Review

Version of Record online: 20 JUL 2016

DOI: 10.1002/jcsm.12127

Introduction

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.

Methods

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 ClinicalTrials.gov 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.

Study flow diagram.

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 graph: review of authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review of authors' judgements about risk of bias items for each included study.

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.

Results

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).

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).

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]

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.

Adverse effects with dietary supplements

Adverse effects were metallic taste after magnesium supplementation,[17] diarrhoea,[14, 15] and nausea[15] after L-carnitine supplementation, or mild abdominal discomfort and transient diarrhoea after a mixture of omega-3 polyunsaturated fatty acids plus vitamin E.[20] HMB in combination with arginine was associated with nausea, constipation, and diarrhoea.[22] EE regimen[26] led to oral mucositis and emesis. Arginine in combination with omega-3 fatty acids and/or RNA[27, 34, 35] was associated with abdominal cramping, bloating, diarrhoea, nausea, and vomiting.

Discussion

A number of studies on the use of minerals, vitamins, proteins, and other supplements for the treatment of cancer cachexia were found. However, only 21 studies fulfilled the inclusion criteria and were part of this systematic review (Figure 1).

The search terms were formulated broadly (Appendix 1–3), to cover all relevant studies. The number of participants varied across studies. Most of them investigated supplementation with a combination of substances and did not provide any information on effects of single ingredients. Outcome measures across all studies included body mass, pain, muscle strength, appetite, grip strength, quality of life, and serum levels of IL-6 and TNF-α. None of the studies reported effect sizes.

The paucity of data from high quality studies on food supplements became evident in the evaluation process, even though deficiency concerning minerals,[36, 37] vitamins,[38] and proteins[39] was found in several studies on cancer patients.

Minerals such as selenium or magnesium have been discussed not only for nutrition but also for immuno-function and cancer prevention; their effect on cachexia has not been investigated in detail. Thus, our literature search identified only one study on mineral supplementation examining the use of magnesium in a randomized controlled trial.[17] There was no effect of this intervention on weight loss (Table 1), so that a recommendation of magnesium to prevent weight loss in cancer is not justified.

Studies with vitamin supplements[18-20] were slightly more promising (Table 2). In one study, vitamin D supplementation showed improvement of muscle weakness in prostate cancer patients;[18] however, as measurement of muscle strength was the only outcome measure, no conclusion can be drawn concerning weight loss. With regard to vitamin C, oral and intravenous supplementation in terminal cancer patients led to improvement of several domains of quality of life such as physical and cognitive function, fatigue and appetite loss, as well as nausea.[19] A single study on vitamin E in combination with omega-3 fatty acids displayed an effect on survival.[20] Altogether, additional research on vitamin D, vitamin C, and vitamin E supplementation is recommended to give a clearer picture of possible advantages of vitamin supplementations in cancer.

Looking at studies with proteins and other dietary supplements the combination of HMB, arginine, and glutamine showed interesting results (Table 3). In one study, 32 patients gained an average of about 2 kg of body weight.[21] This study was one of three studies confirming the positive effects of this combination in a variety of diagnoses/conditions such as HIV/AIDS patients and healthy adults.[40] Another study, on a far larger sample base of around 470 cancer patients, found no significant difference with regard to LBM after 8 weeks however a strong trend in the direction of an increase in LBM as measured by both bio-impedance and skin-fold measurements.[22] In summary, the effect of the combination of HMB, arginine, and glutamine on weight gain should be investigated in further studies on cancer patients investigating time periods of several months.

With regard to perioperative supplementation arginine[27, 30, 32, 34, 35] and glutamine[29, 33] in combination with other supplements displayed interesting clinical effects (length of hospital stay, infections, and overall survival) and improved protein levels (albumin and glutamine). On the other hand, mixtures containing arginine were associated with gastrointestinal side effects such as abdominal cramping, nausea, and vomiting. To date, there is not enough evidence to answer the question, whether clinical benefits of arginine supplementation in the perioperative setting justify abovementioned adverse side effects.

Carnitine deficits have been identified in 78% of patients with advanced cancer, with resurgent levels in most of these patients after carnitine supplementation.[39] One study confirmed carnitine as a promising food supplement in pancreatic cancer patients.[15] Patients with carnitine supplementation significantly gained weight with a BMI increase of over 3% on average and improved overall survival. However, of 72 enrolled patients, only 26 completed the study so that external validity of study findings is limited. In a further study,[14] results showed that L-carnitine in combination with medroxyprogesteron acetate/megestrol acetate, eicosapentaenoic acid, and thalidomide had a positive effect on LBM, fatigue, and appetite. However, L-carnitine supplementation alone did not have the same positive effect; therefore, further investigation on the influence of L-carnitine on cachexia is needed.

Two studies analysing supplementation with BCCA showed clinical benefits as measured by the albumin synthesis rate and leucine flux; however, the very small sample size did not allow for valid conclusions to be drawn. A study using a mixture of minerals, vitamins, proteins, and probiotics (EE regimen) showed improvement in body weight as well as serum albumin and prealbumin levels in head and neck cancer patients with a BMI <19. However, the study design does not allow for differentiation of the contribution of each of the ingredients to weight gain.

Adverse effects were reported in studies supplementing minerals,[17] vitamins,[20] and proteins.[14, 15, 22, 26, 27, 34, 35] In most cases, gastrointestinal side effects were reported. These effects showed mild intensity and seldom led to discontinuation or change of treatment. However, it should be noted that the dosage of supplements was controlled in abovementioned studies. As many supplements can be purchased without prescription or at the local supermarket excessive supplementation may be seen in cancer patients who are concerned about micronutrient deficiencies and there may be a risk of potentially harmful self-medication. A survey among breast cancer patients showed the potential for excessive vitamin/mineral use among one-third of respondents.[41] Even though in studies on humans to date no major adverse events due to food supplementation have been reported, in animal studies, supplementation with N-acetylcysteine and vitamin E accelerated lung cancer progression in mice.[42]

Regarding limitations of our systematic review, expanding the search to additional databases or to non-English literature might have resulted in more hits. However, it seems improbably that there is a significantly larger body of evidence not identified by our search strategy.

In summary, studies with a greater number of participants are urgently needed, although problems with recruitment and high attrition have been identified in many other reviews in advanced cancer or palliative care. Similarly, the positive effects of some studies with combination therapies lend support to the necessity of additional research on the individual components. In order to prioritize research ambitions and provide useful guidance for cancer and palliative care, studies should focus on the effect of food supplements on nutritional status and cachexia-related symptoms in patients and cancer types most affected by cachexia.

Conclusions

Following the GRADE methodology, no positive recommendation could be expressed for the use of minerals, vitamins, proteins, or other supplements in cancer patients. On the other hand, no serious adverse effects have been associated with dietary supplementation. Further research is needed to identify the efficacy and safety of these supplements to be able to give clear evidence-based recommendations.

Acknowledgements

The authors certify that they comply with the ethical guidelines for authorship and publishing of the Journal of Cachexia, Sarcopenia, and Muscle.[43]

The main sources of funding of the PRC are The Norwegian Cancer Society, The Norwegian University of Science and Technology, and Trondheim University Hospital. Additional support has been awarded by the Open Society Institute (USA), the Floriani Foundation (Italy), and by an unrestricted grant from Nycomed.

References