients for a cancer patient is not known. The Cancer Society argues that this demand could not be covered because of loss of appetite, maldigestion, or malabsorption as a consequence of tumour or treatment side effects.[9] To date this recommendation is based on weak evidence.

In our systematic review, the term ‘food supplements’ or the synonymously used term ‘dietary supplements’ is based on the definition of the European Food Safety Authority: ‘Food supplements are concentrated sources of nutrients or other substances with a nutritional or physiological effect, whose purpose is to supplement the normal diet. Food supplements are marketed ‘in dose’ form, for example as pills, tablets, capsules, or liquids in measured doses etc. Supplements may be used to correct nutritional deficiencies or maintain an adequate intake of certain nutrients’.[10]

In a large survey on food supplements, 73% of cancer patients had used supplements in the past month reporting a significant decrease in appetite loss;[11] 67 subjects (29.8%) had breast cancer, 40 (17.8%) had colorectal cancer, 32 (14.2%) had lung cancer, and 86 (38.2%) had other forms of cancer.

As part of the development of guidelines for the treatment of cachexia in cancer patients, the European Palliative Care Research Collaborative performed a Delphi procedure on a set of guideline statements.[1] Two statements where no consensus was reached were used as starting points for a systematic review. Treatment of cachexia in advanced cancer patients using fish oil was subject of another systematic review prepared by Ries et al.[2] The guideline on dietary supplements stated that there is not enough evidence for a general recommendation. Patients who are not able to consume the recommended daily amount of minerals, vitamins, and proteins may try to compensate this deficit with supplements. However, the proposal failed to reach an adequate level of consensus, and a systematic review was commissioned accordingly.

We aimed to evaluate the efficacy of vitamin, mineral, proteins, and dietary supplements for cachexia in cancer patients.


This review is part of the development of clinical practice guidelines of the European Palliative Care Research Centre (PRC) on the treatment of cachexia in patients with cancer.

Criteria for considering studies in this review

The review included studies comparing treatment with or without vitamin, mineral, proteins, or other dietary supplements in cancer patients suffering from cachexia or cachexia-related symptoms. Studies comparing different supplements were also included. Publications were excluded if they reported on animals, children, or non-cancer patients.

Perioperative treatment of cachectic patients for curative or palliative surgery with minerals, vitamins, or other supplements was not the primary focus of the review. These studies were included, but evaluated separately.

Studies were included if they included cancer patients with cachexia, indicated by weight loss >5% in 6 months, ongoing hypermetabolism and/or reduced food intake.

A spreadsheet was designed with data from each included trial. Information on study design, study size by means of patient number, setting, study limitations, patient characteristics, outcome measures, and results were entered and evaluated. A meta-analysis was not possible as a variety of outcome measures were used, and study designs were not comparable.

A recommendation according to the GRADE methodology (positive or negative and strong or weak recommendation)[12, 13] was drafted from the evidence of the reviewed literature.

Search methods for identification of studies

To identify studies, we developed a detailed search strategy (Appendix 1–3) for each electronic database and other resources. The search was restricted to publications in the English language. As a brief quality check for our search strategy, we selected two well-known publications of high relevance for our review and checked whether these publications were covered by the search strategy.[14, 15] Using this strategy, we could confirm the accuracy and validity of our literature search.

Electronic searches

We searched the following electronic databases:

  • Cochrane Central Register of Controlled Trials (CENTRAL) up until 15 April, 2016; search strategy as detailed in Appendix 1;
  • MEDLINE (OVID) from inception up until 15 April, 2016; search strategy as detailed in Appendix 2;
  • PsycINFO (OVID) from inception up until 15 April, 2016; search strategy as detailed in Appendix 3.

Searching other resources:

We screened the references of identified articles for additional studies. Published abstracts were also obtained through searches of database and conference proceedings.

Data collection

Selection of studies

We retrieved in full all studies with an abstract referring to the subject of vitamins, minerals, proteins, or other dietary supplementations aimed at treating cachexia in cancer patients. Eligible studies had to define cachexia as an outcome measure.

Data extraction and management

Two authors (MM and M) extracted data (Figure 1) using a standard data extraction form and reviewed the data from the studies. Findings were cross-checked in a second step by three autors (MM, RC, and CS). Four authors (LR, MMa, SK, and HC) cross-checked a sub-sample. We resolved disagreement by consensus.

Assessment of risk of bias in included studies

Two authors (MM and M) independently assessed risk of bias by the Cochrane risk of bias tool (Figures 2 and 3) for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions,[16] with any disagreements resolved by discussion or by involving other review authors (LR, HC, and RC). We assessed the following for each study:

Random sequence generation (checking for possible selection bias)

We assessed the method used to generate the allocation sequence as follows: low risk of bias (any truly random process, e.g. random number table; computer random number generator); and unclear risk of bias (method used to generate sequence not clearly stated).

Allocation concealment (checking for possible selection bias)

The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We assessed the methods as follows: low risk of bias (e.g. telephone or central randomisation; consecutively numbered, sealed, and opaque envelopes); and unclear risk of bias (method not clearly stated).

Blinding of outcome assessment (checking for possible detection bias)

We assessed the methods used to blind study participants and outcome assessors from the knowledge of which intervention a participant received. We assessed the methods as follows: low risk of bias (study states that it was blinded and describes the method used to achieve blinding, e.g. identical tablets, matched in appearance and smell); and unclear risk of bias (study states that it was blinded but does not provide an adequate description of how this was achieved).

Incomplete outcome data (checking for possible attrition bias due to the amount, nature, and handling of incomplete outcomedata)

We assessed the methods used to deal with incomplete data as follows: low risk (less than 10% of participants did not complete the study and/or used ‘baseline observation carried forward’ analysis); unclear risk of bias (used ‘last observation carried forward’ analysis); and high risk of bias (used ‘computer’ analysis).

Size of study (checking for possible biases confounded by small size)

We assessed studies as being at low risk of bias (200 participants or more per treatment arm); unclear risk of bias (50–199 participants per treatment arm); and high risk of bias (fewer than 50 participants per treatment arm).

Risk of bias in included studies

The findings are presented in the ‘Risk of bias’ graph (Figure 2), which reviews the authors' judgments about each risk of bias item shown as percentages across all included studies and the ‘Risk of bias’ summary (Figure 3), which reviews the authors' judgments about each risk of bias item for each included study.


We screened 4214 publications. Twenty-one papers were considered for final evaluation (Figure 1).

Trials of mineral supplements

The literature search identified one randomized controlled trial on the use of magnesium in 17 patients with advanced testicular cancer and weight loss but found no significant differences in weight loss between groups[17] (Table 1).

Willox et al. 1986[17]RCTMagnesiumi.v; tablet p.o.16Testicular; ovarian cancerMagnesium supplementation (study group) vs. no supplementation (control group) in the course of treatment with cis-diamminedichloroplatinum II (cis-platin) over 14 monthsUrine, bloodEORTCAfter 14 months serum magnesium concentration was significantly higher in the study group (0.62 ± 0.009 vs. 0.50 ± 0.07; P < 0.01). Weight loss did not differ significantly between the groups; control group showed significantly greater renal tubular damage.Discontinuation due to ‘metallic’ taste of magnesium; number of dropouts due to adverse effects not reported.

Trials of vitamin supplements

Our literature search included one crossover study of 16 patients with advanced prostate cancer treated with vitamin D. Six patients reported improved muscle strength after vitamin supplementation.[18]

Vitamin C supplementation was tested in a sample of 39 patients with stomach (10), lung (7), liver (1), breast (4), cervix (1), colorectal (9), biliary (2), and other (5) cancer sites in terminal stage. Vitamin C was substituted intravenously and orally, and patients improved on different subscales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) including physical and cognitive function, appetite loss, fatigue, and nausea/vomiting.[19]

Treatment of 60 patients with generalized solid tumours (breast, gastrointestinal, lung, liver, and pancreas) with a combination of omega-3 fatty acids and vitamin E did not have any effect on body weight compared with placebo.[20] The combination showed significant increase in survival for all patients compared with the placebo group. However, the authors did not differentiate between the specific impact of vitamin E supplementation compared with omega-3 fatty acids (Table 2).

Yeom et al. 2007[19]Prospective studyVitamin Ci.v.; tablet p.o.39Various primary neoplasmsAll patients received 10 g of vitamin C i.v. twice in 3 days and 4 g of vitamin C p.o. per day for a week.BloodEORTCPre-treatment versus post-treatment scores after 1 week supplementation showed improved global health (36 ± 18 vs. 55 ± 16; P = 0.001); patients reported significantly higher scores for physical (66 ± 20 vs. 72 ± 15, P = 0.037), role (59 ± 31 vs. 73 ± 22, P = 0.002), emotional (68 ± 24 vs. 78 ± 19, P = 0.001), and cognitive (69 ± 23 vs. 80 ± 16, P = 0.002) function and significantly lower scores for fatigue (52 ± 24 vs. 40 ± 19, P = 0.001), nausea/vomiting (24 ± 25 vs. 11 ± 15, P = 0.001), pain (30 ± 32 vs. 21 ± 25, P = 0.013), and appetite loss (50 ± 43 vs. 31 ± 29, P = 0.005).None
Van Veldhuizen et al. 2000[18]Phase-II-crossover-studyVitamin DLiquid p.o.16Prostate cancerAll patients received Vitamin D 2000 units daily for 12 weeks following a 4 week placebo periodBloodMuscle strength at enrollment and every 4 weeks; serum calcium and vitamin D measured at each visit12 weeks scores to 4 weeks scores (placebo period) showed no significant pre-post-treatment difference; reduced pain scores in four patients (25%) and improved muscle strength in six patients (37%).None
Gogos et al. 1998[20]RCTOmega-3 fatty acids plus vitamin ECapsule p.o.60Various primary neoplasms18 g fish oil + 200 mg vitamin E (study group) vs. placebo (control group) daily until deathBloodT-cell-subsets, cytokine production, nutritional response, Karnofsky index, survivalAfter 40 days, study group showed a significant increase in TNF-α levels (369 ± 32 vs.784 ± 207, P < 0.05), Karnofsky index (51 ± 3 vs. 72 ± 4, P = 0.01) and a significant prolonged survival (no exact numbers presented; P = 0.025), while there was no effect on IL-1, IL-6, and body weight.Mild abdominal discomfort; transient diarrhoea; number of dropouts due to adverse effects not reported.

Trials with proteins and other dietary supplements

In a randomized controlled study of 32 cachectic advanced solid tumours (stage IV) patients from several types of cancer such as colon, ovarian, lung, pancreatic, and other cancer, May et al. tested a combination of β-hydroxy-β-methylbutyrate (HMB), arginine, and glutamine and showed an overall benefit with an increase in lean body mass (LBM), improved mood, less weakness, and improved haematological parameters after 4 weeks compared with placebo[21] (Table 3). A mixture of HMB, glutamine, and arginine or an isonitrogenous, isocaloric control was supplemented in 472 advanced lung and other cancer patients. However, there was no statistically significant difference in the 8 week LBM between the two arms.[22]

May et al. 2002[21]RCTHMB, arginine, and glutamineLiquid p.o.32Various primary neoplasmsTreatment with HMB (3 g/day), L-arginine 14 g/day), L-glutamine (14 g/day [HMB/Arg/Gln]) (study group) vs. isonitrogenous mixture of nonessential amino acids (control group) over a 24 weeks periodBloodBody weight; FFMAfter 24 weeks of supplementation study group showed significant increase in body weight (2.27 ± 1.17 vs. 0.27 ± 1.39, P = 0.06) and FFM (1.6 ± 0.94 kg vs. 0.48 ± 1.08; P < 0.05).None
Berk et al. 2008[22]RCTHMB, arginineLiquid p.o.472Various primary neoplasmsMixture of HMB, glutamine, arginine (study group) vs. an isonitrogenous, isocaloric mixture (control group) twice a day for 8 weeks LBMPost-treatment measurement after 8 weeks supplementation showed no significant difference in lean body mass.Nausea, constipation, and/or diarrhoea; 30 patients dropped out due to side effects
Mantovani et al. 2010[14]RCTMegesterol, eicosapentaenoic acid, carnitine and thalidomide, plus polyphenol, lipoic acid, carbocysteine, vitamin E, vitamin A, and vitamin C orallyTablet; liquid p.o.332Various primary neoplasms5 groups: (1) Megesterol, (2) eicosapentaenoic acid, (3) carnitine, (4) thalidomide, and (5) mixture of (1)–(4); additionally in all groups polyphenol, lipoic acid, carbocysteine, vitamin E, vitamin A, and vitamin CBloodLBM, REE, MFSI-SF, IL-6, TNF-α, ECOG PS, Appetite VAS, EORTC QLQ-C30, Euro QoL EQ-5DPost-treatment measurement after 4 months supplementation showed that group 5 was superior to all other groups concerning increase in LBM (DEXA) (43.8 ± 9.4 vs. 44.9 ± 7.7; P = 0.015) and appetite (P = 0.0003).Diarrhoea (2 patients)
Kraft et al. 2012[15]RCTL-carnitineLiquid p.o.72Pancreatic cancerOral L-carnitine (4 g) (study group) vs. placebo (control group) for 12 weeksBloodBMI, EORTC-QLQ-C30, BFIPost-treatment measurement after 12 weeks supplementation showed increase of BMI in study group (3.4 ± 1.4% vs. −1.5 ± 1.4%, P < 0.05); trend towards increased overall survival in the study group (median 519 ± 50 d vs. 399 ± 43 d, P = n.s.), and reduced hospital-stay (36 ± 4 days vs. 41 ± 9 days, P = n.s.).Nausea (8 patients), diarrhoea (2 patients), which may have been caused by concomitant chemotherapy
Mantovani et al. 2006[23]Phase II study with Simon two-stage designPolyphenol, antioxidant, pharmaco-nutritional support enrichedTablet; liquid p.o.39Various primary neoplasmsAll patients received integrated treatment over 4 months with high polyphenols content, antioxidants (A-lipoic acid, carbocysteine lysine salt, vitamin E, vitamin A, vitamin C), and pharmaco-nutritional support enriched with two cans per day omega-3 fatty acids, medroxyprogesterone acetate, and selective cyclooxygenase-2 inhibitor celecoxibBloodWeight, LBM, Appetite, REE, Grip strength, laboratory, ECOG, EORTC QLQ-C30, Euro QL-5D, MFSI-SFPost-treatment measurement after 4 months supplementation showed increase of body weight (55.1 ± 10 vs. 57 ± 9.8 kg, P = 0.031) as did LBM (38 ± 9 vs. 39.7 ± 8.7; P = 0.024), and appetite (5.5 ± 2.5 vs.7.0 ± 1.6; P = 0.004).None
Hunter et al. 1989[24]Prospective randomized trialBCAAi.v.9Intra-abdominal carcinomaAll patients received both conventional TPN containing 19% BCAA (AA) and isocaloric, isonitrogenous TPN containing 50% BCAA (BCAA-TPN) in random order for a minimum of 24 hBlood, urine, breath sampleCO2, albumin, leucine, tyrosineAfter a minimum supplementation of 24 h study group showed increased flux of leucine (158.0 ± 37.2 vs. 243.5 ± 75.8 µmol/kg h; P < 0.025) and tyrosine (35.0 ± 84 vs. 42.6 ± 11.0 µmol/kg h; P < 0.05)None
Tayek et al.1986[25]RCTBCAAi.v.10Intra-abdominal carcinomaAll participants were given isonitrogenous amounts of both a conventional total parenteral nutrition (TPN) formula containing 19% BCAA a BCAA-enriched TPN formula containing 50% of the amino acids as BCAA in a random order over 2–5 days.Blood, urineProtein kinetic, albumin synthesisAfter 2–5 days, BCAA-enriched formula group showed significant increases in whole body protein synthesis (2.2 ± 0.2 g protein/kg BW/day vs.3.9 ± 0.3; P < 0.005) and leucine balance (2.5 ± 0.4 g leucine/day vs. 6.5 ± 0.6; P < 0.001).None
Yeh et al. 2013[26]RCTEE and isocal. Ethanwell contains several ingredients, including omega-3 fatty acids, glutamine, selenium, and CoQ10. Ethanzyme is an enzyme product composed of multiple probiotics and vitamins.Liquid p.o.68Head and neck cancerPatients were randomly assigned to receive either EE supplement (study group) or Isocal supplement (control group) for a 3 month periodBloodBody weight, serum albumin, prealbuminAfter 8 weeks, EE regimen significantly improved body weight compared with controls (9.0 ± 1.8 vs. −7.3 ± 3.3; P < 0.05) as well as serum albumin (24.7 ± 9.5 vs. 2.8 ± 6.5; P < 0.05) and prealbumin levels (23.6 ± 7.8 vs. 6.1 ± 14.4; P < 0.05).Some patients suffered from accumulating treatment-related side effects (oral mucositis, emesis). Number of dropouts due to adverse effects not reported.

Seventy-two participants with advanced pancreatic cancer taking L-carnitine showed an increase in body mass index (BMI) by 3.4 ± 1.4%; a decrease in BMI was observed in the control group. There was also a trend towards an increased overall survival in the L-carnitine group and reduced hospital-stay.[15] In another controlled trial, 332 patients were randomized into five treatment arms, comparing megesterol, eicosapentaenoic acid, carnitine, and thalidomide with a combination of all four substances in the fifth arm.[14] An analysis of pre-treatment to post-treatment changes showed that LBM significantly increased, while the resting energy expenditure decreased in the combination arm. Thus, study findings revealed that the combined supplementation was superior. Carnitine alone did not show any benefits.

In a small study of nine malnourished participants with intra-abdominal cancer, participants received both conventional total parenteral nutrition (TPN) containing 19% branched-chain amino acids (BCAA) and isocaloric, isonitrogenous TPN containing 50% BCAA (BCAA-TPN).[24] The trial showed that the fractional albumin synthesis rate increased significantly on daily BCAA-TPN. Another study from Tayek et al. investigated the effect of a BCAA-enriched solution in 10 malnourished patients with intra-abdominal metastatic adenocarcinoma.[25] The participants were given isonitrogenous amounts of both a conventional (TPN) formula containing 19% BCAA and a BCAA-enriched TPN formula containing 50% of the amino acids as BCAA in a random order. BCAA-enriched formulae group showed significant increases in whole body protein synthesis and leucine balance. Both studies demonstrated potential clinical benefits associated with BCAA-enriched TPN in cancer cachexia patients.

Supplementation with combinations of antioxidants, vitamins, omega-3 fatty acids, medroxyprogesterone acetate, and celecoxib[23] was used in a study of 39 cancer patients. The study reported positive effects stabilizing or increasing weight, LBM, and appetite.

In another study, an Ethanwell/Ethanzyme (EE) regimen was investigated in 68 malnourished patients with head and neck cancer.[26] Ethanwell is a protein-dense and energy-dense oral nutritional supplement that contains several ingredients including omega-3 fatty acids, glutamine, selenium, and CoQ10. Ethanzyme is an enzyme product composed of multiple probiotics and vitamins. The result showed that an EE regimen improved body weight as well as serum albumin and prealbumin levels in head and neck cancer patients with a BMI <19. However, methodology in both abovementioned studies did not allow to differentiate the beneficial effects of the individual substances in the combination therapies.

Perioperative supplementation

Nine studies on the use of different combinations of arginine, glutamine, alanine, glycine, BCAA, omega-3 fatty acids, and RNA in a perioperative setting were identified including a total of 791 cancer patients[27-35] (Table 4). Two of these studies investigated patients with major weight loss at the time of admission.[27, 30] In five studies,[27, 30, 32, 34, 35] arginine was supplemented in different mixtures. Supplementation showed beneficial effects with regard to length of hospital stay,[27, 34] postoperative infections,[27] increase in BMI,[35] and albumin, prealbumin, and lymphocyte levels.[35] One study[32] in 32 head and neck cancer patients also reported an overall long-term survival (34.8 months vs. 20.7 months). In two studies, glutamine supplementation was investigated.[29, 33] Improved nitrogene balance and intracellular glutamine concentration[29] and shortened hospital stay[33] were relevant clinical effects.

Gianotti et al. 2002[27]RCTArginine, omega-3 fatty acids, and RNALiquid p.o. (preoperative); per jejunal feeding (postoperative)305Gastrointestinal Cancer(1) Oral supplementation for 5 days before surgery with 1 L/day of a formula enriched with arginine, omega-3 fatty acids, and RNA, with no nutritional support given after surgery; (2) Same preoperative treatment plus postoperative jejunal infusion with the same enriched formula; (3) Control group without supplementationBloodIncidence of postoperative infections, length of hospital staySupplementation significantly shortened length of hospital stay in group 1 vs. controls (11.6 ± 4.7 days vs. 14.0 ± 7.7; P = 0.008) and group 2 vs. controls (12.2 ± 4.1 days vs. 14.0 ± 7.7, P = 0.03) and less postoperative infections in the period up to 30 days after hospital discharge as measured by incidence (group 1 vs. controls 14 vs. 31, P = 0.006; group 2 vs. controls 16 vs. 31, P = 0.02)Abdominal cramping/bloating (72 patients), diarrhoea (13 patients), vomiting (5 patients)
Stehle et al. 1989[29]RCTGlutamine and glycinei.v.12Colon, rectum cancerStudy group was supplemented with a synthetic glutamine-containing dipeptide, l-alanyl-l-glutamine, alanine-N. Control group received glycine-N supplementation.Urine, blood, biopsy of quadriceps femorisNitrogen balance and glutamine concentrationCumulative nitrogen balance was significantly better in the study group on 5th post operative day (−7.1 ± 2.2 vs. −18.1 ± 1.7 g N/day; P < 0.001); muscle intracellular glutamine concentration was maintained in the study group, whereas it decreased in the control group (17.5 ± 1.0 vs. 12.0 ± 0.6 mmol/L, P < 0.001).None
Snyderman et al. 1999[28]RCTImmune-enhancing nutritional supplement from Novartis product (Impact, Replete)Liquid p.o.; enteral136Squamous cell carcinoma of the oral cavity, pharynx, larynxPatients were divided into 4 groups: (1) supplemented diet pre-operative and post-operative, (2) supplemented diet post-operative, (3) standard diet pre-operative and post-operative, and (4) standard diet post-operativeBloodDietary intake, changes in weight, laboratory evaluations of nutritional status, tolerance of tube feedings, infectious and wound healing complications, and duration of hospitalizationSignificant decrease in the incidence of post-operative infectious complications during hospitalization in intention to treat analysis in supplementation groups 1 + 2 vs. standard diet control groups 3 + 4 (23% vs. 45% incidence, P = 0.04)None
van Bokhorst-De Van Der Schueren et al. 2001[30]RCTArginineLiquid per tube feeding49Head and neck cancerPatients were divided into 3 groups: (1) standard pre-operative and post-operative tube feeding, (2) pre-operative enteral nutrition in which 41% of the casein was replaced by arginine and standard post-operative tube feeding, (3) no pre-operative and standard post-operative tube feeding, study period up to 7 days post-operativelyBloodBody weight, body composition, upper midarm circumference, skinfold thickness, muscle function, albumin at recruitment, 1, 4, and 7 days as well as on the day of dischargeNo significant changes in nutritional status on all outcome measurements at 1, 4 and 7 days post-operativelyNone
Yamanaka et al. 1990[31]RCTBCAAi.v.34Gastric cancerTotal parenteral nutrition solution supplemented with 31% BCAA vs. 21% BCAA was administeredBloodPlasma amino acid levels were measured after administrationAdministration of TPN solution supplemented with 31% BCAA was more effective to improve protein metabolism than 21% BCAA-enriched TPNNone
Buijs et al. 2010[32]RCTArginine vs. standard perioperative enteral nutritionLiquid per tube feeding32Head and neck cancerParticipants were divided into 2 groups: (1) arginine-supplemented perioperative enteral nutrition (study group) and (2) standard perioperative enteral nutrition (control group), outcome over a 10 year periodThe primary outcome was long-term (≥10 years) survival. Secondary outcomes included the long-term appearance of loco-regional recurrence, distant metastases, and second primary tumoursStudy group had a significantly better overall survival (34.8 months vs. 20.7 months; P = 0.019) and a better disease-specific survival (94.4 months vs. 20.8 months; P = 0.022)None
Aliyazicioglu et al. 2013[33]RCTStandard and/or glutamine dipeptide and/or omega-3 fatty acids supplemented TPNi.v.36Colorectal cancerPatients were randomly divided into four groups: (1) standard TPN (control group), (2) TPN with glutamine solution (S-D), (3) TPN with omega-3 fatty acid solution (S-O), and (4) TPN with omega-3 fatty acids solution and glutamine (S-D-O). Treatments were given for 7 days after the operationBloodAlbumin, AST, ALT, NAI, IL-8, length of stayThe length of hospital stay in supplemented groups was significantly shorter compared with control group (7.37 ± 1.77 in S-D; 7.13 ± 1.73 in S-O; 8.2 ± 1.14 in S-D-O vs. 12.48 ± 5.43; P < 0.05). All supplemented groups also showed significant increase (7 day postoperative) in NAI compared with control group (P < 0.05)None
Braga et al. 2002[34]RCTArginine, omega-3 fatty acids, and RNALiquid p.o. (preoperative); per feeding tube (postoperative)150Gastrointestinal cancer(1) Post-operative standard diet; (2) For 7 days orally 1 L/day liquid diet enriched arginine, omega-3 fatty acids, and RNA for pre-operative and same as control for post-operative; (3) enriched diet pre-operative and post-operativeBloodPostoperative complication and length of stayAdministration of supplemented diet before and after surgery shortened the pre-operative (13.2 days) and perioperative (12.0 days) length of stay compared with controls (15.3 days) (P = 0.01 and P = 0.001, respectively)Abdominal cramps or distention (29 patients), diarrhoea (13 patients), vomiting (4 patients)
de Luis et al. 2013[35]RCTArginine, omega-3 fatty acidsLiquid p.o.37

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