Taking high-dose vitamin D3 alongside chemotherapy did not slow metastatic colorectal cancer in a phase 3 trial of 455 patients, closing a question that a smaller earlier study had left open and that many patients had acted on.
The SOLARIS randomized clinical trial, published in JAMA, reported median progression-free survival of 11.8 versus 10.3 months for the high-dose and standard-dose groups. The difference did not reach statistical significance, with a hazard ratio of 0.92 and a one-sided log-rank P value of .25, and there were no significant differences in objective response rate or overall survival.
The results were first presented at a European oncology conference in 2024 and have now been published in full. For patients with this diagnosis and the families buying supplements on their behalf, the conclusion the researchers drew is direct: high-dose vitamin D3 cannot be recommended as treatment for previously untreated metastatic colorectal cancer.
Numbers That Closed the Question
The trial was designed to be definitive, and its structure explains why its answer carries more weight than what came before.
SOLARIS was a double-blind randomized phase 3 trial conducted at 151 academic and community cancer centers across the United States through the National Clinical Trials Network. Patients were enrolled between October 2019 and December 2022 and randomized in equal numbers, 228 to the high-dose arm and 227 to the standard-dose arm.
All participants received standard chemotherapy, either modified FOLFOX6 or FOLFIRI, plus bevacizumab. In addition, half received high-dose vitamin D3, meaning 8000 international units daily for 14 days as a loading dose followed by 4000 IU daily, and half received a standard dose of 400 IU daily.
Median patient age was 59, and 40 percent were female. Median follow-up was 20 months. Adherence was 96 percent, and the high dose rapidly normalized blood 25-hydroxyvitamin D levels, so the trial delivered the intended exposure.
One finding matters for anyone worried about the dose itself. Grade 3 or higher adverse events were comparable between arms, and vitamin D-related toxicities were rare. The higher dose did not appear to add harm. It simply did not add benefit.
Phase 2 Signal That Did Not Replicate
The reason this trial existed is the reason its result matters beyond oncology.
An earlier phase 2 trial called SUNSHINE, published in JAMA in 2019 and enrolling 139 patients, found that high-dose vitamin D3 was associated with improved progression-free survival of 13.0 months against 11.0 months. That signal, in an inexpensive and widely available supplement, generated substantial patient interest and justified a confirmatory trial.
SOLARIS was that confirmation attempt, and it did not confirm. The authors offered an explanation for the divergence with two parts: baseline vitamin D levels were higher than in SUNSHINE, and levels also rose unexpectedly in the control group. Both narrowed the contrast in exposure between arms, which would blunt any detectable difference.
One design limitation deserves attention. The trial compared a high dose against a low dose, with no arm receiving no supplementation at all. An outside clinician questioned the missing comparison arm, noting that standard care does not include routine vitamin D supplementation, so a benefit of any supplementation could in principle be missed by this design.
This pattern is otherwise common and worth recognizing. Promising phase 2 results in small populations frequently fail to hold up in larger randomized trials. A well-powered phase 3 trial supersedes a phase 2 signal, and that hierarchy is the reason confirmatory trials are run at all.
Readers should also know the funding. The trial was supported by the National Cancer Institute and by Pharmavite, a supplement manufacturer. That a company-supported trial produced a negative result for its own product category is worth noting rather than obscuring.
Left-Sided Tumor Finding and Its Status
One subgroup result has drawn attention and needs careful framing.
Prespecified subgroups included tumor location and molecular markers alongside performance status, age, sex, race, body mass index and number of metastatic sites. Within those analyses, a significant interaction by primary tumor sidedness emerged, with an apparent progression-free survival benefit in left-sided but not right-sided disease.
Left-sided and right-sided colorectal cancers differ biologically and respond differently to several therapies, so the finding is not implausible. It is still a subgroup analysis within a trial that missed its primary endpoint, which is the weakest form of positive evidence in clinical research.
Subgroup findings of this kind generate hypotheses for future trials. They do not establish that a treatment works in that subgroup, and no clinician should change management on the basis of this one. Commentators have described it as a good question rather than an answer, and the researchers said it warrants prospective confirmation.
Practical Guidance for Patients Taking Supplements
Nobody should start high-dose vitamin D3 to treat colorectal cancer, and nobody currently taking it for that reason should feel they must continue.
At the same time, no one should stop a supplement prescribed by a clinician for a different purpose without asking first. Vitamin D is prescribed for documented deficiency, for bone health, and in the context of certain medications, and those uses are unaffected by a cancer trial.
Patients undergoing chemotherapy should tell their oncology team about every supplement they take, including doses. Some supplements interact with chemotherapy or affect laboratory values, and oncology pharmacists routinely review this. Standard care for metastatic colorectal cancer does not include routine vitamin D supplementation at any dose.
The most useful conversation for a patient now is about proven options: the chemotherapy backbone, targeted therapy based on tumor molecular testing, immunotherapy where mismatch repair status supports it, and clinical trial eligibility. Molecular testing is what determines several of those choices, and patients can ask whether theirs is complete.
Symptoms that warrant prompt contact with an oncology team rather than waiting for the next appointment include new or worsening abdominal pain, persistent vomiting, blood in stool, fever during chemotherapy, or sudden shortness of breath.
The bottom line: the newest confirmed finding is that high-dose vitamin D3 did not improve progression-free or overall survival in metastatic colorectal cancer; the higher dose caused no additional toxicity; the left-sided subgroup signal remains unproven; and treatment decisions should rest on molecular testing and established therapy.
Key Questions Answered
What did the trial find? High-dose vitamin D3 added to standard chemotherapy plus bevacizumab did not significantly improve progression-free survival, response rate or overall survival in 455 patients with previously untreated metastatic colorectal cancer.
Why did an earlier study suggest a benefit? The phase 2 SUNSHINE trial, with 139 patients, found improved progression-free survival. Small early-phase signals frequently fail to replicate in larger randomized trials, which is why confirmatory studies are conducted.
Why might the results have differed? Baseline vitamin D levels were higher than in the earlier trial and also rose unexpectedly in the control group, narrowing the difference in exposure between the two arms.
Was the high dose harmful? No. Serious adverse events were comparable between arms and vitamin D-related toxicities were rare.
What about the left-sided tumor finding? A prespecified subgroup analysis suggested benefit in left-sided tumors, but this came from a trial that missed its primary endpoint. It requires prospective confirmation and does not change treatment.
Should patients stop taking vitamin D? Not without asking. Vitamin D prescribed for deficiency or bone health serves a different purpose. Patients should discuss all supplements with their oncology team.
Who funded the trial? The National Cancer Institute and Pharmavite, a supplement manufacturer.
