Effect of Vitamin D3 Supplements on Development of Advanced Cancer: A Secondary Analysis of the VITAL Randomized Clinical Trial 作者：Paulette D. Chandler, Wendy Y. Chen, Oluremi N. Ajala, Aditi Hazra, Nancy Cook, Vadim Bubes, I-Min Lee, Edward L. Giovannucci, Walter Willett, Julie E. Buring, JoAnn E. Manson, VITAL Research Group 摘要：ImportanceEpidemiologic and trial data suggest that vitamin D supplementation may reduce metastatic cancer and cancer mortality, reflecting shared biological pathways.ObjectiveTo follow up on the possible reduction in cancer death in the Vitamin D and Omega-3 Trial (VITAL) with an evaluation of whether vitamin D reduces the incidence of advanced (metastatic or fatal) cancer and an examination possible effect modification by body mass index.Design, Setting, and ParticipantsVITAL is a randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial of vitamin D3(cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d). This multicenter clinical trial was conducted in the United States; participants included men aged 50 years or older and women aged 55 years or older who were free of cancer and cardiovascular disease at baseline. Randomization took place from November 2011 through March 2014, and study medication ended on December 31, 2017. Data for this secondary analysis were analyzed from November 1, 2011, to December 31, 2017.InterventionsVitamin D3(cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d) supplements.Main Outcomes and MeasuresFor the present analysis, the primary outcome was a composite incidence of metastatic and fatal invasive total cancer, because the main VITAL study showed a possible reduction in fatal cancer with vitamin D supplementation and effect modification by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) for total cancer incidence reduction for individuals with normal BMI, but not for individuals with overweight or obesity. Secondary analyses included examination of BMI (<25, 25 to < 30, and ≥30) as effect modifiers of the observed associations.ResultsAmong 25 871 randomized VITAL participants (51% female; mean [SD] age, 67.1 [7.1] years), 1617 were diagnosed with invasive cancer over a median intervention period of 5.3 years (range, 3.8-6.1 years). As previously reported, no significant differences for cancer incidence by treatment arm were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D compared with placebo (226 of 12 927 assigned to vitamin D [1.7%] and 274 of 12 944 assigned to placebo [2.1%]; HR, 0.83 [95% CI, 0.69-0.99];P = .04). When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI<25: HR, 0.62 [95% CI, 0.45-0.86]) but not among those with overweight or obesity (BMI 25-<30: HR, 0.89 [95% CI, 0.68-1.17]; BMI≥30: HR, 1.05 [95% CI, 0.74-1.49]) (P = .03 for interaction by BMI).Conclusions and RelevanceIn this randomized clinical trial, supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with the strongest risk reduction seen in individuals with normal weight.Trial RegistrationClinicalTrials.gov Identifier:NCT01169259 流行病学研究发现，居住在赤道附近的人，由于长期生活在阳光下，体内产生会更多的维生素D，而且他们某些癌症的发病率和死亡率也比较低。
维生素D是否与癌症风险之间存在关联呢？科学家们也一直在试图确定两者的关系。 在实验室癌细胞研究和动物实验中，发现维生素D能减缓癌症进展。但在人体中进行的研究并没有带来明确答案。2018年结束的VITAL研究发现，维生素D并不能降低癌症发病风险，但随着时间推移，与癌症死亡率下降有关。
近日，来自哈佛医学院布莱根妇女医院（Brigham and Women’s Hospital）的研究人员，对VITAL研究的数据进行了再次分析，并在《美国医学会杂志》子刊JAMA Network Open发表了研究结果。 研究显示，服用维生素D与发生晚期（转移性或致死性）癌症总体风险降低有关，而且体重会对两者之间的关联产生影响。 VITAL研究纳入了美国各地25871名50岁及以上的男性和女性。受试者在加入研究时没有患癌症（非黑色素瘤皮肤癌除外）和心血管疾病史。受试者被分为四组： ·维生素D 2000 IU/天加omega-3鱼油胶囊1克/天
·活性维生素D加omega-3安慰剂
·活性omega-3加维生素D安慰剂
·两种安慰剂 研究人员评估了服用或未服用维生素D补充剂，对晚期癌症发生风险的影响，以及体重指数（BMI）在其中可能起到的调节作用。
在平均5年多的研究期间，共发生500例晚期癌症。其中，12927名服用维生素D补充剂的受试者中，共发生226例（1.7%）；12944名未服用维生素D补充剂的受试者中，共发生274例（2.1%）。 调整其他因素影响后，研究发现相比于未服用维生素D补充剂的受试者，服用维生素D补充剂的受试者发生晚期癌症的风险显著降低了17%。 而且这种关联在体重正常（BMI＜25）的受试者中更明显。相比于未服用维生素D补充剂、体重正常的受试者，服用维生素D补充剂、体重正常的受试者发生晚期癌症的风险显著降低了38%；发生转移性癌症的风险降低了37%；发生致死性癌症的风险降低了42%。而在超重（25≤BMI＜30）和肥胖（BMI≥30）的受试者中，并未发现这种关联。 研究人员分析，维生素D可能抑制癌变和减缓肿瘤进展，包括促进细胞分化、抑制癌细胞增殖以及抗炎、免疫调节、促凋亡和抗血管生成等作用，降低肿瘤侵袭性和转移倾向，进而降低癌症死亡率。而超重、肥胖与慢性、低度炎症和自然杀伤细胞（NK）功能的系统性失调有关，可能会削弱维生素D补充剂的效果。
研究通讯作者、哈佛大学布莱根妇女医院预防医学部Paulette D. Chandler博士表示：“研究结果表明，维生素D可能降低发生晚期癌症的风险。维生素D是一种补充剂，容易获得，价格低廉，已经使用和研究了几十年。我们的发现，尤其是在体重正常的个体中观察到的显著风险降低，提供了关于维生素D和晚期癌症之间关系的新证据。” 不过，研究人员也提醒道，虽然有研究显示癌症患者维生素D缺乏率高达72%，但在服用维生素D补充剂时，应咨询医务人员，确认自己是否缺乏，并遵循他们的建议，切勿自行服用，以免带来不良伤害。
参考资料 [1] Paulette D. Chandler, et al.,(2020). Effect of Vitamin D3 Supplements on Development of Advanced Cancer A Secondary Analysis of the VITAL Randomized Clinical Trial. JAMA Netw Open, DOI: 10.1001/jamanetworkopen.2020.25850.
[2] Vitamin D supplements may reduce risk of developing advanced cancer. Retrieved Nov 2 ,2020,from https:///news/2020-11-vitamin-d-supplements-advanced-cancer.html
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