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Relation
T. Akiba, T. Morikawa, M. Odaka, et al. Vitamin D supplementation and survival of patients with non-small cell lung cancer: a randomized, double-blind, placebo-controlled trial. (Link removed). 2018;24(17):4089-4097.
Draft
Double-blind placebo-controlled study
Participant
The study, conducted in Tokyo, Japan, included 155 patients aged 20 to 75 who had undergone surgery for non-small cell lung cancer (NSCLC). Patients who were already taking vitamin D were excluded.
intervention
Patients were randomized to receive either 1,200 IU/day vitamin D supplementation (n = 77) or placebo (n = 78) for 1 year postoperatively and were followed for a median of 3.3 years.
Results
The primary and secondary endpoints were recurrence-free survival (RFS) and overall survival (OS), respectively.
Key insights
Relapses occurred in 40 (28%) and deaths in 24 (17%) of all patients. In the overall study population, no significant difference was found in either RFS or OS in the vitamin D group compared to the placebo group. However, in the subgroup with early-stage adenocarcinomaandwith low (<20 ng/ml) 25-hydroxyvitamin D [25(OH)D] the vitamin D arm showed significantly better 5-year RFS (86% vs. 50%,P=0.04) and OS (91% vs. 48%,P=0.02) than the placebo group.
Among the polymorphisms examined, the genotypes DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG were markers for a better prognosis, even with multivariate adjustment.
Clinical implications
These results do not support the commonly held belief that more vitamin D is better in all cancer patients and that all patients should take high doses. Instead, these results suggest that we should test vitamin D in all NSCLC patients and supplement those that are low, below 20 ng/ml.
The five-year survival rate of lung cancer patients is very low, ranging from 10% to 30%.1Therefore, anything that could improve these dismal numbers is being investigated, especially if it promises to be low-risk and cost-effective. While the new targeted drugs are gradually improving survival rates, they come with high costs and significant risk. Even with nivolumab, which was announced as a major breakthrough,2The 5-year survival rate is still estimated at only 16%.3.4According to a group that has studied the high cost of cancer drugs,5Between 2000 and 2015, the average price of new cancer drugs rose from $5,000 to $10,000 per year to over $120,000 per year.6So if vitamin D has even a tiny benefit, it could improve the current standard of care.
In this study, vitamin D made no difference in the overall population of NSCLC patients, but it made a significant difference in patients who had low vitamin D concentrations at the start of the study.
Vitamin D is a naturally produced hormone formed in skin that has been exposed to sunlight. It can also be consumed through food or as a dietary supplement. The liver converts vitamin D into its active form 25(OH)D. This chemical is used as a marker of vitamin D concentration in the blood. It is primarily “activated” by the kidneys to produce 1,25-dihydroxyvitamin D. [1,25-(OH)2D]. However, most tissues as well as most cancers also convert 25(OH)D to the 1,25(OH)2D form. The vitamin D receptor is a nuclear receptor that regulates genes within the cell. Theoretically, vitamin D prevents cancer relapse by inhibiting cell proliferation, angiogenesis, and metastasis while inducing apoptosis.7
Over a decade ago, Zhou et al reported that the time of year a patient undergoes surgery for lung cancer affects long-term survival. Patients who had surgery in the summer, when vitamin D levels in the body are likely to be higher, survived longer. The authors examined the joint effects of surgical season and vitamin D supplement use and found that those who underwent surgery in the summer and had the highest vitamin D intake had a better RFS (adjusted risk ratio [HR]: 0.33; 95% confidence interval [CI]: 0.15-0.74) than patients who had winter surgery with the lowest vitamin D intake; The 5-year RFS rate was 56% (34%-78%) for the summer/high-intake surgery group and 23% (4% to 42%) for the winter-low-intake surgery group.8
While such prospective studies report that higher 25(OH)D levels are associated with better survival, these were all observational studies. Therefore, there was a need for a double-blind, placebo-controlled study to determine whether 25(OH)D deficiency plays a causal role. This is the first interventional study attempting to address this question.
In this study, vitamin D made no difference in the overall population of NSCLC patients, but it made a significant difference in patients who had low vitamin D concentrations at the start of the study.
Based on these results, it is advisable to test vitamin D status in all NSCLC patients and to supplement at least those patients whose levels are low, below 20 ng/mL. Setting a limit to what is considered appropriate can prove controversial; There appears to be no risk in increasing serum concentrations higher, so many will argue to use a value higher than 20 ng/ml to select patients in which to initiate treatment. In this study, patients in the experimental group received 1,200 IU of vitamin D3per day.