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Meta-Analysis
. 2023 Jun:87:101923.
doi: 10.1016/j.arr.2023.101923. Epub 2023 Mar 31.

Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials

Sabine Kuznia  1 , Anna Zhu  1 , Taisuke Akutsu  2 , Julie E Buring  3 , Carlos A Camargo Jr  4 , Nancy R Cook  3 , Li-Ju Chen  5 , Ting-Yuan David Cheng  6 , Sari Hantunen  7 , I-Min Lee  3 , JoAnn E Manson  3 , Rachel E Neale  8 , Robert Scragg  9 , Aladdin H Shadyab  10 , Sha Sha  1 , John Sluyter  9 , Tomi-Pekka Tuomainen  7 , Mitsuyoshi Urashima  2 , Jyrki K Virtanen  7 , Ari Voutilainen  7 , Jean Wactawski-Wende  11 , Mary Waterhouse  12 , Hermann Brenner  13 , Ben Schöttker  14
Affiliations
Meta-Analysis

Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials

Sabine Kuznia et al. Ageing Res Rev. 2023 Jun.

Abstract

To evaluate the effect of vitamin D3 supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86-1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78-0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91-1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D3 therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D3 supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D3 did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Keywords: Cancer; Individual patient-data; Mortality; Survival; Systematic review; Vitamin D.

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Conflict of interest statement

Declaration of Competing Interest All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years except for Julie E. Buring who declares an association to Pharmavite. All authors further declare no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig. 1.
Fig. 1.
Flow diagram of study selection. Abbreviations: CENTRAL Cochrane Central Register of Controlled Trials; CDSR Cochrane Database of Systematic Reviews; IPD individual patient data; KSR Kleijnen Systematic Reviews Ltd; Ti/Ab title/abstract.
Fig. 2.
Fig. 2.
Meta-analysis of all included RCTs comparing vitamin D3 and placebo for the outcome “cancer mortality”.
Fig. 3.
Fig. 3.
Subgroup analyses of vitamin D3 supplementation and cancer mortality by duration of intervention, health status, region, dose and regimen in all trials. Note: The FIND study appears twice in the subgroup analysis towards dose. The treatment arm with 1600 IU counted towards moderate dose and the one with 3200 IU counted towards high dose.
Fig. 4.
Fig. 4.
IPD meta-analyses of RCTs comparing vitamin D3 and placebo for the outcome “cancer mortality” in the general population (panel A) and for the outcomes “overall and cancer-specific survival” in cancer patients (panel B and C). Note: Unadjusted results are shown. The adjusted results are almost identical (Supplementary tables 8, 10 and 11).
Fig. 5.
Fig. 5.
IPD subgroup analyses of vitamin D3 supplementation and cancer mortality in the general population by age, sex, BMI, ethnicity, vitamin D baseline level, cancer diagnosis in five years prior baseline, and adherence in all trials (panel A, main analysis) and restricted to trials with a daily dosing regimen (panel B, post-hoc analysis). Note: No studies available for “Cancer diagnosis up to 5 years prior baseline” = yes.
Fig. 6.
Fig. 6.
IPD subgroup analyses of vitamin D3 supplementation and cancer-specific survival in the cancer population by age, sex, BMI, ethnicity, vitamin D baseline level, adherence, cancer stage, cancer site, time of cancer diagnosis in all trials (panel A, main analysis) and restricted to trials with a daily dosing regimen (panel B, post-hoc analysis).
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