Exploratory outcomes of the DHA WIN randomized controlled trial: Supplementing women with docosahexaenoic acid did not reduce the impact of neoadjuvant breast cancer chemotherapy on quality of life or exercise behaviour

TL;DR

A study found that taking DHA supplements did not improve quality of life or exercise habits in breast cancer patients undergoing chemotherapy.

Contribution

This study is the first to explore DHA supplementation's impact on quality of life and exercise behavior in breast cancer patients receiving neoadjuvant chemotherapy.

Findings

DHA supplementation did not significantly improve quality of life or exercise behavior during chemotherapy.

Aerobic exercise volume and resistance training frequency decreased significantly over time, regardless of DHA.

Meeting exercise guidelines did not correlate with better quality of life during treatment.

Abstract

Supplementation of omega-3 (n-3) polyunsaturated fatty acids has been associated with reduced side effects and improved quality of life (QoL) in breast cancer patients receiving chemotherapy. The current study reports secondary outcomes from the DHA WIN randomized controlled trial which was designed to evaluate docosahexaenoic acid (DHA) supplementation (4.4 g/day) in conjunction with six cycles of neoadjuvant chemotherapy (NAC) (3 weeks/cycle) in women with non-metastatic breast cancer (n = 49). The objective of the current study was to assess the effects of DHA supplementation on QoL and exercise behaviour in women undergoing NAC for breast cancer. Self-administered questionnaires were used to measure QoL and exercise behaviour before starting chemotherapy (baseline), before each chemotherapy cycle (exercise), and after completing chemotherapy. DHA supplementation did not significantly affect QoL, aerobic exercise volume or resistance training frequency during treatment. However, mean aerobic exercise volume was significantly lower at week 12 (-53.5 minutes/week; 95% CI, -100.5 to -6.3; p = 0.02) and week 18 (-70.8 minutes/week; 95% CI, -123.0 to -18.6; p = 0.01) compared to baseline. Mean resistance training frequency was lower at week 12 (-0.57 times/week; 95% CI, -1.0 to -0.13; p = 0.02) compared to baseline. Meeting exercise guidelines during chemotherapy was not associated with better QoL. In the current exploratory study, QoL and exercise decreased during treatment regardless of DHA supplementation, highlighting the need for supportive care and potential therapies that may mitigate these declines in breast cancer patients receiving NAC. Adequately powered studies are needed to determine if DHA supplementation improves these two indices of health. The trial is registered at ClinicalTrials.gov (NCT03831178).

Figures

Flow of participants through the DHA WIN RCT. Abbreviations: Docosahexaenoic acid (DHA), Docosahexaenoic acid for Women with Breast Cancer in the Neoadjuvant Setting (DHA WIN), randomized controlled trial (RCT).

Weekly aerobic exercise volume over time for the DHA and placebo groups combined (n = 42). Error bars represent 95% confidence intervals. Generalized estimating equations were used to test statistical significance of differences within and between treatment groups. Models were adjusted for age, BMI and baseline aerobic exercise level. Each week was compared to baseline using unadjusted multiple comparisons. *Indicates statistically significantly different from baseline at p ≤ 0.03. Week 0 indicates baseline. Week 18 indicates the end of chemotherapy. Abbreviations: Docosahexaenoic acid (DHA), body mass index (BMI).

Weekly resistance training frequency over time for the DHA and placebo groups combined (n = 42). Error bars represent 95% confidence intervals. Generalized estimating equations were used to test statistical significance of differences within and between treatment groups. Models were adjusted for age, BMI and baseline resistance training exercise frequency. Each week was compared to baseline using unadjusted multiple comparisons. *Indicates statistically significantly different from baseline at p ≤ 0.03. Week 0 indicates baseline. Week 18 indicates the end of cycle 6. Abbreviations: Docosahexaenoic acid (DHA), body mass index (BMI).

Full text

Introduction

An estimated 2.3 million women were diagnosed with breast cancer in 2022, making it the second most common cancer worldwide [1]. Neoadjuvant chemotherapy (NAC) is used to treat women with early-stage, operable breast cancer to improve surgical resection outcomes [2]. NAC is more frequently prescribed to patients with more aggressive subtypes including triple-negative breast cancer and HER2 + breast cancer [3,4]. Treatment for non-metastatic breast cancer frequently involves preoperative (neoadjuvant) systemic chemotherapy prior to surgical removal of the tumour [4]. Health-related quality of life (QoL) considers how disease and treatment affect an individual’s sense of overall function and well-being [5]. QoL has become an important outcome measure and factor in treatment decisions for NAC [6,7]. Chemotherapy treatment is reported to be associated with several physical and psychosocial side effects including nausea, vomiting, fatigue, impaired cognitive function and pain which influence QoL and exercise capacity [6–11]. All of these contribute to reduced treatment tolerability and worse clinical outcomes [12].

Supplementation of omega-3 (n-3) long chain polyunsaturated fatty acids to women receiving other chemotherapy regimens has been reported to result in reduction of some chemotherapy side effects including modulation of inflammatory profiles, reduction of gastrointestinal side effects, maintenance of skeletal muscle and improved neuronal recovery [13]. A recent review by Newell et al. (2021) concluded that supplementation of n-3 long chain polyunsaturated fatty acids in clinical cancer therapy improved overall QoL among patients with various types of cancer [14]. However, these studies did not report on women receiving NAC.

There are currently no specific dietary recommendations for long chain polyunsaturated fatty acids during cancer therapy or survivorship. Our group has demonstrated that feeding diets supplemented with the n-3 long chain polyunsaturated fatty acid, docosahexaenoic acid (DHA), reduces tumour growth and improves the efficacy of chemotherapy [15]. The effects on QoL or exercise capacity have not been studied. Although exercise has been demonstrated to be beneficial for relieving side-effects and improving QoL during chemotherapy [9], there are no clinical recommendations. However, based on the protective effects of exercise on mortality, the World Health Organization (WHO) recommends that cancer survivors do at least 150–300 minutes of moderate-intensity aerobic physical activity per week, as well as muscle strengthening activities two or more days per week [16].

The objective of the current manuscript was to assess the effects of DHA supplementation and NAC on self-reported QoL and exercise behaviour in women undergoing breast cancer treatment. These represent analyses of secondary outcomes from the Docosahexaenoic Acid for Women with Breast Cancer in the Neoadjuvant Setting (DHA WIN) randomized controlled trial [17].

Materials and methods

Setting and participants

The protocol for the DHA WIN RCT including inclusion and exclusion criteria has previously been published [17]. The trial included women with stage I-III non-metastatic breast cancer prescribed neoadjuvant chemotherapy. Participants were recruited by oncologists and clinical trial nurses at the Cross Cancer Institute (Edmonton, Alberta, Canada) and screened for eligibility. The DHA WIN RCT received Health Canada approval (#HC6–24-c220167) and full ethical approval from the Health Research Ethics Board of Alberta - Cancer Committee (HREBA.CC-18–0381) [17]. Written informed consent was obtained prior to individuals’ involvement in the study. The target sample size of 26 participants per treatment arm was determined based on the primary outcome of the trial (change in the Ki67 index in the tumour).

Study design and procedures

The DHA WIN trial was a two-arm, double-blind, phase II RCT designed to investigate the effects of DHA supplementation concomitant with neoadjuvant chemotherapy in women with non-metastatic breast cancer [17]. All women received standard-of-care chemotherapy, which was one of two docetaxel-based neoadjuvant chemotherapy regimens that were used in this population. Each regimen consisted of six cycles of chemotherapy that were administered in 3-week intervals (for a total of 18 weeks). QoL questionnaires were completed at baseline (week 0) and the end of cycle 6 (week 18). Exercise questionnaires were completed at the start of each 3-week cycle, and the end of cycle 6 (week 18). Participants were given paper copies of the questionnaires to complete during clinic visits.

Randomization

Block randomization occurred as previously described [17]. Briefly, a biostatistician generated a patient randomization list and randomized bottle numbers using covariate-adaptive randomization. The randomized bottle list was provided to DSM Nutritional Products for labelling purposes, as well as the unblinded Clinical Trials Coordinator (CTC) and pharmacist. The REDCap database was used to allocate participants to a study arm and provide a unique study identifier by the study coordinator. Pharmacy staff assigned bottle numbers based on treatment arm on the first day of each chemotherapy cycle. The bottle ID was then entered into the REDCap database by the study coordinator. Participants, pathologists, physicians and researchers were all blinded throughout the trial. The CTC, statistician and pharmacist were unblinded. DHA and placebo supplements were identical in size, shape, colour, texture and bottles.

Intervention

Participants were randomized to receive 4.4 g/day of DHA or a placebo supplement [17]. The DHA group received eleven 1 g DHA-enriched, algae-sourced triglyceride oil capsules (life’sDHA S40-O400), while the placebo group received eleven 1 g capsules of a corn/soy oil blend per day (DSM Nutritional Products, Columbia, Maryland, USA). The placebo supplement contained equal amounts of polyunsaturated fatty acids as the DHA supplement, in the form of linoleic acid. Participants were instructed to orally consume the capsules at any time throughout the day, with or without food. The intervention began at the start of the first cycle of chemotherapy and continued throughout chemotherapy treatment. Compliance was determined by a review of the patient dosing diary and the recorded number of any remaining capsules returned at the end of the study.

Assessment of QoL and exercise behaviour

Questionnaires to record QoL and exercise behaviour were given to participants before starting chemotherapy (baseline), before each chemotherapy cycle (exercise), and after completing chemotherapy. Participants were instructed on how to fill these out, but there was not a method used to ensure accuracy of the responses. Cancer-specific QoL and fatigue were assessed using the Functional Assessment of Cancer Therapy (FACT) – General (FACT-G) [18,19], FACT – Breast (FACT-B) [20,21], FACT – Taxane [22,23], FACT – Endocrine Symptoms (FACT-ES) [24,25] and the Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue (FACIT-Fatigue) scales [26,27]. Higher scores indicate better QoL (and less fatigue) among the aforementioned scales. Psychosocial functioning was assessed using the Perceived Stress Scale (PSS) (with higher scores indicating greater stress) [28], the Fordyce Emotions Questionnaire (with higher scores indicating greater happiness) [29], and modified versions of the Center for Epidemiologic Studies-Depression Scale (CES-D) (with higher scores indicating greater depressive symptomology) [30] and the State-Trait Anxiety Inventory (STAI) (with higher scores indicating greater anxiety) [31].

An adapted version of the Godin Leisure-Time Exercise Questionnaire was used to collect information on the frequency and average duration of light, moderate and vigorous aerobic exercise as well as strength/resistance training per week [32,33]. Average weekly aerobic exercise was determined by adding the average minutes of moderate aerobic exercise to two times the average minutes of vigorous aerobic exercise. Aerobic exercise volume and resistance training frequency were averaged (excluding baseline levels) and used to categorize participants on the basis of meeting WHO’s 2020 exercise recommendations (≥ 150 minutes/week aerobic exercise and ≥ 2 times/week resistance training) [16].

Statistical analyses

Descriptive statistics including means (SD) and proportions (frequencies) were used to describe continuous and categorical variables, respectively. Baseline values were compared between groups using the independent t-test for continuous variables and the chi-squared test for categorical variables. Missing samples were completely at random and were therefore excluded from analysis. One participant in the placebo group had no available QoL data at the end of treatment. The legends of Figures 2 and 3 show the fewest number of participants with data, as this number varied at each time point. Analysis of covariance was used to examine the effects of DHA treatment on QoL scores as well as associations between exercise classifications and QoL scores. Generalized estimating equations (GEE) method was used to assess the effects of time and DHA treatment on the average volume of aerobic exercise and average frequency of resistance training. GEE method is used to analyze correlated data and to assess the between and within subject variability for repeated measures data, and provides unbiased parameter estimates and robust standard errors. Time point comparisons were made to the baseline levels of exercise. Both unadjusted and adjusted analyses were conducted. For the adjusted analysis the GEE models were adjusted for age, BMI and baseline value of the outcome. The post hoc analyses were not adjusted for multiple comparisons. Therefore, the results of this study should be interpreted as exploratory. Statistical significance was defined as a two-sided p-value < 0.05. Statistical analyses and creation of figures were conducted using SPSS (V27.0, IBM Corporation, Armonk, New York, USA).

Flow of participants through the DHA WIN RCT. Abbreviations: Docosahexaenoic acid (DHA), Docosahexaenoic acid for Women with Breast Cancer in the Neoadjuvant Setting (DHA WIN), randomized controlled trial (RCT).

*Weekly aerobic exercise volume over time for the DHA and placebo groups combined (n = 42). Error bars represent 95% confidence intervals. Generalized estimating equations were used to test statistical significance of differences within and between treatment groups. Models were adjusted for age, BMI and baseline aerobic exercise level. Each week was compared to baseline using unadjusted multiple comparisons. Indicates statistically significantly different from baseline at p ≤ 0.03. Week 0 indicates baseline. Week 18 indicates the end of chemotherapy. Abbreviations: Docosahexaenoic acid (DHA), body mass index (BMI).

*Weekly resistance training frequency over time for the DHA and placebo groups combined (n = 42). Error bars represent 95% confidence intervals. Generalized estimating equations were used to test statistical significance of differences within and between treatment groups. Models were adjusted for age, BMI and baseline resistance training exercise frequency. Each week was compared to baseline using unadjusted multiple comparisons. Indicates statistically significantly different from baseline at p ≤ 0.03. Week 0 indicates baseline. Week 18 indicates the end of cycle 6. Abbreviations: Docosahexaenoic acid (DHA), body mass index (BMI).

Results

Participant flow and baseline characteristics

Recruitment of participants took place between September 27, 2019 and May 30, 2022. The trial ended in December 2022 when the sample size was obtained. Follow-up assessments are scheduled for 3, 5 and 10 years to assess long term outcomes. Seventy-six participants were randomized to the placebo or DHA intervention, of which 49 (65%) completed the DHA WIN trial (Fig 1). Adherence to the intervention was 78% for the placebo group and 86% for the DHA group (p = 0.26). At baseline, the participant demographics and clinical characteristics did not differ between groups (Table 1).

Table 1: Participant demographic and clinical characteristics.

Changes in QoL of DHA and placebo groups

Table 2 illustrates the QoL scores of participants at baseline (week 0) and the end of chemotherapy (week 18). There was no significant difference in the adjusted mean change between randomized groups for any QoL indicator (Table 2).

Table 2: Quality of life scores at baseline (week 0) and end of chemotherapy (week 18) in the DHA and placebo groups.

Comparing exercise behaviour within and between treatment groups

Dietary treatment did not significantly affect the change in mean weekly aerobic exercise volume (p-interaction = 0.53) or resistance training frequency (p-interaction = 0.15). Therefore, treatment groups were combined to assess changes over time. Overall, mean aerobic exercise was lower at week 12 (-53.5 minutes/week; 95% CI, -100.5 to -6.3; p = 0.02) and week 18 (-70.8 minutes/week; 95% CI, -123.0 to -18.6; p = 0.01) compared to baseline (Fig 2). Mean resistance training frequency was lower at week 12 (-0.57 times/week; 95% CI, -1.0 to -0.13; p = 0.02) compared to baseline (Fig 3).

Changes in QoL grouped by WHO’s exercise recommendations

Fourteen participants (29%) met WHO’s aerobic exercise recommendation, while 35 (71%) did not. Seven participants (14%) met WHO’s resistance training recommendation, while 42 (86%) did not. Differences in the adjusted mean change between the two groups were not statistically significant for any QoL outcome (Tables 3 and 4).

Table 3: Quality of life scores at baseline (week 0) and the end of chemotherapy (week 18) in participants that met (≥ 150 minutes/week) or did not meet (< 150 minutes/week) WHO’s aerobic exercise recommendation on average during chemotherapy.

Table 4: Quality of life scores at baseline (week 0) and the end of chemotherapy (week 18) in participants that met (≥ 2 times/week) or did not meet (< 2 times/week) WHO’s resistance training exercise recommendation on average during chemotherapy.

Discussion

Consistent with the reported negative effects of chemotherapy on QoL [6] and exercise capacity [10], self-reported QoL as well as resistance and aerobic exercise (at 12 weeks) declined with treatment. Meeting WHO’s aerobic or resistance training exercise recommendation was not associated with a better QoL. DHA supplementation during NAC did not reduce the declines in QoL, aerobic exercise volume or resistance training frequency. A recent systematic review examined RCTs and experimental studies that investigated the effects of supplementation or consumption of foods enriched in n-3 fatty acids (300–6000 mg/day) in breast cancer patients that were receiving treatment or were in the follow-up period [34]. The authors concluded that n-3 fatty acid supplementation led to a significant decrease in perceived stress, sleep disturbance, depression, pain, joint stiffness and fatigue. Among the studies reviewed, only one considered QoL among breast cancer patients that were supplemented with n-3 fatty acids during NAC [35]. It consisted of an RCT in which the treatment group received 2.4 g/day of n-3 PUFAs (1.6 g eicosapentaenoic acid (EPA) and 0.8 g DHA) during the six months of chemotherapy. Both groups experienced an increase at three and six months in fatigue, nausea, drowsiness, appetite and dyspnea and there were no significant differences between groups [35]. These findings are consistent with the current study, which reported an increase in fatigue from baseline to the end of chemotherapy, and no difference between the DHA and placebo groups.

An earlier review done by Newell et al. (2021) concluded that supplementation of EPA and DHA during cancer therapy improved overall QoL among patients with various types of cancer [14]. Focusing on breast cancer patients, Martinez et al. (2019) carried out a single arm clinical trial in which patients were supplemented with n-3 fatty acids (1.4 g EPA + DHA), hydroxytyrosol and curcumin for one month during hormonal therapy [36]. The authors observed a 21.5% decrease in patients’ pain score obtained from the brief pain inventory (BPI) after 30 days of treatment. However, Shen et al. (2018) found in an RCT with women undergoing hormonal therapy for breast cancer, supplementation of 3.3 g/day of EPA + DHA for 24 weeks significantly decreased the BPI worst pain scores among obese patients, but there were no differences in treatment arms among non-obese patients [37]. Another RCT supplemented breast cancer patients with 0.2 g EPA and 1.0 g DHA per day for 16 weeks during treatment and one month following treatment, and the authors observed a significant reduction in peripheral neuropathy in the treatment group compared to the control group [38]. The dose, different combinations of EPA and DHA, duration of supplementation, different assessment tools, cancer types and treatments may contribute to the different findings regarding the effects of DHA supplementation on QoL. For example, the breast cancer studies reviewed by Newell et al. (2021) consist of participants receiving hormonal therapy, which may affect patients’ QoL differently than chemotherapy [39].

Aerobic exercise volume and resistance training frequency declined over time in the DHA WIN cohort. Mean aerobic exercise volume was significantly lower at weeks 12 and 18 compared to baseline, while mean resistance training frequency was significantly lower at week 12 compared to baseline. This was expected as other studies have reported a decrease in physical activity following a breast cancer diagnosis and during treatment [40–42]. Nielsen et al. (2020) performed a qualitative evaluation that looked at barriers to physical activity during chemotherapy and identified recurring themes from patient interviews that contributed to this decline in physical activity, including side effects of chemotherapy as well as a need for education about physical activity during treatment [43,44]. Confusion and a perceived lack of guidance from their oncologist were common reasons stated for not performing physical activity during treatment [43]. The results from the current study suggest that there may be critical points during treatment (i.e., weeks 12 and 18) that require additional supportive care to help prevent the decline in patients’ physical activity.

The American College of Sports Medicine (ACSM) produced a roundtable report in 2018 that detailed the type and duration of exercise shown to improve specific cancer-related side effects [45]. They concluded that moderate-intensity aerobic training for a minimum of 30 minutes at least three times per week, for a minimum of 8–12 weeks positively effects health-related outcomes including anxiety, depression, fatigue, QoL and physical function. They also found that resistance training at least twice weekly in addition to the aerobic exercise recommendation resulted in similar benefits to aerobic exercise alone. Overall, the ACSM recommends avoiding inactivity and attaining the current physical activity guidelines for health (150 minutes/week of aerobic exercise and 2 times/week of strength training) [46]. Unlike the conclusions made by ACSM, patients that reported meeting WHO’s aerobic (≥150 minutes/week) or resistance training (≥2 times/week) exercise recommendation did not have improved anxiety, depression or fatigue. These differences may be due, in part, to the fact that few studies that informed the ACSM guidelines were in the neoadjuvant setting [45], which may result in different side effects than the adjuvant setting [6]. Further, only 29% of participants met WHO’s aerobic exercise recommendation, and 14% met the resistance training recommendation, resulting in small group sizes upon stratification. This proportion is similar to the study discussed by Nielsen et al. (2019), in which only 23.3% of the sample reported achieving the recommendation of 150 minutes of moderate to vigorously intense physical activity per week during chemotherapy. The low percentages of cancer survivors meeting these guidelines highlights the need for increased awareness and education, referrals to counseling for physical activity and additional individual and community programs to help patients achieve the recommended levels [47].

There are several strengths with the current study. The DHA WIN clinical trial was the first phase II RCT to supplement DHA during neoadjuvant chemotherapy in women with non-metastatic breast cancer [17]. The DHA and self-administered exercise and QoL questionnaires were cost-effective and resulted in a small respondent burden. Self-administered exercise (Godin Leisure-Time) and QoL (FACT and FACIT) questionnaires used have a low-respondent burden, are cost-effective and have been validated for use in cancer patients [20,33]. The study was also subject to limitations. The DHA WIN RCT was powered to assess changes in the Ki67 index in the tumour [17] and not exercise or QoL. Lack of statistical significance observed for QoL and exercise outcomes may be due, in part, to lack of power to evaluate these secondary outcomes. Therefore, the results can only be interpreted as exploratory and require a larger sample size to make definitive conclusions. For example, the estimated minimal clinically important difference is 4 points for the FACT-General scale [48]. A group sample size of 194 patients would be required to achieve 80% power to detect a difference of 4 points between treatment groups for this scale. Recall and response bias are inherent with self-administered questionnaires [49]. More quantitative techniques should be used to measure exercise in future trials, such as accelerometers, wearable technology and more in-depth questionnaires, as described for other patient populations [50].

In summary, the current exploratory study did not find that DHA supplementation during NAC prevented a decline in QoL or exercise behaviour during treatment. Aerobic and resistance training exercise levels decreased below baseline at various timepoints throughout the trial. Meeting WHO’s aerobic and resistance training exercise guidelines was only achieved by 29% and 14% of the patients, respectively, and was not associated with better QoL. Generally, QoL and exercise decreased throughout the trial, highlighting the need for supportive care and potential therapies that may mitigate these changes in patients receiving cancer treatment. Adequately powered studies are needed to determine if DHA supplementation improves these two indices of health.

Supporting information

S1 FileBaseline Quality of Life Questionnaire.(PDF)

S2 FilePost-intervention Quality of Life Questionnaire.(PDF)

S3 FileDHA-WIN Study Protocol.(DOCX)

S4 FileConsort Checklist.(DOC)