Supplements

WHAT THE EVIDENCE SAYS

Selenium entered cancer-prevention research on the strength of observational data and a single 1990s trial in which reduced cancer incidence was a secondary, not a primary, endpoint ^[1]. The test came with SELECT (Selenium and Vitamin E Cancer Prevention Trial): 35,533 healthy men randomly assigned to selenium, vitamin E, both, or placebo ^[2]. No prevention of prostate cancer was found ^[2]. Moreover, the vitamin E arm showed a SIGNIFICANT INCREASE in prostate cancer risk — 620 cases versus 529 on placebo (HR 1.17; 99% CI 1.004–1.36; p = 0.008), that is 1.6 additional cases per 1,000 person-years (JAMA 2011) ^[2].

A nested analysis from the same trial (Journal of the National Cancer Institute 2014; 1,739 prostate cancer cases including 489 advanced, versus 3,117 comparison men) showed that the effect of supplementation DEPENDS ON BASELINE SELENIUM STATUS: in men with high baseline selenium, supplementation increased the risk of high-grade disease by 91% (p = 0.007), while in men with low selenium, vitamin E increased overall risk by 63% (p = 0.02) and high-grade risk by 111% (p = 0.008) ^[3]. The authors state the conclusion plainly: men should avoid selenium or vitamin E supplementation at doses exceeding recommended dietary intakes ^[3].

The 2018 Cochrane review (PMID 29376219) pooled the randomised evidence: no effect on overall cancer incidence (RR 1.01; 95% CI 0.93–1.10; 3 trials, 19,475 participants) and no effect on cancer mortality (RR 1.02; 95% CI 0.80–1.30; 1 trial, 17,444 participants) ^[1]. The absence of effect also held for individual sites: colorectal, lung, breast, bladder and prostate cancer ^[1]. The authors did, however, note signals of harm: increased melanoma risk in trials at low risk of bias, increased risk of type 2 diabetes, and more frequent alopecia and dermatitis ^[1].

STRENGTH OF THE EVIDENCE

High — and this is the key point here. This is not a topic where evidence is missing; on the contrary, the trials are large, randomised and long, and they agree: selenium supplementation does not reduce cancer risk ^[1]. Cochrane rates the certainty of that conclusion as high ^[1]. Continuing to look for benefit here is no longer a knowledge gap but a conclusion already drawn.

WHO THIS ENTRY IS FOR

For people considering selenium capsules as a way to prevent cancer or to support treatment, and for people after a diagnosis who encounter claims about the "anticancer action of selenium". This entry does not cover documented selenium deficiency diagnosed and treated by a physician — that is a clinical situation governed by its own rules and decided by the treating team.

INTERACTIONS WITH CANCER TREATMENT

Selenium is an antioxidant, and taking antioxidants during chemotherapy and radiotherapy is a matter of justified caution: both modalities work partly through oxidative damage to tumour cells ^[4]. The best available data come from a prospective observational study nested in the SWOG S0221 clinical trial (Journal of Clinical Oncology 2020, PMID 31855498; 1,134 breast cancer patients receiving chemotherapy) ^[4]. Use of any antioxidant supplement (vitamins A, C, E, carotenoids, coenzyme Q10) both before and during treatment was associated with numerically worse outcomes — recurrence adjHR 1.41 (95% CI 0.98–2.04) and death adjHR 1.40 (95% CI 0.90–2.18) — but THE CONFIDENCE INTERVALS INCLUDE 1.0, so for antioxidants alone this is not a statistically significant result and must not be presented as proof of harm ^[4]. What did reach significance in the same study were vitamin B12 (disease-free survival adjHR 1.83; 95% CI 1.15–2.92; overall survival adjHR 2.04; 95% CI 1.22–3.40) and iron taken during chemotherapy (recurrence adjHR 1.79; 95% CI 1.20–2.67) ^[4]. The authors advise caution with supplements other than multivitamins during chemotherapy ^[4].

There is also the question of dose itself: selenium in excess is toxic (selenosis — brittle hair and nails, hair loss, gastrointestinal and neurological symptoms), and the Cochrane review recorded an increased risk of type 2 diabetes in selenium groups ^[1]. The National Cancer Institute states the general rule without exceptions: "Tell your doctor if you're taking any dietary supplements, even vitamins, no matter how safe you think they are ^[5]."

THE SCOPE OF WHAT WE WRITE HERE

We give no doses and no blood-level thresholds, because that would be advice for an individual, and cancer3.ai is an information portal, not a clinic. We also do not cover intravenous selenium in hospital settings or the management of diagnosed deficiency — those are decisions for the treating team. We describe only what is known about selenium supplementation in relation to cancer risk and the course of oncological treatment.

Sources

1. Vinceti M et al. — Selenium for preventing cancer, Cochrane Database of Systematic Reviews 2018: europepmc.org ↗
2. Klein EA et al. — Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT), JAMA 2011: europepmc.org ↗
3. Kristal AR et al. — Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk, Journal of the National Cancer Institute 2014: europepmc.org ↗
4. Ambrosone CB et al. — Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221), Journal of Clinical Oncology 2020: europepmc.org ↗
5. National Cancer Institute — Complementary and Alternative Medicine (CAM), cancer.gov 2024: cancer.gov ↗

WHAT THE EVIDENCE SHOWS

Beta-carotene is one of the few supplements assessed in large randomised trials rather than observational data alone — and both trials came out against supplementation ^[1][2].

• ATBC (New England Journal of Medicine 1994): 29,133 male smokers aged 50-69 from south-western Finland, beta-carotene 20 mg daily, five to eight years of follow-up ^[1]. Among 876 new lung cancer cases, the beta-carotene group had an 18% higher incidence and 8% higher total mortality, driven mainly by lung cancer and ischaemic heart disease ^[1].
• CARET (New England Journal of Medicine 1996): 18,314 smokers, former smokers and asbestos-exposed workers, beta-carotene 30 mg daily combined with 25,000 IU retinol ^[2]. The relative risk of lung cancer was 1.28 (95% CI 1.04-1.57; p=0.02), of death from any cause 1.17 (95% CI 1.03-1.33) and of death from lung cancer 1.46 (95% CI 1.07-2.00) ^[2]. The trial was stopped 21 months ahead of schedule ^[2].
• US Preventive Services Task Force (JAMA 2022): a grade D recommendation, that is, an explicit recommendation against beta-carotene supplements for the prevention of cancer or cardiovascular disease ^[3].

Both trials started from the opposite premise: epidemiological data linked carotenoid-rich diets and high serum beta-carotene with a LOWER risk of lung cancer ^[1][2]. A pharmacological-dose supplement did not reproduce that association — it reversed it ^[1][2]. This is the most frequently cited demonstration that a finding about dietary patterns does not transfer automatically to a pill.

WHO IS MOST CONCERNED

The harm signal comes from people who smoke and from workers exposed to asbestos, and it is best documented in those groups ^[1][2]. Trials of comparable size in never-smokers do not exist, which means "harm has not been demonstrated", not "safety has been demonstrated".

WHAT ABOUT BETA-CAROTENE FROM FOOD

These results concern supplements at doses far above dietary intake. They are not an argument against carotenoid-rich fruit and vegetables, which remain part of recommended eating patterns.

INTERACTIONS AND CAUTIONS DURING CANCER TREATMENT

• Beta-carotene is an antioxidant. The effect of high-dose antioxidants on the efficacy of radiotherapy and chemotherapy remains unresolved, and for that reason their routine use during treatment is not recommended.
• For people who smoke during cancer treatment, the documented increase in lung cancer incidence described above applies as well ^[1][2].
• The CARET regimen combined beta-carotene with retinol; that combination carries an additional risk of hypervitaminosis A ^[2].

A treating team can assess interaction risk only if it knows about every preparation being taken — a supplement left out of the history stays outside any control.

SCOPE OF THIS ENTRY

This entry covers beta-carotene supplements in an oncological context. It does not cover treatment of vitamin A deficiency or ophthalmological and dermatological uses, which follow separate indications.

Sources

1. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group — The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers, New England Journal of Medicine 1994: pubmed.ncbi.nlm.nih.gov ↗
2. Omenn GS et al. — Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease, New England Journal of Medicine 1996: pubmed.ncbi.nlm.nih.gov ↗
3. US Preventive Services Task Force — Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer: US Preventive Services Task Force Recommendation Statement, JAMA 2022: pubmed.ncbi.nlm.nih.gov ↗

WHAT SELECT TESTED

SELECT (the Selenium and Vitamin E Cancer Prevention Trial) was a large randomised trial designed to test whether vitamin E and selenium PREVENT prostate cancer ^[1]. More than 35,000 men aged 50 and over took part, assigned to receive vitamin E at 400 IU per day, selenium, both together, or placebo ^[1]. Mean follow-up was seven years: 5.5 years on supplements and a further year and a half of observation after they were stopped ^[1].

A RESULT OPPOSITE TO THE ONE INTENDED

The trial was designed to demonstrate benefit and demonstrated harm. In the group taking vitamin E alone, 76 prostate cancers were diagnosed per 1,000 men versus 65 per 1,000 on placebo — a relative increase of 17% ^[1]. The NCI states that this difference is statistically significant ^[1].

THE RISK DID NOT DISAPPEAR WHEN THE SUPPLEMENT STOPPED. The most important practical observation concerns not the increase itself but its persistence: the number of diagnoses continued to rise during the year and a half after men stopped taking vitamin E ^[1]. The effect therefore cannot be undone simply by stopping the supplement at the moment concern arises — which is an argument against starting high doses without an indication.

WHAT ABOUT SELENIUM

Men taking selenium alone, and selenium together with vitamin E, were also diagnosed with prostate cancer more often than the placebo group, but those differences were smaller and did not reach statistical significance ^[1]. This is therefore not evidence that selenium protects against the adverse effect of vitamin E — it is an absence of a finding, and the two are not the same thing.

WHAT THESE DATA DO NOT SAY

They do not say that vitamin E in food is harmful; the trial studied a supplement at a dose many times dietary intake ^[1]. Nor do they say anything about the management of someone already diagnosed with cancer, or about patients given vitamin E for a documented deficiency or fat malabsorption — those are separate situations decided by the treating physician. The SELECT result concerns men without a cancer diagnosis taking a high-dose preparation to prevent disease. This entry gives no doses or schedules, as that would be advice for an individual.

Sources

1. National Cancer Institute — Selenium and Vitamin E Cancer Prevention Trial (SELECT): Questions and Answers: cancer.gov ↗

WHAT IT IS AND WHY IT CONCERNS ONCOLOGY

St John's wort is a herb used for mild to moderate low mood, sold over the counter as capsules, tablets and infusions. It appears in this catalogue not because it has antitumour activity, which has not been demonstrated, but because it is one of the best documented herbs causing drug interactions. The indication for which people take it overlaps with a common experience during cancer treatment, so the risk of concurrent use is real rather than theoretical.

MECHANISM OF THE INTERACTION

St John's wort induces the CYP3A4 enzyme in the liver and the membrane transporter P-glycoprotein ^[1]. Both systems clear drugs from the body. Inducing them means a drug is broken down and excreted faster, so its blood level is lower than assumed when the dose was set. The direction of this interaction runs against everyday intuition: the problem is not overdose but LOSS OF TREATMENT EFFICACY.

WHAT HAS BEEN MEASURED IN PEOPLE

• Irinotecan (used among others in colorectal cancer): in a crossover study in 5 cancer patients taking St John's wort 300 mg three times daily for 18 days, plasma levels of the active metabolite SN-38 fell by 42%, and markedly deeper suppression of bone marrow function was described alongside it ^[1][2].
• Imatinib: in two independent studies enrolling 12 and 10 subjects, at the same herb dose for 14 days, the area under the concentration curve, the maximum concentration and the half-life all decreased; the estimated magnitude is a 30-40% reduction in drug exposure ^[1].

WHY THIS IS MORE DANGEROUS THAN IT LOOKS

The interaction does not produce a new complaint the patient could report — only a silent fall in drug levels. Neither the patient nor the treating team has a symptom prompting them to look, unless the herb is asked about directly. St John's wort is also often regarded as harmless precisely because it is natural and sold without prescription, so it frequently goes unmentioned when medication is reviewed.

HOW LONG THE EFFECT LASTS AFTER STOPPING

Enzyme induction does not stop overnight. CYP3A4 activity returns to baseline roughly one week after St John's wort is discontinued, with an estimated half-life of this effect of about 46 hours ^[1]. Stopping the herb on the day the drug is given therefore does not remove the problem.

LIMITS OF THE EVIDENCE, STATED PLAINLY. The studies in cancer patients are SMALL: five people in the irinotecan study, ten and twelve in the imatinib studies. Groups that size cannot tell us how large the fall in drug levels will be in any individual, or in whom it will be greatest. What is strong is the MECHANISM itself and its direction, confirmed across many drugs and not only anticancer ones. Herbal preparations also vary in active content between manufacturers, so the potency of one package need not match another.

SCOPE OF THIS ENTRY

This entry describes a documented pharmacological phenomenon and contains no recommendations for any individual and no management schedules. Decisions about what to take and what to stop during cancer treatment belong to the treating physician, who knows the full medication list. The one point that matters for the reader: taking St John's wort or other herbal preparations is worth telling the treating team about, because without that information the interaction cannot be anticipated.

Sources

1. Borrelli F, Izzo AA. Herb-Drug Interactions with St John's Wort (Hypericum perforatum): an Update on Clinical Observations. AAPS Journal 2009 (przeglad; PMC2782080): pmc.ncbi.nlm.nih.gov ↗
2. Mathijssen RHJ i wsp. Effects of St John's wort on irinotecan metabolism. Journal of the National Cancer Institute 2002 (PMID 12189228): pubmed.ncbi.nlm.nih.gov ↗

WHY THIS ENTRY DIFFERS FROM THE REST OF THE CATALOGUE: Most entries here describe preparations a patient considers on their own, where the evidence is weak or conflicting. This one is the opposite. Folic acid and vitamin B12 with pemetrexed are part of the treatment regimen: not 'support', but a condition of delivering that treatment safely. Pemetrexed acts by targeting the folate pathway ^[2], so the body's folate and vitamin B12 status translates directly into the severity of adverse effects.

THE EVIDENCE THAT CHANGED A PROTOCOL MID-TRIAL

In the phase 3 trial comparing pemetrexed plus cisplatin with cisplatin alone in malignant pleural mesothelioma, folic acid and vitamin B12 were added to the protocol during recruitment - after 117 patients had enrolled - specifically in order to reduce toxicity ^[1]. The authors report that this resulted in a significant reduction in toxicities in the pemetrexed/cisplatin arm ^[1], and that the addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time ^[1]. Median survival in that trial was 12.1 months with pemetrexed plus cisplatin versus 9.3 months with cisplatin alone (p = .020) ^[1].

THIS IS AN UNUSUAL EVIDENTIAL SETUP AND IT IS WORTH SAYING SO PLAINLY: Changing the protocol midway means some patients received pemetrexed without the vitamins and some with them, and the difference in toxicity was seen within a single trial. At the same time this was not a randomised comparison of 'with vitamins' against 'without vitamins', so the strength of that particular finding differs from the strength of the trial's main result. We say this because the distinction matters: the direction is certain and has entered practice, but the trial did not measure the size of the benefit from supplementation itself as an endpoint.

THE SIGNAL FROM THE OTHER DIRECTION - WHAT HAPPENS WITHOUT SUPPLEMENTATION: In a retrospective analysis of patients given intrathecal pemetrexed for leptomeningeal disease, neutropenia occurred in about one third of patients, and a higher incidence and earlier onset were observed among those NOT receiving vitamin B12 and folic acid ^[3]. An important methodological caveat applies: the analysis covered 16 patients and 138 doses, it is retrospective, and the intrathecal route is off-label use. It is an observation consistent with the rest of the material, not a standalone proof. In a phase I/II study of the same route, folic acid and vitamin B12 supplementation was initiated BEFORE the first dose ^[4], reflecting the principle applied in intravenous regimens as well.

WHAT THIS ENTRY DOES NOT CONTAIN, AND WHY: We give no doses, no preparation forms and no timing. This is not an omission: the supplementation schedule is part of the medical prescription, depends on the specific protocol and on the patient's condition, and setting it out on an information page would be advice to an individual. The patient receives that schedule from the treating team along with the treatment itself.

WHAT MUST NOT BE READ INTO THIS ENTRY

• that folic acid 'helps in cancer' generally - the evidence presented concerns only patients treated with pemetrexed, and only the safety of that treatment;
• that an over-the-counter preparation replaces the schedule prescribed by the oncologist - starting, interrupting or altering supplementation during pemetrexed treatment on one's own may change the toxicity of that treatment;
• that this applies to other anticancer drugs - pemetrexed is a folate-pathway-targeting agent ^[2], and the whole relationship described here follows from that.

THE GENERAL RULE, WHICH APPLIES HERE TOO: The treating physician should be told about all supplements being taken, including those that seem harmless. Decisions about treatment and supplementation are made by the specialist physician. This page describes the state of knowledge and is not advice for any individual.

Sources

1. [1] Vogelzang NJ i wsp. — Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma, Journal of Clinical Oncology (dodanie kwasu foliowego i witaminy B12 po włączeniu 117 chorych; znamienne zmniejszenie toksyczności bez wpływu na przeżycie; mediana przeżycia 12,1 vs 9,3 miesiąca, p = 0,020): europepmc.org ↗
2. [2] Adverse events profiles of pemetrexed: a Food and Drug Administration Adverse Event Reporting System, Frontiers in Medicine 2026 (pemetreksed jako lek działający na szlak folianowy; najsilniejsze sygnały w zaburzeniach krwi i układu chłonnego, ROR = 7,31; znaczenie przestrzegania protokołu suplementacji): europepmc.org ↗
3. [3] Incidence of neutropenia with intrathecal pemetrexed for leptomeningeal disease associated with solid tumors — a retrospective analysis, Journal of Oncology Pharmacy Practice 2026 (16 chorych, 138 podań; większa częstość i wcześniejszy początek neutropenii u chorych bez suplementacji witaminą B12 i kwasem foliowym): europepmc.org ↗
4. [4] Intrathecal pemetrexed for newly diagnosed leptomeningeal metastases: a multicenter, open-label, phase I/II study, Journal of Neuro-Oncology 2025 (suplementację kwasem foliowym i witaminą B12 rozpoczynano przed pierwszą dawką): europepmc.org ↗

WHAT THE EVIDENCE SHOWS

The strongest evidence is the VITAL trial (NEJM 2019) — randomised, placebo-controlled, two-by-two factorial, 25,871 participants (men aged 50+, women aged 55+), vitamin D3 2000 IU daily ^[1]. The primary endpoint, invasive cancer, did not differ between groups (HR 0.96; 95% CI 0.88-1.06; p=0.47), and neither did site-specific cancers: breast HR 1.02, prostate HR 0.88, colorectal HR 1.09 ^[1]. The NCI summarises the randomised evidence in the same way: vitamin D supplements, with or without calcium, do not reduce the risk of developing cancer overall or of specific cancers ^[2].

STRENGTH OF EVIDENCE

High for the absence of an effect on incidence (a large randomised trial with a hard endpoint). Low for cancer mortality: the HR of 0.83 comes from a secondary endpoint and its confidence interval crosses 1.0, so the result cannot be distinguished from chance ^[1].

WHO IT CONCERNS

Measuring and correcting vitamin D status in a person with cancer is justified by bone health and deficiency, not by cancer treatment — particularly in patients who are immobilised, hospitalised for long periods, have limited sun exposure, or receive drugs affecting calcium metabolism.

CAUTION AND CONTRAINDICATIONS

The NCI gives a safe upper limit of 100 µg per day (4000 IU) for adults and children aged 8+, with recommended intakes of 15 µg (600 IU) up to age 70 and 20 µg (800 IU) above ^[2]. Excess vitamin D causes calcinosis (calcium salt deposits in kidneys, heart or lungs) and hypercalcaemia ^[2]. Doses far above 4000 IU, marketed as "anticancer", have no support in the evidence and carry this risk ^[2]. The NCI also advises against increasing sun exposure to raise vitamin D levels, as this increases skin cancer risk ^[2].

INTERACTIONS WITH CANCER TREATMENT

The cited reference sources describe no direct interaction between vitamin D and anticancer drugs at the level of drug metabolism ^[1][2]. What is clinically relevant is the metabolic consequence of excess: hypercalcaemia ^[2]. In a person with cancer, hypercalcaemia may also be a manifestation of the disease itself (bone metastases, paraneoplastic syndromes), so its occurrence during supplementation calls for medical assessment rather than self-directed dose changes.

Sources

1. Manson JE et al. — Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease, N Engl J Med 2019 (badanie VITAL, PMID 30415629): europepmc.org ↗
2. National Cancer Institute — Vitamin D and Cancer, NCI Fact Sheet 2023: cancer.gov ↗

WHAT THE EVIDENCE SHOWS

The National Cancer Institute lists St John's wort among supplements that must be discussed with the treating team, stating plainly: "St. John's [wort], which some people use for depression, may cause certain cancer drugs to not work as well as they should ^[1]." A review of herb–chemotherapy interactions in Frontiers in Oncology (2019) names St John's wort among six herbal products with interactions demonstrated in humans rather than only in the laboratory, mediated by inhibition or induction of drug-metabolising enzymes ^[2].

HOW IT WORKS

St John's wort induces the CYP3A4 isoenzyme of the cytochrome P450 system and P-glycoprotein — the very pathways by which the body breaks down and clears a large share of anticancer drugs, particularly oral ones ^[2]. The effect is the opposite of what the patient intends: the drug is cleared faster, blood levels fall, and treatment may lose effectiveness even though the full prescribed dose is being taken ^[1][2].

THE SCOPE OF WHAT WE STATE HERE

We deliberately do not quote by how many per cent the levels of specific drugs fall. Publications reporting such figures exist, but we could not confirm them in the reference-class sources available to us — and an unverified number is worse than no number. For a patient's decision the direction of the effect is enough, and it is not disputed: St John's wort WEAKENS the action of some anticancer drugs.

WHO SHOULD PAY PARTICULAR ATTENTION

Anyone on systemic treatment, especially oral targeted agents and oral chemotherapy, and anyone reaching for St John's wort because of low mood during cancer treatment — precisely the situation in which the interaction risk is highest. St John's wort is also an ingredient in herbal blends and calming preparations, so the composition is worth checking, not just the brand name.

WHAT TO DO

Every supplement taken, including herbal and over-the-counter products, should be reported to the treating physician and clinical pharmacist BEFORE treatment starts ^[1]. Antidepressants should never be stopped or replaced with St John's wort on one's own; low mood during cancer is a medical problem with treatment that can be chosen with interactions in mind.

Sources

1. National Cancer Institute — Complementary and Alternative Medicine (CAM), cancer.gov 2024: cancer.gov ↗
2. Fasinu PS, Rapp GK — Herbal Interaction With Chemotherapeutic Drugs — A Focus on Clinically Significant Findings, Frontiers in Oncology 2019 (PMID 31850232): europepmc.org ↗