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Abstract

Background:

Cancer cachexia is a common debilitating weight loss syndrome in advanced cancer, particularly lung cancer. Omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, with their immune-modulating effects, have been used to improve the nutritional status of patients with cancer cachexia.

Aim:

Evaluate the effects of omega-3 fatty acids in change in weight and lean body/skeletal mass, and health-related quality of life scores (HRQoL) in patients with advanced non-small cell lung cancer and cancer cachexia.

Design and Data Sources:

Clinical trials from electronic databases and unpublished literature (date of last search 20 December 2023) were independently reviewed and evaluated by authors for their methodological quality. Data from eligible trials were extracted and analyzed in a meta-analysis.

Results:

Six trials were included. Five trials (354 patients) assessed change in weight; 2 trials (132 patients) assessed change in lean body/skeletal mass and HRQoL scores (Global Health and Physical Functioning subscales). There is a significant difference in change in weight (mean difference [MD]: 1.22, 95% CI: 1.05-1.38, P < .01) and HRQoL scores (Global Health [MD: 14.40, 95% CI: 9.22-19.59, P < .01] and Physical Functioning [MD: 10.38, 95% CI: 8.50-12.27, P < .01] subscales) favoring the omega-3 fatty acids group. The change in lean body/skeletal mass is not significant (MD: 2.05, 95% CI: −0.55 to 4.66, P = .12).

Conclusions:

Among patients with advanced non-small cell lung cancer and cancer cachexia, supplementation with omega-3 fatty acids leads to a significant increase in weight and HRQoL scores but not in change in lean body/skeletal mass.

Keywords

omega-3 fatty acids cachexia non-small cell lung carcinoma weight loss quality of life meta-analysis

Key Statements

What is already known about the topic?

• Omega-3 fatty acids have been used to improve the nutritional status of patients with cancer cachexia because of their immune-modulating effects.

• For patients with advanced non-small cell lung cancer (NSCLC), trials have shown contradicting conclusions regarding the benefit of omega-3 fatty acids for cancer cachexia.

What this paper adds

• This study demonstrates that supplementation with omega-3 fatty acids leads to a significant increase in weight and health-related quality of life (HRQoL) scores (Global Health and Physical Functioning subscales) among patients with advanced NSCLC and cancer cachexia.

Implications for practice, theory, or policy

• Omega-3 fatty acids, which are widely available worldwide and safe, can be recommended for patients with advanced NSCLC and cancer cachexia because of their benefit to weight gain and improvement in HRQoL.

Background

Description of the Condition

Cancer cachexia is a common debilitating weight loss syndrome among advanced cancer patients.^1,2 It is characterized by anorexia and extreme weight loss because of decreased adipose tissue and muscle mass.² Cancer patients with cachexia have shorter survival time, decreased response to therapy, functional decline, and poorer quality of life.^2,3 It is commonly observed in patients with solid tumors of the stomach, lung, and pancreas.^1,4 In patients with non-small cell lung cancer (NSCLC), in particular, cancer cachexia contributes to treatment toxicity, poor quality of life, and decreased survival.⁵

More complex than simple starvation, the mechanism behind cancer cachexia is multifactorial and several explanations include the following: (1) biochemical and metabolic disturbances because of tumor-related systemic effects; (2) mechanical obstruction from the mass itself; and (3) consequence of treatment toxicity.¹ The changes brought about by cancer cachexia are largely mediated by proinflammatory cytokines and acute phase reactants such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6).^4,6,7 Improving appetite^8,9 and providing extra calories does not easily reverse the body composition changes in cancer cachexia² as evidenced by the failure of increasing intake through routine dietary counseling¹⁰ or total parenteral nutrition.¹¹

Description of the Intervention and How It Might Work

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are long-chain omega-3 (n-3) polyunsaturated fatty acids derived from fish oils which have been demonstrated to confer immune-modulating effects.⁴ EPA has been shown to inhibit tumor-induced lipolysis and muscle protein breakdown, by suppressing cytokine IL-6 and proteolysis-inducing factor.¹² Consequently, this reduces oxidative stress⁷ and inhibits activation of the ubiquitin-proteasome pathway.¹³ These molecular events help stabilize wasting and resting energy expenditure in patients with cancer² leading to significant weight gain, decreased lean tissue wasting, improved performance status, and increased appetite.^3,14 A randomized controlled trial even showed prolonged survival of malnourished patients with advanced cancer who received omega-3 fatty acids.¹⁵

Omega-3 fatty acids are commonly available worldwide as over-the-counter fish oil preparations in soft gelatin capsule form. Some oral nutritional supplementation preparations also have omega-3 fatty acids incorporated. However, the actual concentrations and quality of omega-3 fatty acids in these preparations may vary greatly. It is generally well-tolerated, and its widespread use revealed few concerns about its safety.¹

Why It is Important to Do This Review

Evidence suggests that EPA is beneficial in cancer cachexia by improving weight gain or decreasing weight loss, and even improving survival.^14-16 However, there are contradictory study results on the effects of omega-3 fatty acids in cancer cachexia and nutritional status.^13,17 Aside from the small sample sizes, these trials used different dosages and preparations. A previous Cochrane review also showed that there was still insufficient evidence to support the use of omega-3 fatty acids in cancer cachexia among patients with advanced cancer.¹ Since the publication of this review, various trials investigating the use of omega-3 fatty acids in cancer cachexia have already been published. In addition, this previous review only included trials of supplements containing EPA but not DHA or both. Given the wide availability and use of supplements containing EPA and/or DHA, and the scarcity of published trials investigating only 1 fatty acid in cancer cachexia, our meta-analysis included trials of supplements containing EPA, DHA, or both.

For patients with NSCLC, several non-randomized and randomized small trials have shown contradicting conclusions regarding the benefit of using omega-3 fatty acids for cancer cachexia. Thus, this meta-analysis of quality-assessed clinical trials aimed to synthesize the available data.

Research Question

Among patients with advanced NSCLC and cancer cachexia, how effective is omega-3 fatty acids supplementation in improving weight, lean body mass or skeletal mass, and HRQoL?

Objective

Our objective for this meta-analysis is to evaluate the effect of omega-3 fatty acids in the change in weight, lean body mass or skeletal mass, and HRQoL scores in patients with advanced NSCLC and cancer cachexia.

Methods

Criteria for Considering Studies for This Review

Types of studies

Clinical trials satisfying the methodological quality assessment process were included in this review. Both blinded and open-label studies, inpatient or outpatient studies, and studies of any duration were included.

Types of participants

Adult patients with advanced non-small cell lung cancer (stage III-IV) and cancer cachexia regardless of sex, race, and ethnicity were included.

Types of interventions

This review included trials that compared omega-3 fatty acids (either EPA and/or DHA) in any dosage or preparation (eg, gelatin capsule, liquid supplementation, or contained in an oral nutritional supplement), versus placebo or an active matched control (without EPA and/or DHA).

Types of outcome measures

Primary outcomes

The primary outcome measures assessed were: (1) change in weight; and (2) change in lean body mass or skeletal mass. The lean body or skeletal mass were measured by computed tomography (CT) or bioimpedance analysis.

Secondary outcomes

The secondary outcome measures assessed were HRQoL scores, specifically the Global Health and Physical Functioning subscales of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQ-C30).

Search methods for identification of studies

Electronic searches

Electronic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, ClinicalTrials.gov, and Google Scholar were searched using the following search terms (date of last search 20 December 2023): “omega-3 fatty acids,” “eicosapentaenoic acid,” “docosahexaenoic acid,” “cachexia,” “lung neoplasms,” and “clinical trial.” Both free text and MESH were used for these search terms. Appropriate Boolean and truncation terms were used for each database. There were no restrictions based on date of publication, language used, or publication status.

Searching other resources

Manual handsearching and cross-checking of the references of the articles included were done to look for other relevant articles. Conference and symposium proceedings, unpublished articles, and internal reports were also included in the search. Online library databases and gray literature databases including OpenGrey and NLM Bookshelf were also checked for unpublished articles.

Data collection and analysis

Selection of studies

Three authors (AVC, ARBH, and MJLM) independently reviewed the literature searches to identify potential trials to be included in the review. These trials were then independently assessed for inclusion by 2 authors (AVC and MJLM). The following were the inclusion criteria:

1. Study type: clinical trial

2. Population: adult patients diagnosed with advanced NSCLC (stage III -IV) and cancer cachexia

3. Intervention: omega-3 fatty acids (EPA and/or DHA) in any dosage or preparation (eg, gelatin capsule, liquid supplementation, or contained in an oral nutritional supplement)

4. Comparison: placebo or an active matched control (without EPA and/or DHA)

5. Outcome measures:

(a) Primary outcomes: change in body weight and change in lean body mass or skeletal mass

(b) Secondary outcomes: HRQoL scores, specifically the Global Health and Physical Functioning subscales of the EORTC-QLQ-C30

Data extraction and management

Data from the eligible studies were extracted using a data collection form. This form included the baseline characteristics of the study participants, inclusion and exclusion criteria, intervention for the experiment and control/comparison group, methods, quality assessment/risk of bias table, and the primary and secondary outcome measures. Two review authors independently reviewed each study and extracted the necessary information. These were then cross-checked for accuracy and agreed upon. When necessary, a third review author was asked for arbitration and discussion for any disparity. Authors of the included studies were contacted if necessary for additional or missing information.

Specifically, we extracted the means and standard deviations (SD) of the change in weight (in kilogram) and lean body mass or skeletal mass as measured by computed tomography (CT) or bioimpedance analysis. For the secondary outcomes, we extracted the mean HRQoL scores and their standard deviations, specifically from the Global Health and Physical Functioning subscales of the EORTC-QLQ-C30. Means and SDs were used in our analyses as these were consistently used and available for extraction from all included trials. In addition, previous reviews also used mean differences in their analyses.^1,18

Assessment of risk of bias in included studies

The included eligible studies were independently assessed by 2 review authors for methodological quality and bias using the Cochrane Collaboration risk of bias assessment tool. This tool assesses the following 6 domains of each study: sequence generation, allocation concealment, blinding of participants/care providers, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other issues that may introduce bias in the study. Each domain was categorized as “low,” “high,” or “unclear risk” of bias. The criteria for judging biases are based on the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions. A third review author was asked for arbitration for any difference in assessment. Justifications for the assessments were documented.

Given the limited number of studies included in this meta-analysis, traditional methods for assessing publication bias, such as funnel plots and Egger’s test, may lack sufficient power and reliability. Therefore, we conducted a qualitative assessment. The included studies were examined for characteristics that might suggest a publication bias, such as funding sources, sample sizes, and the presence of small or negative studies. Despite the inherent limitations, this assessment helped provide context for interpreting the findings and underscored the need for further research with more comprehensive data.

Measures of treatment effect

Data were combined using the mean difference method for all the outcomes in this study and were presented as mean differences with their associated 95% confidence intervals. Forest plots were created to summarize the data of the included studies graphically.

Unit of analysis issues

The studies included in this meta-analysis were not cross-over trials or involved cluster randomization; thus, there were no special issues in the analysis of studies involving non-standard designs.

Dealing with missing data

Authors of the included studies were contacted for unpublished data, if necessary. An electronic mail requesting for unpublished information was sent. However, for the studies of van der Meij et al^4,5, the mean and standard deviations of the change in body weight and HRQoL scores were not available despite contacting the authors. Since the results presented by the authors were relative or based on the differences with the reference group, the reviewers assumed that there was no change in the control group and subsequent computation of the standard deviations based on the baseline data was performed.

Assessment of heterogeneity

Heterogeneity among the included studies was assessed by comparing the characteristics of the studies and similarities between the participants and interventions. The I² statistic was calculated, defined as the proportion of total variation observed between the trials attributable to differences in the trials rather than to sampling error (chance) with values <25% considered as low and >75% as high. A P-value of <0.1 was deemed significant.

Data synthesis

The statistical analysis was done in line with the recommendations of the Cochrane Collaboration and the Quality of Reporting of Meta-analyses (QUORUM) guidelines using Review Manager (RevMan) version 5.3 version (Copenhagen, Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

Subgroup analysis and investigation of heterogeneity

For the outcomes with high heterogeneity, a random effects model was used to account for the high degree of inter- and intra-study variation in the included studies. However, the small number of studies and the lack of detailed covariate data precluded a meta-regression to be performed to examine the relationship between study-level characteristics and the effect sizes. Performing meta-regression with these limitations increases the risk of overfitting and could yield unreliable results, and potentially lead to misleading conclusions.

Sensitivity analysis, subgroup analysis, or adjunct methods such as the trim-and-fill procedure were also difficult to perform. The difficulty would be the ascertainment of outcomes because not all authors responded to provide unpublished data and the small size of these studies would amount to many possibilities to do such an approach.

Results

Data Collection and Analysis

Results of the search

Description of included studies

The reviewers were able to identify 6 eligible trials using the search strategy outlined in Figure 1. One study was excluded from preliminary screening because it was a Cochrane review exploring the use of EPA for the treatment of cachexia in all cancer types.¹ The 6 full-text articles were assessed and eventually included in the meta-analysis. Five trials (354 patients) assessed change in weight, while 2 trials (132 patients) assessed change in lean body mass or skeletal mass, and HRQoL scores (Global Health and Physical Functioning subscales).

Figure 1.

PRISMA study flow diagram.

The first study is a multicenter, double-blind, placebo-controlled, randomized clinical trial by Fearon et al¹⁷ published in 2006. It involved 518 weight-losing patients with advanced gastrointestinal or lung cancer (149 patients) randomized to either 2 g or 4 g per day of a 95% pure EPA diester given as 2 1 g soft gel capsules twice daily or placebo capsules containing medium chain triglycerides. Patients receiving chemotherapy or have undergone chemotherapy, surgery, or radiotherapy in the past 4 weeks were excluded. They were then assessed at 4 and 8 weeks. Results showed that there were no statistically significant improvements in survival, weight, or other nutritional variables from single-agent EPA in the treatment of cancer cachexia. However, a trend in favor of EPA was seen for mean weight increase at 8 weeks but this was not statistically significant (P = .066). Interestingly, increase in mean weight is greater in the 2 g EPA group than in the 4 g EPA group (1.2 kg [95% CI: 0 kg-2.3 kg] vs 0.3 kg [95% CI: ≥0.9 to 1.5 kg], respectively).

The second study is a randomized, double-blind, placebo-controlled trial by van der Meij et al⁴ published in 2010. This study done in the Netherlands involved 40 patients diagnosed with stage III NSCLC who were randomized to receive either 2 cans per day of a protein- and energy-dense oral nutritional supplement containing n-3 fatty acids (2.02 g/days EPA + 0.92 g/days DHA) or an isocaloric control supplement. In contrast to the trial by Fearon et al, patients received chemotherapy and concurrent thoracic radiotherapy. Patients receiving the intervention had better weight maintenance after 2 and 4 weeks (1.3 kg and 1.7 kg, respectively, P = .05). There was also better fat-free mass maintenance, reduced resting energy expenditure, and a trend for a greater mid-upper arm circumference, lower IL-6 levels, and higher energy and protein intake in the intervention group.

Another study done by van der Meij et al published in 2012 investigated the effects of an oral nutritional supplement containing omega-3 polyunsaturated fatty acids on quality of life, performance status, handgrip strength, and physical activity in the same population.⁵ Patients given omega-3 fatty acids had significantly higher quality of life parameters, physical and cognitive function, global health status, and social function than the group who received an isocaloric oral nutritional supplement without EPA and DHA after 5 weeks.

The fourth study included in the analysis was an open-label trial done by Murphy et al in Canada published in 2011.³ Forty patients with histologically confirmed diagnosis of NSCLC were assigned to receive a dose of 2.2 g of EPA per day either as gelatin capsules or liquid fish oil per day (16 patients) or standard of care (24 patients). Patients who received just the standard of care had an average weight loss of 2.3 ± 0.9 kg while the patients who received EPA maintained their weight (0.5 ± 1.0 kg; P = .05). Patients who had the greatest increase in plasma EPA were also found to have the greatest increase in muscle mass.

The fifth study is a multicenter, randomized, double-blind, placebo-controlled trial published in 2011 by Finocchiaro et al involving 33 patients from Italy with advanced inoperable NSCLC.⁷ Patients were randomized into a daily dose of 4 capsules containing 510 mg of EPA and 340 mg of DHA for the entire period of chemotherapy or a daily dose of 4 capsules containing 850 mg of placebo (olive oil). There was a significant increase in weight in patients who received omega-3 fatty acids after 66 days of chemotherapy. There were also decreased inflammatory markers like C-reactive protein and IL-6 in the EPA + DHA group.

The last study included in the analysis is a randomized controlled trial published by Sánchez-Lara et al in 2014.⁶ This trial done in Mexico enrolled 92 patients with stage IIIb and IV NSCLC randomized to either a standardized diet alone or a standardized diet with additional 2 containers of oral nutritional supplement containing EPA. All patients received chemotherapy (paclitaxel and cisplatin/carboplatin treatment). Patients who received EPA maintained weight and gained 1.6 ± 5 kg of lean body mass while the control group had a loss of −2.0 ± 6 kg (P = .01). Fatigue, loss of appetite, and neuropathy decreased in the EPA group but there were no differences in response rate or overall survival between groups.

The characteristics of the included trials are shown in Supplemental Table 1.

Excluded Studies

None of the 6 full-text articles assessed for eligibility were excluded from the analysis.

Risk of bias in included studies

The reviewers’ assessment of the risk of bias for each included study is depicted in Supplemental Figure 1. The methods of randomization sequence, allocation concealment, and blinding of participants and personnel were clear and deemed low risk for all studies except for Murphy et al because it is an open-label trial. However, only Sanchez-Lara et al explicitly specified an independent blinded outcome assessor. All trials were deemed low risk for reporting bias because all pre-specified primary and secondary outcomes were completely reported as planned. Importantly, all trials except Murphy et al and Sanchez-Lara et al were assessed to be high risk for attrition bias because of the significant number of dropouts in the other trials that were deemed clinically relevant to affect the outcomes. For example, in Fearon et al, there was an approximately 50% decrease in the number of patients remaining in the study after 8 weeks. Also, in van der Meij et al, it was stated by the authors that without the selective dropout, they would possibly observe an “even stronger and more significant effect” in the intervention group.

Effects of Interventions

Primary outcome: change in body weight

Five trials (354 patients) assessed change in body weight either as their primary or secondary outcome during the follow-up period which varies between studies from 4 to 9 weeks. As shown in Figure 2, there is a significant difference in the change in weight among those who received omega-3 fatty acids (MD: 1.22, 95% CI: 1.05-1.38; ƶ: 14.49, P < .01). A fixed effects model was used because the inter- and intra-study variation was low as evidenced by the heterogeneity indices (I²: 0%, χ²: 2.79, df: 4, P = .59).

Figure 2.

Forest plot for the primary outcome: change in body weight.

Primary outcome: change in lean body mass or skeletal mass

Only 2 studies (132 patients) were included in the analysis for change in lean body mass or skeletal mass. Figure 3 shows that there is no significant difference in the change in lean body mass or skeletal mass among patients in the intervention group compared to the control group (MD: 2.05, 95% CI: −0.55 to 4.66; ƶ: 1.54, P = .12). A random effects model was used because it was noted that the inter- and intra-study variation was high as evidenced by the heterogeneity indices (I²: 78%, τ²: 2.83, P = .03). There was significant variation between the two studies due to their relatively small but different sample sizes.

Figure 3.

Forest plot for the primary outcome: change in lean body mass or skeletal mass.

Secondary outcomes: HRQoL scores (Global Health and physical functioning subscales of the EORTC-QLQ-C30)

Only 2 studies (132 patients) measured HRQoL as their secondary outcome. In terms of the change in the Global Health subscale of the EORTC-QLQ-C30 tool, patients who received omega-3 fatty acids have higher scores compared to the control group. The mean difference was statistically significant at 14.40 (95% CI: 9.22-19.59, ƶ: 5.44, P < .01). The random effects model was used because there was a high degree of inter- and intra-study variation as seen by the heterogeneity indices (I²: 84%, τ²: 11.87, P < .01).

Similarly, the change in the Physical Functioning subscale scores was also significantly different between the intervention and control groups (MD: 10.38, 95% CI: 8.50-12.27, ƶ: 10.78, P < .01). The fixed effects model was used because there was a low level of heterogeneity (I²: 25%, χ²: 1.34, P: .25) between the studies included. Figures 4 and 5 show the forest plots for the secondary outcomes, Global Health and Physical Functioning subscales of the EORTC-QLQ-C30, respectively.

Figure 4.

Forest plot for the secondary outcome: HRQoL score (Global Health Subscale of the EORTC-QLQ-C30).

Figure 5.

Forest plot for the secondary outcome: HRQoL score (Physical Functioning Subscale of the EORTC-QLQ-C30).

Discussion

Main Findings/Results of the Study

The aim of this meta-analysis is to evaluate the effect of omega-3 fatty acids supplementation in the change in weight, lean body mass or skeletal mass, and HRQoL scores in patients with advanced NSCLC and cancer cachexia. In summary, this meta-analysis shows a significant difference in the weight and HRQoL scores (Global Health and Physical Functioning subscales of the EORTC-QLQ-C30) among patients with advanced NSCLC and cancer cachexia, favoring the omega-3 fatty acids group. However, the association of change in lean body mass or skeletal mass and omega-3 fatty acids supplementation is not statistically significant (MD: 2.05, 95% CI: −0.55 to 4.66; ƶ: 1.54, P = .12).

What This Study Adds

One study found to be similar to our meta-analysis was the Cochrane review done by Dewey et al but this included studies involving patients with any incurable or advanced cancer type (not just NSCLC) with cachexia.¹ In addition, this review by Dewey et al focused on oral fish oil supplementation containing EPA alone, not DHA or both. The primary outcomes were weight gain, body composition, and median survival. The secondary outcomes were functional or performance status, improvement in quality of life, energy expenditure, reduction in fatigue, nutritional status, compliance rates, side effects, and adverse events. In the 2 trials included in the meta-analysis by Dewey et al that investigated change in body weight, there was no significant benefit of EPA for weight gain versus the matched active treatment control (P = .63). For lean body mass, 2 included trials showed no statistically significant difference for patients in the EPA treatment arm compared with those in the placebo arm or matched active treatment control arm (P = .88). For quality of life, the included trials provided no evidence to suggest that quality of life in the EPA arm was significantly improved compared with that of the control arm (P = .45). In contrast, our meta-analysis adds that there are significant differences in change in weight and HRQoL scores, particularly Global Health and Physical Functioning subscales, in favor of the omega-3 fatty acids group. Possible explanations for the differences in the findings of the review by Dewey et al and our meta-analysis are the different participants included (all advanced cancer types versus NSCLC only), including EPA + DHA in our meta-analysis (not just EPA), and the inclusion of more recent trials published after 2007.

Another study similar to our meta-analysis is the systematic review and meta-analysis of 14 randomized controlled trials published by Delpino and Figueiredo.¹⁸ Although the authors of this review also included EPA or DHA as the intervention, they included randomized trials of patients of all cancer types (i.e., pancreatic, gastrointestinal, lung, head and neck, and breast) and stages whereas we focused on patients with advanced NSCLC and cancer cachexia. They investigated the effects of omega-3 supplementation on lean body mass, body mass index (BMI), and body weight but did not include HRQoL in their outcomes. Their analyses showed a statistically significant effect on body weight but not lean body mass or BMI. Similarly, our findings also showed a significant effect on weight but not lean body mass. Importantly, this suggests that the effects of omega-3 supplementation on body weight and lean body mass of patients with cancer cachexia may not be influenced by cancer type and that patients of any cancer type can derive benefit from this intervention in terms of weight increase.

Strengths and Weaknesses/Limitations of the Study

Overall completeness and applicability of evidence

Supplementation with omega-3 fatty acids can be recommended for patients with advanced NSCLC and cancer cachexia because of the benefits in weight gain and improvement in HRQoL, specifically Global Health and Physical Functioning, as shown by the results of this meta-analysis. Omega-3 fatty acids are commonly available as over-the-counter soft gelatin capsule preparations and are incorporated into some ONS preparations. It is also generally well-tolerated and safe.¹

The included studies were sufficient to address the objectives of this review. However, it should be noted that only 2 studies (Murphy et al and Sanchez-Lara et al) were included for the outcome change in lean body mass or skeletal mass. Similarly, only 2 studies (van der Meij et al and Sanchez-Lara et al) were included for the analysis of the secondary outcomes (Global Health and Physical Functioning subscales of the EORTC-QLQ-C30). It is possible that this meta-analysis would have shown different results if more studies were available for inclusion in the analysis of these outcomes.

Quality of the evidence

Except for Murphy et al which was an open-label, non-randomized trial, all the other included studies were randomized controlled trials. There was low heterogeneity between estimates of effect from the included studies for the primary outcome, change in body weight, and the secondary outcome, HRQoL score (Physical Functioning Subscale). The high heterogeneity observed in the other 2 outcomes can be explained by the relatively small but different sample sizes of the included studies.

Another limitation of the selected trials was the lack of a uniform definition for the comparison treatment (i.e., no intervention, standard of care) and the outcomes examined (i.e., percentage weight change, relative change in weight; varying presentation of results such as mean, median, standard error, interval estimate). The selected trials also included patients who are and are not undergoing chemotherapy. It was also noted that there is still a lack of available literature regarding the intervention, and the included studies have relatively small sample sizes that may have affected the precision of the results. Furthermore, the low number of studies and their small sample sizes included in our analyses could have led to reduced statistical power and may not have detected a true effect or difference. This also introduced a limitation in representativeness and generalizability especially since we only included trials on NSCLC. As such, our findings may not be applicable to other populations such as patients with other cancer types.

Potential biases in the review process

A methodical approach for the identification and selection of studies, data collection, and data analysis was followed to ensure a high degree of internal and external validity. Relevant studies, both published and unpublished, were searched using sensitive search strategies in several databases. Manual searching and cross-checking of the references were also done. Data on the primary and secondary outcomes were taken from the studies identified. Authors of the included studies were contacted for missing data, if necessary.

Conclusions

Among patients with advanced NSCLC and cancer cachexia, supplementation with omega-3 fatty acids leads to a significant increase in weight and HRQoL scores but not in change in lean body mass or skeletal mass.

Implications for Practice

Omega-3 fatty acids, which are widely available worldwide and safe, can be recommended for patients with advanced NSCLC and cancer cachexia because of their benefit to weight gain and improvement in HRQoL.

Implications for Research

Because this meta-analysis included advanced NSCLC patients with and without ongoing chemotherapy, further investigation is needed to explore the differences in the effect of omega-3 fatty acids in these 2 groups of patients. Furthermore, because of its immune-modulating effects, the possible effects on patients with NSCLC who have received or are currently receiving immunotherapy can also be explored. In terms of outcomes, other outcomes that can be investigated include the effects of omega-3 fatty acids on survival, reduction in symptoms like fatigue, compliance rates, and adverse effects. The effects of this intervention on other cancer types and the potential benefit or harm when this intervention is combined with other supportive measures like appetite enhancers or steroids can also be explored. Overall, this meta-analysis has revealed that there is still a paucity of clinical trials exploring the possible beneficial effects of omega-3 fatty acids in cancer patients.

Supplemental Material

sj-docx-1-ict-10.1177_15347354241275052 – Supplemental material for Omega-3 Fatty Acids Increase Weight and Quality of Life Scores in Patients With Advanced Non-Small Cell Lung Cancer and Cancer Cachexia: A Meta-Analysis

Supplemental material, sj-docx-1-ict-10.1177_15347354241275052 for Omega-3 Fatty Acids Increase Weight and Quality of Life Scores in Patients With Advanced Non-Small Cell Lung Cancer and Cancer Cachexia: A Meta-Analysis by Alfredo V. Chua, Aylmer Rex B. Hernandez, Marvin Jonne L. Mendoza and Michael D. San Juan in Integrative Cancer Therapies

Footnotes

Acknowledgements

The authors acknowledge the help of Alvin Duke R. Sy, MPH, RN for his help with the data analysis and presentation of results.

Authorship

AVC and MDSJ conceived the study topic and design. Literature search was done by AVC, ARBH, and MJLM. Data analysis was performed by AVC and ARBH. AVC, ARBH, and MJLM assessed the methodological quality of the included studies. The first draft of the manuscript was written by AVC. All authors commented on previous versions of the manuscript and revised as needed. MDSJ provided comments and valuable inputs throughout the entire process. All authors read and approved the final manuscript for submission.

Data Management and Sharing

The data that support the findings of this study are available from the corresponding author, AVC, upon reasonable request.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Research Ethics and Patient Consent

The University of the Philippines Manila Research Ethics Board (UPMREB) confirmed this study to be exempt from ethical review based on the criteria for exemption in the National Ethical Guidelines from Health and Health-related Research 2017 (provision 3.1, page 38), that is, “protocols that neither involve human participants nor identifiable human tissue, biological samples, and data (e.g., meta-analysis protocols).”

ORCID iD

Alfredo V. Chua

Supplemental Material

Supplemental material for this article is available online.

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Finocchiaro

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