Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials
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...
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| Published in | Ageing research reviews Vol. 87; p. 101923 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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Elsevier B.V
01.06.2023
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| 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 %.
•Systematic review with individual participant data of randomized controlled trials.•Vitamin D3 did not reduce cancer mortality in main meta-analysis of 14 trials.•Vitamin D3 reduced cancer mortality with daily but not with bolus dosing regimen.•Adults aged ≥ 70 years benefited more from daily vitamin D3 than middle-aged adults.•Cancer survival improved when daily vitamin D3 was started before cancer diagnosis. |
|---|---|
| AbstractList | To evaluate the effect of vitamin D
3
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 D
3
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 D
3
therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D
3
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 D
3
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 D
3
administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %. 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 %.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 %. 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 %. •Systematic review with individual participant data of randomized controlled trials.•Vitamin D3 did not reduce cancer mortality in main meta-analysis of 14 trials.•Vitamin D3 reduced cancer mortality with daily but not with bolus dosing regimen.•Adults aged ≥ 70 years benefited more from daily vitamin D3 than middle-aged adults.•Cancer survival improved when daily vitamin D3 was started before cancer diagnosis. |
| ArticleNumber | 101923 |
| Author | Sluyter, John Zhu, Anna Hantunen, Sari Shadyab, Aladdin H. Lee, I.-Min Manson, JoAnn E. Wactawski-Wende, Jean Tuomainen, Tomi-Pekka Chen, Li-Ju Sha, Sha Camargo Jr, Carlos A. Scragg, Robert Brenner, Hermann Kuznia, Sabine Neale, Rachel E. Virtanen, Jyrki K. Voutilainen, Ari Akutsu, Taisuke Cheng, Ting-Yuan David Cook, Nancy R. Urashima, Mitsuyoshi Waterhouse, Mary Schöttker, Ben Buring, Julie E. |
| AuthorAffiliation | d Department of Medicine, Brigham and Women’s Hospital, USA k School of Population Health, University of Auckland, New Zealand l Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA b Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany g Division of Cancer Prevention and Control, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA a Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany o Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Germany h Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland p German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Germany e Harvard Medical School, USA n Network Aging Research (NAR), Heidelberg University, Germany j School of Public Health, University of Queensland, Br |
| AuthorAffiliation_xml | – name: n Network Aging Research (NAR), Heidelberg University, Germany – name: h Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland – name: b Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany – name: p German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Germany – name: e Harvard Medical School, USA – name: g Division of Cancer Prevention and Control, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA – name: m School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA – name: j School of Public Health, University of Queensland, Brisbane, Australia – name: o Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Germany – name: a Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany – name: c Division of Molecular Epidemiology, Jikei University School of Medicine, Japan – name: l Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA – name: f Department of Emergency Medicine, Massachusetts General Hospital, USA – name: k School of Population Health, University of Auckland, New Zealand – name: d Department of Medicine, Brigham and Women’s Hospital, USA – name: i Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia |
| Author_xml | – sequence: 1 givenname: Sabine surname: Kuznia fullname: Kuznia, Sabine organization: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany – sequence: 2 givenname: Anna surname: Zhu fullname: Zhu, Anna organization: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany – sequence: 3 givenname: Taisuke surname: Akutsu fullname: Akutsu, Taisuke organization: Division of Molecular Epidemiology, Jikei University School of Medicine, Japan – sequence: 4 givenname: Julie E. surname: Buring fullname: Buring, Julie E. organization: Department of Medicine, Brigham and Women's Hospital, USA – sequence: 5 givenname: Carlos A. surname: Camargo Jr fullname: Camargo Jr, Carlos A. organization: Harvard Medical School, USA – sequence: 6 givenname: Nancy R. surname: Cook fullname: Cook, Nancy R. organization: Department of Medicine, Brigham and Women's Hospital, USA – sequence: 7 givenname: Li-Ju surname: Chen fullname: Chen, Li-Ju organization: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany – sequence: 8 givenname: Ting-Yuan David surname: Cheng fullname: Cheng, Ting-Yuan David organization: Division of Cancer Prevention and Control, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA – sequence: 9 givenname: Sari surname: Hantunen fullname: Hantunen, Sari organization: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland – sequence: 10 givenname: I.-Min surname: Lee fullname: Lee, I.-Min organization: Department of Medicine, Brigham and Women's Hospital, USA – sequence: 11 givenname: JoAnn E. surname: Manson fullname: Manson, JoAnn E. organization: Department of Medicine, Brigham and Women's Hospital, USA – sequence: 12 givenname: Rachel E. surname: Neale fullname: Neale, Rachel E. organization: Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia – sequence: 13 givenname: Robert surname: Scragg fullname: Scragg, Robert organization: School of Population Health, University of Auckland, New Zealand – sequence: 14 givenname: Aladdin H. surname: Shadyab fullname: Shadyab, Aladdin H. organization: Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA – sequence: 15 givenname: Sha surname: Sha fullname: Sha, Sha organization: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany – sequence: 16 givenname: John surname: Sluyter fullname: Sluyter, John organization: School of Population Health, University of Auckland, New Zealand – sequence: 17 givenname: Tomi-Pekka surname: Tuomainen fullname: Tuomainen, Tomi-Pekka organization: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland – sequence: 18 givenname: Mitsuyoshi surname: Urashima fullname: Urashima, Mitsuyoshi organization: Division of Molecular Epidemiology, Jikei University School of Medicine, Japan – sequence: 19 givenname: Jyrki K. surname: Virtanen fullname: Virtanen, Jyrki K. organization: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland – sequence: 20 givenname: Ari surname: Voutilainen fullname: Voutilainen, Ari organization: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland – sequence: 21 givenname: Jean surname: Wactawski-Wende fullname: Wactawski-Wende, Jean organization: School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA – sequence: 22 givenname: Mary surname: Waterhouse fullname: Waterhouse, Mary organization: Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia – sequence: 23 givenname: Hermann surname: Brenner fullname: Brenner, Hermann organization: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany – sequence: 24 givenname: Ben surname: Schöttker fullname: Schöttker, Ben email: b.schoettker@dkfz.de organization: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany |
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| Copyright | 2023 Elsevier B.V. Copyright © 2023 Elsevier B.V. All rights reserved. |
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| Keywords | Systematic review Vitamin D Individual patient-data Survival Mortality Cancer |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 All authors meet the ICMJE criteria for authorship as follows: BS and SK are the guarantors of the systematic review, therefore, are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. BS conceived and designed the base of the systematic review and all analyses. SK searched the literature, collected data and was responsible for data management as well as author contact. SK and BS conducted all the meta-analyses. SK drafted the manuscript, which BS revised critically for important intellectual content. All authors made substantial contributions to the interpretation of the findings, the discussion and approved the final version to be published. However, we would like to note that Rachel Neale and Mary Waterhouse agree with results and interpretation of the main cancer mortality findings. However, they have concerns about the interpretation of the subgroup analyses relating to studies using a daily dosing regimen, in light of the lack of significant interaction and the small sample size in some subgroups. Further, they would not have included analyses of cancer survival as they do not believe the design of the trials included is appropriate for this outcome; thus they would like to dissociate themselves from these aspects. Authors’ contribution |
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