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Post-Diagnosis use of Antioxidant Vitamin Supplements and Breast Cancer Prognosis: A Systematic Review and Meta-Analysis

  • Yong Li
    Affiliations
    Department of Breast surgery, Jiangmen Hospital of Sun Yat-Sen University, Jiangmen, Guangdong, P.R. China
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  • Qimou Lin
    Affiliations
    Department of Breast surgery, Jiangmen Hospital of Sun Yat-Sen University, Jiangmen, Guangdong, P.R. China
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  • Xiaoju Lu
    Affiliations
    Department of Critical Care Medicine, Jiangmen People`s Hospital, Jiangmen People`s Hospital, Jiangmen, Guangdong, P.R. China
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  • Weiwen Li
    Correspondence
    Address for correspondence: Weiwen Li, BSc, Department of Breast Surgery, Jiangmen Hospital of Sun Yat-Sen University, No. 23, Haibang St., Beijie, Jiangmen, Guangdong, P.R. China, 529030
    Affiliations
    Department of Critical Care Medicine, Jiangmen People`s Hospital, Jiangmen People`s Hospital, Jiangmen, Guangdong, P.R. China
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Open AccessPublished:September 12, 2021DOI:https://doi.org/10.1016/j.clbc.2021.09.001

      Highlights

      • Antioxidant vitamin supplements can be safely used by breast cancer survivors
      • Post-diagnosis vitamin C intake can benefit overall survival in breast cancer
      • Concern in guideline might limit post-diagnosis antioxidant use and efficacy

      Abstract

      Antioxidant vitamin supplements (AVSs) are widely used among breast cancer survivors. Whether post-diagnosis use of AVSs would impair cancer survival is unclear. To assess the association between breast cancer survival and post-diagnosis AVSs use. We performed a literature search using PubMed, Cochrane Library, and Embase from their inception to October 1, 2020. Studies that investigated the association between breast cancer survival and post-diagnosis AVS use included. The AVSs included 1 or more of the following: vitamin A, C, or E. The meta-analysis included 8 studies with 17,062 patients. There was no significant difference between AVS use or not after diagnosis (HR 0.92, 95% CI 0•82–1•03) or during chemotherapy (HR 1.15, 95% CI 0.78–1.68) in overall survival (OS). Whenever during chemotherapy or after diagnosis, AVS users had a worse prognosis in the later studies. There was no significant inverse association between post-diagnosis vitamin A or E supplements use and OS. Vitamin C intake after breast cancer diagnosis was significantly associated with better OS (HR 0.84, 95% CI 0.76–0.93). Our findings suggest that post-diagnosis AVSs use would not worsen breast cancer survival, while vitamin C use after diagnosis might benefit OS. The discrepancy of survivals associated with post-diagnosis AVS use between earlier and later studies may cast doubt on the recommendation on guidelines. RCTs with large sample sizes are needed.

      Keywords

      Introduction

      Breast cancer is the most common malignancy and the second leading cause of cancer-related death among females.
      • Siegel RL
      • Miller KD
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      Cancer statistics.
      Breast cancer survivors reported a higher prevalence of dietary supplement use than other cancer types.
      • Du M
      • Luo H
      • Blumberg JB
      • et al.
      Dietary Supplement Use among Adult Cancer Survivors in the United States.
      However, because of emerging reports on the detrimental effects of dietary supplements on cancer survival, there has been some advice against taking supplements during and after treatment given by many cancer experts.
      • Rock CL
      • Doyle C
      • Demark-Wahnefried W
      • et al.
      Nutrition and physical activity guidelines for cancer survivors.
      Antioxidant vitamin supplements (AVSs), which mainly included vitamin A, vitamin C, vitamin E, were commonly used supplements with reports ranging from 17.5% to 81%.
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      ,
      • Jung AY
      • Cai X
      • Thoene K
      • et al.
      Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy.
      • Wang H
      • Gao Z
      • Liu X
      • et al.
      Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance.
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      Given the prevalence of AVS use after diagnosis in breast cancer, it is necessary to clarify whether AVSs are harmful to breast cancer survival.
      Meanwhile, breast cancer has shown improved survival owing to cancer screenings and comprehensive treatment strategies, including radiotherapy and chemotherapy. Chemotherapy and radiotherapy exert an antitumor effect through producing reactive oxygen species (ROS),7, 8 which can be neutralized by antioxidants. There exists a concern that the use of supplemental antioxidants during treatment could reduce treatment efficacy. A randomized controlled trial (RCT) reported that head and neck cancer patients who received radiation therapy concurrent with vitamin E and β-carotene had poorer overall survival.
      • Bairati I
      • Meyer F
      • Jobin E
      • et al.
      Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients.
      However, another RCT showed that radiotherapy combined with antioxidants increased survival for patients with stage IIIB non-small-cell lung cancer.
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      • Ugur I
      • Altundag K.
      Effect of concomitant use of pentoxifylline and alpha-tocopherol with radiotherapy on the clinical outcome of patients with stage IIIB non-small cell lung cancer: a randomized prospective clinical trial.
      There has been little agreement on whether post-diagnosis antioxidants could interfere with cancer survival. Even the evidence of several existing guidelines is insufficient on this issue.
      • Rock CL
      • Doyle C
      • Demark-Wahnefried W
      • et al.
      Nutrition and physical activity guidelines for cancer survivors.
      ,

      World Cancer Research Fund/American Institute for Cancer Research. Diet, nutrition, physical activity and cancer: a global perspective. Washington, DC: AICR. 2018; Available at: https://www.wcrf.org/sites/default/files/Summary-of-Third-Expert-Report-2018.pdf.doi.

      ,
      • Huebner J
      • Follmann M.
      Complementary medicine in guidelines of the German Guideline Program in Oncology: comparison of the evidence base between complementary and conventional therapy. [email protected]
      To date, there have been few RCT studies on this issue in breast cancer. Much of the existing studies regarding this question are controversial. Therefore, we conducted a systematic review to assess the association between breast cancer survival and post-diagnosis AVS use.

      Methods

      The systematic review was registered with PROSPERO CRD42020200821 (https://www.crd.york.ac.uk/PROSPERO/). The meta-analysis presented according to the PRISMA
      • Moher D
      • Liberati A
      • Tetzlaff J
      • Altman DG.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      and MOOSE
      • Stroup DF
      • Berlin JA
      • Morton SC
      • et al.
      Meta-analysis of Observational Studies in Epidemiology A Proposal for Reporting.
      statement.

      Study Eligibility and Identification

      We performed a literature search using PubMed, Cochrane Library, and Embase from inception to October 1, 2020, according to the predetermined inclusion and exclusion criteria, and covered publications in the English language. Search terms included ‘Breast Neoplasms’, ‘Antioxidants’, ‘Dietary Supplements’, ‘Survival or Recurrence’, and associated search terms. The search strategies were adapted for each electronic database (see Supplemental Tables 1–3). Two reviewers independently analyzed all potentially relevant studies, and discrepancies were resolved by consensus. The same method was also used for quality assessment and data extraction. The quality of cohort or retrospective studies would be checked by Newcastle Ottawa Scale (NOS) analysis, which was based on the following 3 subscales: selection (4 items), comparability (1 item), and outcome (3 items). Studies scoring 8 to 9 would be considered to be of high quality; 6 to 7 would be considered to be of medium quality.

      Inclusion and Exclusion Criteria

      Studies were included if they met the following criteria: (1) They investigated the association of prognosis and post-diagnosis intake of AVSs. The AVSs included 1 or more of the following: vitamin A, vitamin C, vitamin E. Selenium (Se), and Zinc (Zn) were not antioxidant but also included for their important role in antioxidant enzyme; (2) The outcome of interest was overall survival (OS), breast cancer-specific survival (BCSS) or disease-free survival (DFS). Referent group was defined as nonusers of the AVS of interest or, the lowest category among the studies which compared the highest to lowest category. (3) They reported adjusted hazard risks (HRs) with their corresponding 95% confidence intervals (CI) and detailed adjustment variables. Since our purpose was to assess the association between breast cancer survival and post-diagnosis intake of AVSs, studies that investigated the association between breast cancer prognosis and plasma level of antioxidant vitamin, or antioxidant vitamin administered intravenously were excluded. Editorials, case reports, letters to the editor, review articles, and other studies with insufficient information for data extraction were excluded.

      Data Extraction

      The following data were extracted (1) first author's name; (2) year of publication; (3) sample size; (4) study location; (5) characteristics of the participants; (6) design of study; (7) type of AVS; (8) the maximally adjusted HR and corresponding 95% CI; (9) adjustment variables.
      The primary outcomes of interest were OS, BCSS, or DFS in patients intaking AVSs after diagnosis and those in patients using AVSs during chemotherapy. The secondary outcome was the association between OS and post-diagnosis individual AVS intake.

      Statistical Analysis

      The random-effects model was used after exploring the causes of heterogeneity. Otherwise, the fixed-effects model was used.
      • Lau J
      • Ioannidis JP
      • Schmid CH.
      Quantitative synthesis in systematic reviews.
      Statistical heterogeneity was calculated using Cochrane's Q statistic and the I2 statistic, and it was considered significant when p less than 0.1. Subgroup analysis and sensitivity analysis were performed to dissect the heterogeneity. Funnel plot asymmetry with Begg`s and Egger`s tests was used to evaluate the publication bias. A 2 tailed P value of less than 0.05 was considered statistically significant. Statistical analyses were performed using RevMan5.3 software (Cochrane Collaboration, Copenhagen, Denmark) and Stata 12.0 (Stata Corporation, College Station, Texas, USA).

      Results

      A total of 2166 search results were obtained using the predefined search strategy. After title and abstract screening, 46 articles remained. 37 studies were excluded for different reasons (Figure 1).

      Study Characteristics

      A total of 8
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      • Greenlee H
      • Kwan ML
      • Kushi LH
      • et al.
      Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort.
      • Jung AY
      • Cai X
      • Thoene K
      • et al.
      Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy.
      ,
      • Harris HR
      • Bergkvist L
      • Wolk A.
      Vitamin C intake and breast cancer mortality in a cohort of Swedish women.
      • Poole EM
      • Shu X
      • Caan BJ
      • et al.
      Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project.
      • Harris HR
      • Orsini N
      • Wolk A.
      Vitamin C and survival among women with breast cancer: a meta-analysis.
      • Inoue-Choi M
      • Greenlee H
      • Oppeneer SJ
      • Robien K.
      The association between postdiagnosis dietary supplement use and total mortality differs by diet quality among older female cancer survivors.
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      studies involving 17,062 patients met our inclusion criteria and were included in the review. One study was conducted in China,
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      2 studies in Europe,
      • Jung AY
      • Cai X
      • Thoene K
      • et al.
      Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy.
      ,
      • Harris HR
      • Bergkvist L
      • Wolk A.
      Vitamin C intake and breast cancer mortality in a cohort of Swedish women.
      and other studies were from the US. No RCT study was found, and all included studies were prospective cohort studies. We obtained some unpublished data from 2
      • Poole EM
      • Shu X
      • Caan BJ
      • et al.
      Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project.
      ,
      • Harris HR
      • Orsini N
      • Wolk A.
      Vitamin C and survival among women with breast cancer: a meta-analysis.
      meta-analyses. One
      • Harris HR
      • Orsini N
      • Wolk A.
      Vitamin C and survival among women with breast cancer: a meta-analysis.
      of these 2 meta-analyses provided the unpublished data on the association of post-diagnosis vitamin C use and overall mortality in the After Breast Cancer Pooling Project (ABCPP). The ABCPP was a consortium of 4 prospective studies: the Shanghai Breast Cancer Survival Study (SBCSS), the Life After Cancer Epidemiology (LACE) Study, the Women's Healthy Eating and Living (WHEL) Study, and the Nurses’ Health Study (NHS). Another meta-analysis
      • Poole EM
      • Shu X
      • Caan BJ
      • et al.
      Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project.
      included was a meta-analysis based on the individual patient data of ABCPP. The study characteristics, regional distribution, type of administrated AVSs, quality scoring, and other details for each study were shown in Table 1. Given the difference of definition, we modified previous designs and did not assess DFS as the endpoints.
      Table 1Characteristics of the included studies
      StudyStudy type/ Breast cancer cases/ Media follow-upPopulationCountryType of AVSfrequency /durationOutcomes of interestYear of diagnosis, rangeQuality
      Harris 2013Prospective cohort Swedish Mammography Cohort (SMC) n = 717 follow-up: 7.8 yearswomen diagnosed with invasive breast cancerSwedenvitamin Cnot mentionedOS, BCSS19977
      Poole 2013a consortium of 4 prospective studies After Breast Cancer Pooling Project (ABCPP) n = 12019 follow-up: 4.2-10.7 yearsNot mentionedChina and USAvitamin C, vitamin E, multivitaminsNot mentionedOS, BCSS, RecurrenceNHS: 1976 WHEL: 1991 LACE: 1997 SBCSS: 2002NA
      Nechuta 2010Prospective cohort Shanghai Breast Cancer Survival Study (SBCSS) n = 4877 follow-up: 4.1 yearswomen firstly diagnosed with invasive breast cancer and aged 20 to 75 yearsChinavitamin C, vitamin E, multivitamins.any use/any durationOS, BCSS, Recurrence20028
      Greenlee 2011Prospective cohort Life After Cancer Epidemiology (LACE) n = 2264 follow-up: 8.3 yearsearly stage, primary breast cancer (stage I [>1 cm], stage II, or stage IIIA); ages 18 to 79 years at diagnosisUSAvitamin C, vitamin E, selenium, zinc, combination carotenoids, beta-carotene, lycopene, multivitamins>1 day per weekOS, BCSS, Recurrence19978
      Choi 2014Prospective cohort Iowa Women's Health Study (IWHS) n = 969 follow-up: 6.1 yearsolder women with no history of cancer, invasive breast cancerUSAvitamin C, vitamin E, vitamin A, selenium, zincnot mentionedOS19867
      Jung 2019Prospective cohort Mamma Carcinoma Risk Factor Investigation (MARIE) n = 2223 follow-up: 6.0 yearspostmenopausal female with invasive, nonmetastatic breast cancerGermanyvitamin C, vitamin E, vitamin A, selenium, zinc, multivitamin>3 times per week/> 1yearOS, BCSS, DFS20029
      Christine 2019Prospective cohort Diet, Exercise, Lifestyle and Cancer Prognosis (DELCaP) n = 1134 follow-up: 8.1 yearshigh-risk pathologic stage I to III breast cancerUSAvitamin C, vitamin A, vitamin E, carotenoids, coenzyme Q10>1 time per weekOS, DFS20139
      AVS = anti-oxidant supplement; BCSS = breast cancer specific survival; OS = overall survival; NA = not applicable.

      Primary Outcomes

      survival and post-diagnosis AVSs use

      Six
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      • Greenlee H
      • Kwan ML
      • Kushi LH
      • et al.
      Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort.
      • Jung AY
      • Cai X
      • Thoene K
      • et al.
      Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy.
      ,
      • Harris HR
      • Bergkvist L
      • Wolk A.
      Vitamin C intake and breast cancer mortality in a cohort of Swedish women.
      ,
      • Poole EM
      • Shu X
      • Caan BJ
      • et al.
      Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project.
      ,
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      studies with a total sample size of 16,015 assessed the association between breast cancer survival and post-diagnosis AVSs use. One study
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      was from China`s population, other studies were from Europe or the United States. The prevalence of post-diagnosis AVSs use in the ABCPP study was 57.8%, and much higher than the other studies.
      Five studies
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      ,
      • Jung AY
      • Cai X
      • Thoene K
      • et al.
      Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy.
      ,
      • Harris HR
      • Bergkvist L
      • Wolk A.
      Vitamin C intake and breast cancer mortality in a cohort of Swedish women.
      ,
      • Poole EM
      • Shu X
      • Caan BJ
      • et al.
      Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project.
      ,
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      examined post-diagnosis antioxidant vitamins supplement intake and OS (16,105 cases and 1946 deaths). DELCaP study
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      evaluated the association in 2 separate population cohorts, a cohort with the administration of AVS(s) both before and during chemotherapy and a cohort only during chemotherapy. Both cohorts were adopted for data synthesis. DELCaP study was used in the same way in all our subsequent synthesis and analysis. Figure 2A showed that there was no significant difference between AVS use or not in OS (HR 0.92, 95% CI 0•82–1•03), with moderate between-study heterogeneity (P = .16; I² = 36%). no publication bias was detected by Begg's test (P = .26) (Egger's test, P = .24).
      Figure 2
      Figure 2A: Meta-analysis of OS compared any AVS use group versus non-AVS use group after breast cancer diagnosis; B: Forest plot for subgroup analyses by study period (exclude SBCSS study)
      As showed in Table 1, the frequency and duration of use in included studies were broad and vague. It was difficult to assess how frequency, durations, and type of AVS affect heterogeneity. However, these factors could be varied by the lifestyle of study location and different periods. Therefore, we next analyzed whether location or period was the source of heterogeneity.
      To make a further analysis, we excluded the SBCSS study because of different populations. We performed a subgroup analysis according to the year of study starting recruitment (earlier studies and later studies). We chose the year 2001 as a time point because a guideline from the American Cancer Society mentioned that antioxidant vitamins should be prudently used during the treatment in that year.
      • Brown J
      • Byers T
      • Thompson K
      • Eldridge B
      • Doyle C
      • Williams AM.
      Nutrition during and after cancer treatment: a guide for informed choices by cancer survivors.
      Subgroup analysis could decrease the heterogeneity. Pooled earlier studies showed post-diagnosis AVS use borderline benefited OS (HR 0.85, 95% CI 0.72–1.00). The heterogeneity came from the study period (Figure 2B).
      Four studies
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      ,
      • Jung AY
      • Cai X
      • Thoene K
      • et al.
      Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy.
      ,
      • Harris HR
      • Bergkvist L
      • Wolk A.
      Vitamin C intake and breast cancer mortality in a cohort of Swedish women.
      ,
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      examined post-diagnosis AVSs intake and BCSS (12,958 cases and 1049 deaths). The summary HR (95% CIs) was not statistically significant (HR 1.00, 95% CI 0.75–1.32), with significant between-study heterogeneity (P = .03; I² = 66%) (Figure 3A). We used STATA 12.0 to conduct sensitivity analysis for every study to determine the influence of individual studies on the results and detected the MARIE study as the main source of heterogeneity. When omitting the MARIE study, post-diagnosis AVSs intake was also associated with a borderline significant reduction of BCSS (HR 0.86,95% CI 0.74 –1.00) (Figure 3B). No publication bias was detected by Begg's test (P = .73) (Egger's test, P = .35).
      Figure 3
      Figure 3A: Meta-analysis of BCSS compared any AVS use group versus non-AVS use group after breast cancer diagnosis; B: Sensitivity analysis for BCSS in post-diagnosis AVS use

      Survival and AVSs use during chemotherapy

      Four studies
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      • Greenlee H
      • Kwan ML
      • Kushi LH
      • et al.
      Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort.
      • Jung AY
      • Cai X
      • Thoene K
      • et al.
      Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy.
      ,
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      reported the association between breast cancer survival and AVSs use during chemotherapy. HRs in 3 studies
      • Greenlee H
      • Kwan ML
      • Kushi LH
      • et al.
      Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort.
      ,
      • Jung AY
      • Cai X
      • Thoene K
      • et al.
      Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy.
      ,
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      were adjusted for radiotherapy. Although the total sample size was 6123, the number of participants who chose AVSs during chemotherapy in the MARIE and DELCaP study was only 70 and 200 separately.
      Three studies
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      ,
      • Jung AY
      • Cai X
      • Thoene K
      • et al.
      Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy.
      ,
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      examined AVS use during chemotherapy and total mortality. Pooling the data of the 3 studies showed that there was no significant difference between AVS use or not during chemotherapy (HR 1.15, 95% CI 0.78–1.68), with high between-study heterogeneity (P = •05; I² = 62%). When omitting the SBCSS study, AVSs intake during chemotherapy was associated with a statistically significant reduction of OS (HR 1.39,95% CI 1.01–1.91). No publication bias was detected by Begg's test (P = .73) (Egger's test, P = .17).
      Two studies
      • Jung AY
      • Cai X
      • Thoene K
      • et al.
      Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy.
      ,
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      examined AVS use during chemotherapy and BCSS. The summary HR showed that there was no significant difference for AVS use or not (HR 1.18, 95% CI 0.50–2.82), with high between-study heterogeneity (P = •03; I² = 80%). Because of the low number of studies, no further analyses were carried out.

      Secondary Outcomes

      Vitamin A supplements and OS

      A total of 3 studies
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      ,
      • Poole EM
      • Shu X
      • Caan BJ
      • et al.
      Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project.
      ,
      • Inoue-Choi M
      • Greenlee H
      • Oppeneer SJ
      • Robien K.
      The association between postdiagnosis dietary supplement use and total mortality differs by diet quality among older female cancer survivors.
      examined post-diagnosis vitamin A supplement use and overall survival. There was no significant inverse association between post-diagnosis vitamin A supplement use and OS in breast cancer (HR 1.06, 95% CI 0.80–1.41), with moderate between-study heterogeneity (P = .22; I² = 33%) (Figure 4). No publication bias was detected by Begg's test (P = .31) (Egger's test, P = .39).
      Figure 4
      Figure 4Meta-analysis of overall survival compared vitamin A, vitamin C and vitamin E use group versus non-use group after breast cancer diagnosis

      Vitamin C supplements and OS

      A total of 6 studies
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      ,
      • Greenlee H
      • Kwan ML
      • Kushi LH
      • et al.
      Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort.
      ,
      • Harris HR
      • Bergkvist L
      • Wolk A.
      Vitamin C intake and breast cancer mortality in a cohort of Swedish women.
      ,
      • Harris HR
      • Orsini N
      • Wolk A.
      Vitamin C and survival among women with breast cancer: a meta-analysis.
      • Inoue-Choi M
      • Greenlee H
      • Oppeneer SJ
      • Robien K.
      The association between postdiagnosis dietary supplement use and total mortality differs by diet quality among older female cancer survivors.
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      reported the association between post-diagnosis vitamin C supplement use and overall survival from 7 cohort studies. Figure 4 showed that vitamin C intake after breast cancer diagnosis was significantly associated with reduced overall mortality (HR 0.84, 95% CI 0.76–0.93), with low between-study heterogeneity (P = .66; I² = 0%). Neither Begg's funnel plot nor Egger's test indicated the existence of publication bias. (Begg's test, P = .31; Egger's test, P = .39).

      Vitamin E supplements and OS

      Three studies
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      ,
      • Poole EM
      • Shu X
      • Caan BJ
      • et al.
      Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project.
      ,
      • Inoue-Choi M
      • Greenlee H
      • Oppeneer SJ
      • Robien K.
      The association between postdiagnosis dietary supplement use and total mortality differs by diet quality among older female cancer survivors.
      examined post-diagnosis vitamin E supplement use and overall survival. No significant difference was found (HR 0.94, 95% CI 0.79–1.13), with low between-study heterogeneity (P = .30; I² = 18%) (Figure 4). No publication bias was detected by Begg's test (P = .73) (Egger's test, P = .29).

      Quality of Included Studies and Sensitivity analysis

      Four studies were of high quality (NOS score > 7), 2 studies were of moderate quality (NOS score 7) (Table 2). Since some studies mentioned in the 2 meta-analyses were not published, we could not assess their quality. We performed sensitivity analysis by excluding the low-quality studies (NOS < 6) or studies without assessment. Only outcomes with 3 studies or more were included for sensitivity analysis. There was no change in the significance of any of the results (Table 3).
      Table 2Risk of bias summary for each included prospective cohort studies using the Newcastle-Ottawa Scale
      SelectionComparabilityOutcome
      StudyRepresentativeness of the exposed participantsRepresentativeness of the non-exposed participantsAscertainment of AVS supplementDemonstration that outcomes were not present at start of studyComparability of the exposure groups on the basis of the design or analysisAssessment of outcomesWas follow-up long enough for outcomes to occurAdequacy of follow-up of exposure groupsStar total
      MARIE111121119
      IWHS110021117
      SMC111011117
      LACE110121118
      SBCSS111021118
      DELCaP111121119
      Table 3Sensitivity analysis excluding the low‐quality studies
      Outcomes of interestStudies.No.HR (95% CI)P valueStudy heterogeneity
      Chi2dfI2P value
      Primary outcomes
      OS and post-diagnosis AVSs use50.97 (0.83, 1.13)0.666.95442%0.14
      BCSS and post-diagnosis AVSs use31.09 (0.65, 1.83)0.748.59277%0.01
      Secondary outcomes
      Vitamin C supplements and OS60.84 (0.73, 0.97)0.025.0160%0.41
      Vitamin E supplements and OS30.91 (0.71, 1.17)0.473.51243%0.17

      Discussion

      The results of this meta-analysis on over 17,000 breast cancer survivors showed that post-diagnosis use of antioxidant vitamin supplements (AVSs) was not associated with overall mortality. Vitamin C supplement intake after diagnosis was statistically significantly associated with a reduced risk of total mortality.
      Although we only selected the maximally adjusted HRs from cohort studies for pooling analyses, there had substantial heterogeneity. We searched the source of heterogeneity through subgroup analyses and found the study period the source of heterogeneity. In contrast to the later studies, the earlier studies indicated that post-diagnosis AVS use portended a better prognosis. With the increasing concern antioxidant might affecting the efficacy of treatment and impairs patient survival,
      • Rock CL
      • Doyle C
      • Demark-Wahnefried W
      • et al.
      Nutrition and physical activity guidelines for cancer survivors.
      ,
      • Brown J
      • Byers T
      • Thompson K
      • Eldridge B
      • Doyle C
      • Williams AM.
      Nutrition during and after cancer treatment: a guide for informed choices by cancer survivors.
      ,
      • Brown JK
      • Byers T
      • Doyle C
      • et al.
      Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices.
      fewer patients use antioxidant supplements during treatment, especially in high-risk breast cancer. On on hand, post-diagnosis AVS users were 58.3% in ABCPP, but 20.1% in MARIE and 17.6% in DELCaP.
      • Ambrosone CB
      • Zirpoli GR
      • Hutson AD
      • et al.
      Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).
      In addition, among them in ABCPP, more than half took more than 2 AVSs. Participants in earlier studies might take multiple AVSs more frequently for a longer duration. As shown in ABCPP, multiple AVS users had better overall survival,
      • Poole EM
      • Shu X
      • Caan BJ
      • et al.
      Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project.
      while breast cancer survivors intaking AVSs frequently or for more than 3 months significantly reduced the risk of mortality.
      • Greenlee H
      • Kwan ML
      • Kushi LH
      • et al.
      Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort.
      ,
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      On the other hand, confounding due to adherence to treatments is another possible explanation for the worse prognosis among post-diagnosis AVS users in later studies. Physician recommendations and participants in later studies were more prudent to choose AVSs during treatment. Near 80% of pre-diagnosis AVS users stop use AVSs after breast cancer diagnosis in S0221. However, a substantial number of patients still used antioxidants for mitigating the complications caused by conventional treatment, although ingested antioxidants may have little effect on it. A survey study contemporary with DELCaP and MARIE studies showed that more than a quarter of patients used complementary and alternative medicine (CAM) during oncology therapy to alleviate the side effects of treatment.
      • Molassiotis A
      • Fernández-Ortega P
      • Pud D
      • et al.
      Use of complementary and alternative medicine in cancer patients: a European survey.
      A present multicenter cross-sectional study in Southern and Northern Germany showed 70.4% of breast patients wanted to reduce the side effects of conventional therapy with CAM.
      • Grimm D
      • Mathes S
      • Woelber L
      • et al.
      Demand for integrative medicine among women with breast and gynecological cancer: a multicenter cross-sectional study in Southern and Northern Germany. Archives of gynecology and obstetrics.
      These patients were generally more likely to interrupt tumor therapy than non-AVS users because of the side effects of treatment. Therefore, Patients in DELCaP and MARIE study who chose to take AVSs may have poorer adherence to adjuvant chemotherapy or other treatments, which could be associated with poorer survival outcomes.
      We combined the studies which evaluated the associations of survival outcome with AVSs use during chemotherapy. The results showed no statistically significant effect but with high heterogeneity. The SBCSS study was the source of heterogeneity. When we excluded the SBCSS study, the results indicated concurrent AVSs use with chemotherapy worsened overall survival. Apart from the previously mentioned reasons, there may be 2 other reasons. Firstly, the SBCSS study was a prospective cohort study in China population. Dietary and lifestyle factors differed between populations. Secondly, few patients taking antioxidants during chemotherapy in DELCaP and MARIE studies may reduce power to detect statistical differences or lead to non-functional and spurious associations. Another interesting and initially confusing comparison was that those studies with a high rate of AVS use during chemotherapy had better prognoses.
      • Greenlee H
      • Kwan ML
      • Kushi LH
      • et al.
      Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort.
      ,
      • Nechuta S
      • Lu W
      • Chen Z
      • et al.
      Vitamin supplement use during breast cancer treatment and survival: a prospective cohort study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research.
      The implication that patients could benefit from AVS use during chemotherapy is inconsistent with existing guidelines. But, given the low number of existed studies and small sample size, we consider that the evidence for recommendations against AVS using during chemotherapy in breast cancer is insufficient.
      In this study, we also analyzed how individual antioxidants impact the prognosis of breast cancer. Post-diagnosis use of vitamin C improved overall survival, while vitamin A and vitamin E were not associated with total death. The present findings were compatible with those of other meta-analyses.
      • Harris HR
      • Orsini N
      • Wolk A.
      Vitamin C and survival among women with breast cancer: a meta-analysis.
      ,
      • He J
      • Gu Y
      • Zhang S.
      Vitamin A and Breast Cancer Survival: A Systematic Review and Meta-analysis.
      ,
      • Kanellopoulou A
      • Riza E
      • Samoli E
      • Benetou V.
      Dietary Supplement Use after Cancer Diagnosis in Relation to Total Mortality, Cancer Mortality and Recurrence: A Systematic Review and Meta-Analysis.
      Furthermore, our study had higher reliabilities than the previous studies. Firstly, Hazard ratios (HR), risk ratios (RR), and odds ratios (OR) were considered equivalent for data combining in these studies, but we only extracted adjusted HR for analysis. Secondly, compared to diet alone, the type and amounts of antioxidants from supplements could be more easily recorded or recalled. Studied on post-diagnosis intake of vitamin antioxidants from diet only were not considered in our meta-analysis. It could reduce bias and measurement error in the administration of food frequency questionnaires. But 1 thing still needs to be pointed out any included study could not adjust for all healthy lifestyle behaviors. Vitamin C use could be a surrogate for an overall healthy lifestyle, therefore correlating with improved OS.
      All of the included studies were prospective cohort studies with strict inclusion and exclusion criteria. However, several limitations should be mentioned. First, the number of studies was small despite the large sample size, which would weaken the value of summary HR. Second, there was heterogeneity in terms of design among our included studies. These studies came from different regions or countries with different life and dietary habits. These variations would add complexity in comparing and summarizing the results. Third, when the number of studies included in a meta-analysis is less than 10, both Egger`s test and Begg`s test have relatively lower power. Hence, the publication bias may not be detected by Egger`s and Begg`s tests. Forth, duration and type of AVS, as well as subtype and staging of breast cancer, in included studies were broad and vague. We failed to assess how these factors affect heterogeneity. Finally, this study was limited to studies published in the English language only. Thus, the possibility of publication bias cannot be excluded.
      To our knowledge, it was the first systematic review and meta-analysis examining the association between post-diagnosis of AVS use and breast cancer outcomes. Evidence is presented, which shows that post-diagnosis AVSs use did not worsen overall survival, and vitamin C use after breast cancer diagnosis could benefit overall survival. The discrepancy of survivals associated with post-diagnosis AVS use between earlier and later studies may cast doubt on the recommendation on guidelines. Currently, the quality of evidence in recommendations on CAM is low, and sources of evidence are weak. Future studies involving high-quality RCT with a large sample size are needed to confirm the results, especially regarding antioxidants administrated during chemotherapy.

      Authors’ contributions

      Study concept and design: Y. Li. and W. Li. Literature selection and quality assessment: W. Li and Lu. Acquisition of data: Lu, Lin and Y. Li. Statistical analysis: Lu, Y. Li. Manuscript editing: Y. Li.
      All authors read and approved the final manuscript.

      Availability of data and materials

      All data is included in the article

      Acknowledgments

      This work is dedicated to the memory of Professor Yi Zhou, our mentor and friend.

      Disclosure

      The authors declare no conflict of interest.

      Appendix. Supplementary materials

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