Vitamin D Supplementation and Survival of Patients with Non–small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

Akiba, Tadashi; Morikawa, Toshiaki; Odaka, Makoto; Nakada, Takeo; Kamiya, Nobuo; Yamashita, Makoto; Yabe, Mitsuo; Inagaki, Takuya; Asano, Hiroaki; Mori, Shiro; Tsukamoto, Yo; Urashima, Mitsuyoshi

doi:10.1158/1078-0432.ccr-18-0483

Cited by 81 publications

(67 citation statements)

References 31 publications

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“…This finding can be attributed to the fact that adenocarcinoma subtype is associated with a poorer prognosis than the squamous cell carcinoma. [19] The decrease in vitamin D levels which is inversely associated with an increase in clinical stage at the time of diagnosis also supports the findings of Wang et al [20] In their study, Akiba et al [21] compared patients with NSCLC who received vitamin D replacement for one year after tumor surgery with the placebo group and found no significant difference than general population in terms of progression-free survival (PFS) and overall survival (OS); however, they observed a significant increase in the PFS and OS rates with vitamin D replacement in the early-stage adenocarcinoma patients. The most recent meta-analysis of 17 prospective cohort studies involving 139,000 patients also suggested that high serum vitamin D levels played a role in the prevention of lung cancer.…”

Section: Discussionsupporting

confidence: 70%

Clinical Significance of Serum 25-Hydroxyvitamin D Levels in Non-Small Cell Lung Cancer

Değirmencioğlu

Tanrıverdi

Oktay

et al. 2019

EJMO

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ed deaths worldwide and non-small cell lung cancer (NSCLC) comprising a variety of histological subtypes such as adenocarcinoma, squamous-cell carcinoma, large-cell carcinoma and bronchoalveolar carcinoma accounts for 80% of all patients with lung cancer. [1] The use of tobacco and tobacco products is among the leading risk factors with proven association with lung cancer, although various environmental and dietary factors have been also implicated. [2] In recent years, there is a growing evidence from epidemi-Objectives: Lung cancer is the most common cause of cancer-related deaths worldwide. The use of tobacco and tobacco products is among the leading risk factors with proven association with lung cancer, although various environmental and dietary factors have been also implicated. Vitamin D deficiency has been identified as a poor prognostic factor in advanced stage colon cancer and breast cancer. The aim of the present study was to compare 25-hydroxyvitamin D [25(OH)D] levels between patients with non-small cell lung cancer (NSCLC) at the time of diagnosis and healthy controls and to evaluate the differences in serum 25(OH)D levels across the subgroups and stages of NSCLC. Methods: A total of 462 patients with NSCLC who were followed and treated in three participating centers were compared retrospectively with and age-and sex-matched 462 healthy controls who underwent testing for serum calcium, lactate dehydrogenase (LDH), magnesium, phosphorus, creatinine, and vitamin D levels in the between January 2016 and June 2018. The patients with NSCLC were further classified according to the histological subtype. Results: The mean age was 63.46±8.86 years. The patient group was composed of 58 females (12.6%) and 404 males (87.4%). Serum 25(OH)D, calcium, LDH, and magnesium levels were significantly different between the patient and the control group (p=0.0001, p=0.0001, p=0.0001, p=0.0001, respectively). Among patients with NSCLC, serum 25(OH) D was significantly lower in patients with adenocarcinoma subtype than in patients with squamous-cell carcinoma subtype (p=0.001). There was a significant correlation between advanced stage with decreased serum 25(OH)D and increased LDH levels (p=0.0001, p=0.0001, respectively). Conclusion: The study is the most extensive study in our region in terms of the number of participating patients. Demonstration of a difference in serum 25(OH)D levels between histological subtypes also contributes to the literature.

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Section: Discussionsupporting

confidence: 70%

Clinical Significance of Serum 25-Hydroxyvitamin D Levels in Non-Small Cell Lung Cancer

Değirmencioğlu

Tanrıverdi

Oktay

et al. 2019

EJMO

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“…A similar RCT that included 155 patients found that 1200 IU/d of vitamin D supplementation did not improve relapse-free survival or overall survival of patients with non-small cell lung cancer. 23 However, a meta-analysis of 64 observational studies with a total of 44 165 patients with cancer found higher 25(OH)D levels to be associated with better progression-free and overall survival. 24 In addition, a meta-analysis of individual participant data from 8 cohort studies in Europe and the United States found higher cancer mortality in patients in the lowest quintiles of 25(OH)D levels among people with a history of cancer.…”

Section: Discussionmentioning

confidence: 99%

Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers

Urashima

Ohdaira

Akutsu

et al. 2019

JAMA

Self Cite

114

131

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IMPORTANCE Randomized clinical trials of vitamin D supplementation for secondary prevention in patients with cancer are needed, given positive results of observational studies. OBJECTIVE To determine whether postoperative vitamin D 3 supplementation can improve survival of patients with digestive tract cancers overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. DESIGN, SETTING, AND PARTICIPANTS The AMATERASU trial, a randomized, double-blind, placebo-controlled trial conducted at a single university hospital in Japan. Enrollment began in January 2010 and follow-up was completed in February 2018. Patients aged 30 to 90 years with cancers of the digestive tract from the esophagus to the rectum, stages I to III, were recruited. Of 439 eligible patients, 15 declined and 7 were excluded after operation. INTERVENTIONS Patients were randomized to receive oral supplemental capsules of vitamin D (2000 IU/d; n = 251) or placebo (n = 166) from the first postoperative outpatient visit to until the end of the trial. MAIN OUTCOMES AND MEASURES The primary outcome was relapse-free survival time to relapse or death. The secondary outcome was overall survival time to death due to any cause. Subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/mL, 20 to 40 ng/mL, and greater than 40 ng/mL; because of small sample size for the highest-baselinelevel group, interactions were tested only between the low-and middle-baseline-level groups. RESULTS All 417 randomized patients (mean age, 66 years; male, 66%; esophageal cancer, 10%; gastric cancer, 42%; colorectal cancer, 48%) were included in the analyses. There was 99.8% follow-up over a median 3.5 (interquartile range, 2.3-5.3) years, with maximal follow-up of 7.6 years. Relapse or death occurred in 50 patients (20%) randomized to vitamin D and 43 patients (26%) randomized to placebo. Death occurred in 37 (15%) in the vitamin D group and 25 (15%) in the placebo group. The 5-year relapse-free survival was 77% with vitamin D vs 69% with placebo (hazard ratio [HR] for relapse or death, 0.76; 95% CI, 0.50-1.14; P = .18). The 5-year overall survival in the vitamin D vs placebo groups was 82% vs 81% (HR for death, 0.95; 95% CI, 0.57-1.57; P = .83). In the subgroup of patients with baseline serum 25(OH)D levels between 20 and 40 ng/mL, the 5-year relapse-free survival was 85% with vitamin D vs 71% with placebo (HR for relapse or death, 0.46; 95% CI, 0.24-0.86; P = .02; P = .04 for interaction). Fractures occurred in 3 patients (1.3%) in the vitamin D group and 5 (3.4%) in the placebo group. Urinary stones occurred in 2 patients (0.9%) in the vitamin D group and 0 in the placebo group. CONCLUSIONS AND RELEVANCE Among patients with digestive tract cancer, vitamin D supplementation, compared with placebo, did not result in significant improvement in relapse-free survival at 5 years.

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“…Flow diagram of search strategy and trial exclusion with specific reasons is shown in Figure 1. Using predefined search terms, 786 potentially relevant articles were identified, and only ten articles were eligible for inclusion in this meta-analysis [13][14][15][16][25][26][27][28][29][30], corresponding to ten randomized controlled trials and a total of 81362 study participants. All eligible trials reported data on cancer incidence, and seven (including 77653 study participants) of them reported data on cancer mortality.…”

Section: Eligible Trialsmentioning

confidence: 99%

Meta-analysis of randomized controlled trials on vitamin D supplement and cancer incidence and mortality

Zhang

Niu

2019

Bioscience Reports

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Objectives:We aimed to meta-analyze the results of published randomized controlled trials to test the hypothesis that low vitamin D supplement is associated with an increased risk of cancer incidence and mortality. Methods: Randomized controlled trials that explored the association between vitamin D supplement and cancer incidence or mortality as primary outcomes were identified through searching the PubMed and EMBASE. Literature search and data extraction were performed independently and in duplicate. Results: Ten randomized controlled trials pooled in 81362 participants. The incidence rate of cancer was 9.16% (3716 cases) and 9.29% (3799 cases) in vitamin D intervention group and placebo group, respectively, resulting in a nonsignificant relative risk (RR) (95% confidence interval (95% CI)) of 0.99 (0.94-1.03) (P=0.532). The mortality rate of cancer was 2.11% (821 cases) and 2.43% (942 cases) in vitamin D intervention group and placebo group, respectively, resulting in a significant reduction in risk (RR = 0.87, 95% CI: 0.79-0.95, P=0.003). There was no observable heterogeneity or publication bias. Subgroup analyses revealed that history of cancer, extra use of vitamin D and calcium supplement were potential sources of heterogeneity. Conclusions: Our findings support a beneficial effect of vitamin D supplement on lowering cancer mortality, especially in subpopulations with no history of cancer, extra use of vitamin D, or calcium supplement.

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Vitamin D Supplementation and Survival of Patients with Non–small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

Cited by 81 publications

References 31 publications

Clinical Significance of Serum 25-Hydroxyvitamin D Levels in Non-Small Cell Lung Cancer

Clinical Significance of Serum 25-Hydroxyvitamin D Levels in Non-Small Cell Lung Cancer

Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers

Meta-analysis of randomized controlled trials on vitamin D supplement and cancer incidence and mortality

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