Adding high-dose vitamin D3 to standard first-line chemotherapy did not improve progression-free survival for patients with previously untreated metastatic colorectal cancer. Results from the phase 3 SOLARIS trial showed no significant benefit compared to standard dosing, failing to confirm the promise of earlier studies.
The trial was a double-blind, multicenter study conducted at 151 academic and community cancer centers throughout the National Clinical Trials Network. Investigators randomized 455 patients to receive either modified FOLFOX6 or FOLFIRI, both combined with bevacizumab. Participants also took either a high dose of vitamin D3—starting at 8000 international units daily for 14 days before dropping to 4000 IU—or a standard dose of 400 IU daily.
After a median follow-up of 20 months, the median progression-free survival was 11.8 months for the high-dose group and 10.3 months for the standard-dose group. The difference was not statistically significant, with a hazard ratio of 0.92. Objective response rates were 51% for the high-dose group versus 44% for the standard group, while overall survival was similar at 25.6 months and 27.0 months respectively.
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Adherence to the assigned protocols was notably high, reaching 96% in both groups, and the high-dose regimen consistently corrected vitamin D insufficiency by the first restaging scan. Safety profiles were comparable between the two arms. Rates of grade 3 or higher adverse events, such as neutropenia and hypertension, remained consistent, and vitamin D–associated toxicities like hypercalcemia were rare in both groups.
Left-Sided Tumors Show a Different Response
A prespecified subgroup analysis identified a significant interaction between primary tumor location and treatment effect. Patients with left-sided tumors experienced a progression-free survival benefit of 13.8 months compared to 10.2 months. No benefit was observed among those with right-sided tumors. The study authors cautioned that this finding is consistent with past translational studies but remains exploratory.
The distinct split between tumor sides implies that the vitamin’s mechanism interacts differently with the varying biology of left and right colon cancer. It is plausible that future research will abandon the broad approach in favor of targeting only specific molecular or anatomical subtypes where the metabolic pathway is actually active.
Why the Results Differed From Earlier Studies
The findings did not confirm the benefit seen in the earlier phase 2 SUNSHINE trial. That smaller study of 139 patients had associated high-dose supplementation with improved progression-free survival, showing a median of 13.0 months versus 11.0 months. Those earlier results had positioned vitamin D3 as a promising, low-cost adjunct to standard therapy, which the SOLARIS trial was designed to verify.
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Authors offered several explanations for the discrepancy. Patients enrolled in SOLARIS had higher baseline vitamin D levels, with a median of 21.8 ng/mL compared to 17.6 ng/mL in the SUNSHINE trial. Lower baseline levels have been linked to greater responses to supplementation. By chance, the high-dose group in SOLARIS started with statistically higher levels than the control group, and the standard-dose group saw levels rise more than expected, narrowing the contrast.
Vitamin D’s relationship with colorectal cancer outcomes has long interested researchers due to potential anti-inflammatory and immunomodulatory benefits. The SOLARIS results reinforce a pattern where interventions supported by observational data do not always succeed in phase 3 trials. The study authors noted that the findings do not support the routine use of high-dose vitamin D3 for unselected patients.
The authors acknowledged limitations regarding the specific chemotherapy regimens used and potential consumption of vitamins outside the protocol. They stated that these issues did not alter the trial’s overall negative findings. “Among patients with previously untreated mCRC enrolled in a large phase 3 randomized trial, addition of high-dose vitamin D3 vs standard dose vitamin D3 to standard chemotherapy plus bevacizumab did not improve PFS,” they wrote.
