Reference
Akiba T, Morikawa T, Odaka M, et al. Vitamin D supplementation and survival of patients with non-small cell lung cancer: a randomized, double-blind, placebo-controlled trial. Clin Cancer Res. 2018;24(17):4089-4097.
Design
Double-blind placebo-controlled trial
Participants
The study, conducted in Tokyo, Japan, included 155 patients aged 20 to 75 years who had undergone surgery for non–small cell lung cancer (NSCLC). Patients who were already taking vitamin D were excluded.
Intervention
Patients were randomly assigned to receive either 1,200 IU/day vitamin D supplement (n=77) or placebo (n=78) for 1 year after operation was conducted and were followed for a median of 3.3 years.
Outcomes
The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively.
Key Findings
Relapse occurred in 40 (28%) and death occurred in 24 (17%) of the total patients. In the total study population, no significant difference in either RFS or OS was seen in the vitamin D group compared to the placebo group. However, in the subgroup with early-stage adenocarcinoma and with 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 examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment.
Clinical Implications
These results do not support the commonly held assumption 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 who are low, below 20 ng/mL.
Five-year survival of lung cancer patients is very low, in the range of 10% to 30%.1 Thus, anything that might improve these dismal numbers is readily investigated, especially if it promises to be low-risk and inexpensive. While the new targeted drugs offer incremental improvements in survival, these come at great costs and significant risk. Even with nivolumab, which has been heralded as a major breakthrough,2 5-year survival is still estimated to be only 16%.3,4 According to a group who has studied the high cost of cancer drugs,5 between 2000 and 2015 the average price of new cancer drugs increased from between $5,000 and $10,000 per year to more than $120,000 per year.6 Thus if vitamin D has even a tiny benefit it could improve the current standard of care.
In this study, vitamin D did not make a difference in the entire population of NSCLC patients, but it did make a significant difference in patients who had low concentrations of vitamin D at the study start.
Vitamin D is a naturally produced hormone made in skin that has been exposed to sunlight. It can also be obtained from the diet or as a nutritional supplement. The liver converts vitamin D into 25(OH)D, its active form. This chemical is used as the marker for vitamin D concentration in the blood. It is “activated” primarily by the kidneys into 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. In theory, 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 is operated on for lung cancer influences long-term survival. Patients who underwent surgery in the summer, when vitamin D levels in the body are presumably higher, survived longer. The authors studied the joint effects of surgery season and intake of vitamin D supplements and found that those who had surgery during summer with the highest vitamin D intake had better RFS (adjusted hazard ratio [HR]: 0.33; 95% confidence interval [CI]: 0.15-0.74) than patients who had winter surgery with the lowest vitamin D intake; 5-year RFS rate was 56% (34%-78%) for summer surgery/high intake group and 23% (4%-42%) for the winter surgery/low-intake group.8
While such prospective studies report higher 25(OH)D levels are associated with better survival, these have all been observational studies. Thus, there has been a need for a double-blinded, placebo-controlled trial to determine whether 25(OH)D deficiency has a causal role. This is the first interventional trial that attempts to elucidate this question.
In this study, vitamin D did not make a difference in the entire population of NSCLC patients, but it did make a significant difference in patients who had low concentrations of vitamin D at the study start.
Based on these results it is prudent to test vitamin D status in all NSCLC patients and supplement at least those patients whose levels are low, below 20 ng/mL. Setting a cutoff level of what to consider adequate may prove to be contentious; there does not appear to be risk in raising serum concentrations higher so many will argue to use a higher level than 20 ng/mL to select patients with whom to initiate treatment. In this study the patients in the experimental group received 1,200 IU of vitamin D3 per day.
