High-dose vitamin D supplements show potential as adjunct therapy for CRC
Adding high-dose vitamin D3 to standard chemotherapy for metastatic colorectal cancer (mCRC) may confer potential benefit to previously untreated patients in terms of progression-free survival (PFS) compared with supplemental standard-dose vitamin D3, the phase II SUNSHINE* study suggests.
“In this era of rising healthcare cost and potentially some very toxic drugs, vitamin D represents a very important potential advance,” said lead author Dr Kimmie Ng from the Dana-Farber Cancer Institute in Boston, Massachusetts, US. “[The study] identifies a cost-effective, safe, and easily accessible agent as a potential new treatment for mCRC.”
Compared with patients who received standard-dose vitamin D3 supplements on top of the standard chemotherapy regimen, the primary endpoint of PFS was longer in those receiving supplemental high-dose vitamin D3 over a median follow-up of 22.9 months (median PFS, 13 vs 11 months). [JAMA 2019;321:1370-1379]
Although the difference between the two groups was not statistically significant by the log-rank test (log-rank p=0.07), adjusted analyses using a supportive Cox proportional hazards model revealed a significantly improved hazard ratio for death or PFS of 0.64 (1-sided p=0.02). This potential beneficial role of vitamin D3 supplementation warrants further evaluation in larger randomized trials in the future, according to the researchers.
The double-blind, multicentre, phase II trial randomized 139 patients (mean age 56 years, 43 percent women) with advanced or mCRC to receive either a supplemental high- or standard-dose vitamin D3 daily, both in addition to the standard chemotherapy regimen of mFOLFOX6 plus bevacizumab intravenously once every cycle of 14 days. High-dose vitamin D3 supplementation comprised 8,000 IU/day loading dose for cycle 1, followed by 4,000 IU/day for subsequent cycles; whereas standard-dose vitamin D3 referred to 400 IU/day during all cycles.
Median plasma levels of 25-hydroxyvitamin D [25(OH)D] rose from baseline to a sufficiently high range during the study in the high-dose vitamin D3 group while the levels remained unchanged in the standard-dose vitamin D3 group (p<0.001 between groups), indicating no contamination of the control group by over-the-counter vitamin D3 supplements which were easily accessible.
No significant differences between the high-dose and standard-dose groups were found for overall survival (OS; median, 24.3 vs 24.3 months; log-rank p=0.43) and tumour objective response rate (58 percent vs 63 percent; p=0.27).
However, the researchers pointed out that the trial was not powered to detect an OS benefit, which would require a longer study duration and a larger sample size.
Adverse events (AEs) of grade ≥3 that were most commonly reported were neutropenia (35 percent vs 31 percent) and hypertension (13 percent vs 16 percent). The only AEs considered as “possibly related to” vitamin D3 included one case of hyperphosphataemia in the high-dose vitamin D3 group and one case of kidney stones in the standard-dose vitamin D3 group.
“The results of our trial suggest an improved outcome for patients who received vitamin D supplementation, and we look forward to launching a larger trial to confirm these exciting and provocative findings,” said study co-author Dr Charles Fuchs, Director of Yale Cancer Center in New Haven, Connecticut, US.
Although the exact mechanisms of action were unclear, previous studies have suggested that vitamin D may have antineoplastic activity through induction of cell death and modulation of inflammatory response. [Cancer Res 2000;60:2304-2312; Trends Mol Med 2002;8:174-179]