Drug Repurposing for Cancer: Evidence-Based Review (2026 Update)

Medically Reviewed by: Dr Frank Yap, MD | Written by:  OneDayMD Editorial Team | Last Updated: August 2026

Abstract

Background: Cancer is increasingly understood as a biologically heterogeneous disease involving not only genetic alterations but also profound changes in cellular metabolism, mitochondrial function, inflammation, immune surveillance, and the tumor microenvironment. Despite significant advances in surgical, radiotherapeutic and immunological approaches, which have improved cancer treatment outcomes, drug therapy continues to serve as a key therapeutic strategy. However, the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects, and thus there remains a critical need to develop novel cancer therapeutics. One promising strategy that has received widespread attention in recent years is drug repurposing: the identification of new applications for existing, clinically approved drugs.

Objective: To review and contextualize various methods employed in drug repurposing, specifically focusing on the repurposing of drugs to treat cancer, with particular emphasis on the quality of human evidence, biological rationale, potential clinical applications, and limitations.

Methods: This evidence-based narrative review evaluates various drug repurposing methods and categorizes them into four evidence tiers according to the strength and maturity of available evidence: Tier 1, strong clinical evidence; Tier 2, moderate clinical evidence; Tier 3, emerging clinical or observational evidence; and Tier 4, experimental or predominantly preclinical evidence. Priority is given to randomized controlled trials, systematic reviews, meta-analyses, prospective studies, and established clinical indications, while preclinical findings and case reports are presented as hypothesis-generating rather than confirmatory evidence.

Results: The reviewed interventions encompass diverse mechanisms, including modulation of glucose and insulin signaling, AMPK/mTOR and mevalonate pathways, mitochondrial metabolism, inflammation, angiogenesis, immune surveillance, tumor hypoxia, cancer stem-cell biology, and the tumor microenvironment. Interventions with comparatively stronger clinical evidence include exercise, selected cardiovascular or metabolic drugs in specific cancer contexts, and established cancer therapies such as BCG and tumor treating fields for defined indications. Other approaches—including ivermectin, benzimidazoles, curcumin, berberine, disulfiram, itraconazole, ketogenic or glucose-modulating strategies, and several experimental metabolic interventions—remain investigational and require substantially more prospective clinical evidence. Nutritional quality, physical activity, metabolic health, sleep, and stress management are considered foundational supportive strategies rather than substitutes for evidence-based cancer treatment.

Conclusion: Drug repurposing represents a promising framework for understanding and potentially complementing conventional cancer treatment, but the evidence is highly heterogeneous and intervention-specific. Preclinical activity or observational associations should not be interpreted as proof of anticancer efficacy. The emerging direction of the field is toward precision, multimodal oncology, in which metabolic and repurposed interventions are selected according to cancer type, molecular and metabolic characteristics, treatment context, patient fitness, potential drug interactions, and the strength of clinical evidence. Well-designed randomized trials and biomarker-driven studies are needed to determine which metabolic interventions improve clinically meaningful outcomes and for which patients.

Keywords: Drug development, Cancer therapy

Diverse cancer hallmarks targeted by repurposed non-oncology drugs. Source: Nature 2024

Introduction

Traditionally, drug development involves preclinical research and clinical trials. Preclinical studies involve testing the efficacy, toxicity, pharmacokinetics, and pharmacodynamics of drugs in human tumor cells and animal models. Once the therapeutic efficacy of a drug has been determined, the drug moves into the clinical trial phase, which includes Phase I, II, and III human clinical trials, to determine the safety and effectiveness of the drug. As such, it takes 10–15 years and costs $1–2 billion to produce a new drug approved for clinical use. Despite these investments, less than 1% of compounds are expected to enter clinical trials, let alone reach the market.

The strategies of drug repurposing involve exploring new therapeutic applications for drugs that have already been approved. Drugs that were originally approved for one indication and have since been studied and used to treat different medical conditions are gaining prominence. This approach is exemplified in the comprehensive review by Kirtonia et al., which underscores the innovative methodologies and potential transformative impact of drug repurposing specifically in the field of oncology. Drug repurposing has several inherent advantages including a faster and more cost-efficient drug development time due to prior knowledge about the safety, dosage, and toxicity profiles of existing medications. In recent years, the interest in drug repurposing has risen. 

In this review, we embark on a comprehensive examination of drug repurposing as a potential strategy for the treatment of cancer. It examines major and popular repurposed drugs, immune-modulating approaches, and experimental compounds, and ranks them according to the quality, consistency, and volume of available evidence. The goal is to provide patients, caregivers, and clinicians with a structured reference and context for understanding the evolving cancer-treatment landscape.

Think of cancer treatment as a chessboard: no single piece wins the game alone. Outcomes may depend on how different therapeutic strategies are coordinated to address the biology of an individual cancer. The interventions with the strongest supporting evidence should therefore be considered first, as part of a comprehensive treatment plan developed with qualified oncology professionals.

Targeting specific genetic alterations has nevertheless transformed the treatment of several cancers and has produced some of the most important advances in modern oncology. Precision therapies can deliver substantial and sometimes durable responses in patients whose tumors harbor actionable molecular alterations.

However, important limitations remain:

• Many responses are partial rather than complete.
• Responses can be temporary.
• Acquired or intrinsic drug resistance is common.
• A mutation-centered approach does not fully address the biological complexity and heterogeneity of advanced cancer.

For these reasons, the future of oncology will likely depend increasingly on combination therapies, biomarker-guided treatment, and personalization. Rather than relying on a single target or pathway, researchers are investigating combinations designed to address multiple mechanisms of tumor growth, immune evasion, metabolism, and treatment resistance.

Repurposed drugs may have an important role in this research landscape. Because many have established safety profiles, known pharmacology, and potentially lower development costs, they may offer opportunities to investigate additional therapeutic combinations more efficiently and affordably. However, stronger evidence from well-designed clinical trials is still needed before such approaches can be considered established cancer treatments.

📌 Access note: Effective modern cancer therapies (immunotherapy, targeted agents) remain unevenly distributed globally. Repurposed drugs offer lower-cost options worth investigating — particularly in low- and middle-income countries where treatment infrastructure lags behind clinical need (WEF 2024, WHO 2024).

Methodology: Evidence Tier Framework

Evidence quality hierarchy. Meta-analyses of RCTs occupy the apex; preclinical studies form the base.

Interventions are organized into four evidence tiers:

Tier	Evidence Quality	Examples
Tier 1 — Strong	Meta-analyses of RCTs; approved clinical indications; landmark guideline-changing trials	Aspirin (PIK3CA-mutant CRC), Exercise, Metformin, Statins, Cimetidine (CRC)
Tier 2 — Moderate	Individual RCTs; systematic reviews with clinical trial data; prospective cohorts	TTF/Optune (GBM), BCG (bladder cancer), Mistletoe, Low Dose Naltrexone (LDN), Propranolol, Vitamin D3, Omega-3, Vitamin C (IV), Hyperthermia, Melatonin
Tier 3 — Emerging	Observational studies, retrospective analyses, small clinical series, case series with mechanistic support	Ivermectin, Benzimidazoles, Curcumin, Green Tea (EGCG), Berberine, Disulfiram, Itraconazole, Sildenafil/PDE5i, Glucose/Keto, Methylene Blue
Tier 4 — Experimental	Primarily preclinical (cell/animal); limited or no human data; case reports only	DMSO, Ashwagandha, HBOT, Gerson Therapy, Hydralazine (GBM), Stress/Sleep/Sunshine

📋 Contents

1. Tier 1: Strong Clinical Evidence
2. Tier 2: Moderate Clinical Evidence
3. Tier 3: Emerging / Clinical Series Evidence
4. Tier 4: Experimental / Preclinical Evidence
5. Anticancer Nutrition: The Dietary Foundation
   1. Why Cancer Hospitals Must Stop Serving Junk Food
   2. ACS & WCRF/AICR Dietary Guidelines
   3. Ultra-Processed Foods, Sugar & Insulin Resistance
   4. Plant-Based & Mediterranean Diets
   5. Dietary Fiber
   6. Fasting, Keto & Low-Carb (Controversial)
   7. Meat: Cooking, Processing & Cancer Risk
   8. Coffee & Cancer
6. Discussion: Where the Field Is Heading
7. Conclusion
8. References

Tier 1: Strong Clinical Evidence

These five interventions have the most robust human data — including meta-analyses of randomised controlled trials or landmark trials that have directly influenced clinical guidelines. BCG has been moved to Tier 2 because, despite its approved status, its evidence base is narrow (single cancer type, single administration route) compared with the multi-cancer, meta-analysis-supported interventions below.

1. Aspirin & COX-2 Inhibitors (Celecoxib). Tier 1 · RCT + Guideline

The ALASCCA Trial (2025) is the most clinically important recent development in this space. Stage I–III colorectal cancer patients with PIK3CA-pathway mutations — found in over one-third of all CRC — were randomised to 160 mg aspirin or placebo daily for three years post-surgery. The NCCN has since updated guidelines to formally recommend PIK3CA mutation testing in Stage II–III colon cancer and three years of low-dose aspirin for mutation carriers. Aspirin becomes one of the first widely available drugs integrated into precision oncology guidelines.

Separately, a Cardiff University review (BJC 2023) of 118 observational studies in ~1 million cancer patients found daily low-dose aspirin associated with a 21% reduction in all-cause cancer mortality, with particularly strong signals for colorectal (27% risk reduction), gastric (36%), and hepatobiliary (38%) cancers.

For celecoxib, a 2009 landmark study found patients taking COX-2 inhibitors for ≥6 months post-diagnosis were nearly 80% less likely to develop bone metastases in breast cancer. Ben Williams' long-term glioblastoma survival (diagnosed 1995) famously included celecoxib as part of his off-label drug cocktail.

🔗 Read more: ALASCCA Trial Results — Aspirin in PIK3CA-mutant CRC

⚠️ Aspirin increases bleeding risk. Not recommended in patients on anticoagulants without specialist guidance. Celecoxib is contraindicated in patients with severe heart failure.

2. Metformin. Tier 1 · Multiple RCTs

Metformin's anticancer potential is one of the most extensively studied areas in repurposed oncology pharmacology. Population studies consistently show cancer incidence and mortality reductions in diabetic patients taking metformin versus other glucose-lowering agents. Its safety profile, low cost, and multi-pathway activity make it a cornerstone of metabolic oncology protocols.

⚠️ GI side effects common at initiation. Contraindicated in severe renal impairment (eGFR <30). Long-term use associated with B12 deficiency — supplement with B-complex. Do not combine with berberine without blood glucose monitoring.

3. Statins (Atorvastatin / Simvastatin / Pitavastatin). Tier 1 · Meta-analyses

Meta-analyses across multiple cancer types show statin use associated with 15–35% reductions in cancer-specific mortality. Pitavastatin is increasingly preferred in oncology protocols due to its minimal drug interactions. Statins synergise well with metformin, aspirin, and benzimidazoles in multi-drug repurposing regimens.

🔗 Related: Ivermectin synergy with statins in ovarian cancer (2023 UK/Iraqi study)

4. Cimetidine and H2 Blockers. Tier 1 · Cochrane Meta-analysis

Cimetidine is arguably the most underappreciated repurposed drug in oncology. Its dramatic survival benefit in colorectal cancer — a 10-year survival rate of 84.6% versus 49.8% in the Japanese long-term cohort — has been validated across multiple independent studies. The Cochrane meta-analysis confirms a statistically significant overall survival benefit. Importantly, the benefit appears specific to cimetidine (not other H2 blockers), pointing to mechanisms beyond H2 receptor blockade.

⚠️ Cimetidine raises plasma levels of propranolol; adjust beta-blocker dosing accordingly. Multiple drug interactions — review carefully with your pharmacist.

Tier 2: Moderate Clinical Evidence

These interventions are supported by individual RCTs, systematic reviews of clinical trial data, prospective cohort studies, or Phase I/II data or approved-indication status in a narrowly defined cancer type. The evidence is meaningful but not yet at multi-cancer meta-analysis level.

5. BCG Immunotherapy. Tier 2 · Approved (Single Cancer Type)

BCG remains the gold-standard adjuvant treatment for high-risk NMIBC and is an approved, guideline-recommended immunotherapy. Its placement in Tier 2 (rather than Tier 1) reflects the evidence framework used in this review: Tier 1 requires multi-cancer meta-analysis-level data. BCG's evidence is deep and unambiguous within its specific indication — but it applies to one cancer, delivered by one route, supervised by one specialist type. Aspirin, exercise, metformin, and statins all carry broader multi-cancer evidence bases, which is why they occupy Tier 1 in this ranking.

⚠️ BCG therapy is not suitable for all patients (immunocompromised individuals, active TB). Side effects include bladder irritation and, rarely, systemic BCG infection. Requires urological supervision and cannot be self-administered.

6. Low Dose Naltrexone (LDN). Tier 2 · Small RCTs + Systematic Reviews

LDN is one of the most under-investigated compounds in integrative oncology relative to its mechanistic rationale and safety profile. At the low doses used (1.5–4.5 mg), naltrexone does not block opioid receptors continuously — it occupies them transiently for 4–6 hours during sleep, triggering a rebound overshoot in endogenous opioid production. This intermittent OGF upregulation is the key anti-proliferative mechanism, distinct from the pharmacology of full-dose naltrexone (50 mg) used in addiction medicine.

The foundational research comes from Dr Ian Zagon's laboratory at Penn State, spanning over three decades and demonstrating the OGF/OGFr pathway's role in regulating tumour cell proliferation across pancreatic, colorectal, squamous cell, and haematological cancers. The 2024 systematic review in Cureus pooled data from 16 studies and found consistent signals for improved quality of life and tumour response. A Phase II RCT in pancreatic cancer (NCT04401579) and ongoing case series documentation are strengthening the evidence base.

LDN's safety profile is exceptional — at doses below 5 mg, significant adverse effects are rare and typically limited to transient sleep disturbance in the first 1–2 weeks of use. It has no known organ toxicity, no significant drug interactions at low doses (except with full opioid agonists — see caution below), and costs approximately USD $30–50/month from compounding pharmacies.

⚠️ Critical contraindication: LDN must NOT be used by patients on full opioid agonists (morphine, oxycodone, fentanyl, tramadol, codeine, methadone) — it will precipitate acute opioid withdrawal. Patients must be opioid-free for at least 7–10 days before starting LDN. Also avoid with Vivitrol (extended-release naltrexone implant). Requires a compounding pharmacy prescription — standard 50 mg naltrexone tablets cannot be split to therapeutic LDN doses reliably.

🔗 Resources: LDN Research Trust · Phase II Pancreatic Cancer Trial (NCT04401579) · 2024 Systematic Review (Cureus, PMID 38966634) . Low-Dose Naltrexone for Cancer: Case Series and Human Studies (2026)

7. Propranolol (Beta-Blocker). Tier 2 · RCTs + Meta-analysis

The perioperative window — the days around cancer surgery — represents a period of heightened metastatic risk due to surgical stress hormones. Propranolol blunts this by blocking beta-adrenergic signalling. The COMPIT trial's results (50% vs 12.5% recurrence) are striking, and the 2025 meta-analysis of 31 studies confirms the signal across cancer types. Perioperative propranolol + etodolac represents one of the most compelling low-cost surgical adjuncts in integrative oncology.

⚠️ Contraindicated in asthma, severe bradycardia, uncompensated heart failure. Never stop abruptly — taper under medical supervision.

8.Vitamin D3. Tier 2 · RCTs

Vitamin D3 is commonly classified and marketed as a dietary supplement rather than a conventional pharmaceutical drug. However, vitamin D3 (cholecalciferol) is a biologically active secosteroid precursor that is converted in the body to hormonally active metabolites and influences numerous physiological processes through the vitamin D receptor. Because of these established biological effects, vitamin D3 is appropriately included in this review when evaluating potential metabolic, immunological, and cancer-related interventions.

⚠️ Patients on warfarin need close monitoring before adding Vitamin K2. Toxicity possible at very high doses — check serum levels before high-dose supplementation.

9. Omega-3 Fatty Acids (EPA/DHA). Tier 2 · RCTs

⚠️ Increased bleeding risk at high doses — use caution with anticoagulants. Choose pharmaceutical-grade, mercury-free supplements.

10. Melatonin. Tier 2 · Multiple RCTs

⚠️ High-dose melatonin may cause vivid dreams and daytime somnolence. Start low. Potential interaction with immunosuppressants.

11. Ivermectin. Tier 2 · Phase I/II Trial Active

• Cancer types: Triple-negative breast cancer (active trial); leukemia, colorectal, gastric, lung, prostate, ovarian (case series).
• Human evidence: De Castro 2020 (refractory AML, paediatric, 1 mg/kg/day); Ishiguro 2022 (12 mg BID); NCT05318469 Phase I/II TNBC trial (Cedars-Sinai, 2025 ASCO results); 700+ compiled case reports including Stage 4 NED cases — see Ivermectin Cancer Case Reports Compilation.
• Research funding: $60 million Florida Cancer Innovation Fund; multiple Phase I/II trials registered.
• Mechanism: Targeting Multiple Cancer Pathways; T-cell activation and tumour infiltration; synergy with immune checkpoint blockade; PAK1 inhibition; Wnt/β-catenin pathway suppression; P-glycoprotein inhibition; mitochondrial membrane disruption in cancer cells.

Ivermectin dosage for cancer treatment — dosing differs significantly from antiparasitic use

Ivermectin occupies a unique position: it has 400+ publications (mostly preclinical), a growing case series dataset, active Phase I/II trials, and $60 million in dedicated research funding. The 2025 ASCO results from the Cedars-Sinai TNBC trial (NCT05318469) mark the first formal clinical efficacy data in a solid tumour.

⚠️ Standard antiparasitic dosing might be inadequate for oncology use. Dosing should be guided by an integrative oncologist familiar with current cancer protocols. See: Dr Makis Protocol (2026)

12. Benzimidazoles: Fenbendazole / Mebendazole / Albendazole. Tier 2 · Phase I/II Trial Active

• Cancer types: Multiple cancers (lung, colorectal, prostate, ovarian, glioma — case series); glioma (mebendazole clinical studies)
• Human evidence: Mebendazole Phase I/II trials in glioma and colorectal cancer; fenbendazole and ivermectin case series across 700+ patients; Joe Tippens Protocol (fenbendazole, small-cell lung cancer NED, 8+ years)
• Dosage: Mebendazole: 250 mg/day; Fenbendazole: 222 mg 3×/week (Tippens) to daily dosing; Albendazole: 400 mg BID with food.
• Mechanism: Targeting Multiple Cancer Pathways; Disrupts β-tubulin polymerisation → inhibits cancer cell mitosis (similar to taxanes/vinca alkaloids); inhibits glucose uptake (GLUT-1); blocks STAT3 signalling; targets cancer stem cells; anti-angiogenic via VEGFR2 inhibition

Mebendazole has the strongest human data of the three, with formal Phase II trials in glioma showing it crosses the blood-brain barrier. Fenbendazole achieved international attention via Joe Tippens' survival from metastatic SCLC. Both are affordable and widely available. Of note: fenbendazole is a veterinary drug without human approval; mebendazole is the human-approved equivalent and is preferred for human use.

🔗 Read: Fenbendazole vs Mebendazole for Cancer: What Is the Difference?

13. High-Dose Intravenous Vitamin C. Tier 2 · Phase I/II Trials

The key distinction from earlier negative studies (Mayo Clinic 1985): oral vitamin C does not achieve pharmacologic serum levels. Intravenous administration is essential for anticancer effects. The aspirin–vitamin C combination shows synergistic activity in animal models (73% lifespan extension vs untreated controls; 46% tumour volume reduction).

⚠️ IV Vitamin C is contraindicated in patients with G6PD deficiency (risk of haemolysis). Requires specialist administration and monitoring.

14. Disulfiram + Copper Tier 2 · Phase I/II Trials

⚠️ Patients must strictly avoid alcohol — severe cardiovascular reactions can occur. Not suitable for patients with hepatic impairment.

🔗 Related: Disulfiram in APC-Mutated CRC: Precision Oncology Application

15. Itraconazole Tier 2 · Phase II Trials

⚠️ Significant drug interactions including with statins, rituxumab, and cimetidine. Hepatotoxicity risk at high doses — monitor LFTs regularly.

16. PDE5 Inhibitors (Sildenafil / Tadalafil / Vardenafil). Tier 2 · Phase I/II Trials

⚠️ Absolutely contraindicated with nitrates (risk of severe hypotension). Caution in patients with history of NAION. Serious cardiovascular side effects possible.

17. Atovaquone. Tier 2 · Phase I/II Trials

Atovaquone is an FDA-approved antimalarial and anti-Pneumocystis drug (brand name Mepron) repurposed for its ability to inhibit mitochondrial complex III, reducing tumor hypoxia by lowering cancer cells' oxygen consumption. Hypoxic tumor regions are a well-established driver of resistance to radiotherapy and chemotherapy, which is the central rationale for atovaquone's oncology development program.

• ARCADIAN trial (University of Oxford, Cancer Research UK-funded): A Phase I dose-escalation study combining atovaquone with concurrent chemoradiotherapy (cisplatin, vinorelbine, and radiation) in locally advanced non-small cell lung cancer (NSCLC). Atovaquone was dosed twice daily, beginning roughly three weeks before radiotherapy and continuing through treatment, and reached its planned dose level with a manageable side-effect profile in a small evaluable cohort.
• ATOM trial (Oxford, NCT02628080): A companion imaging study using hypoxia PET-CT, which found that atovaquone reduced tumor hypoxic volume in NSCLC patients relative to untreated controls, with the largest reductions in the outer and inner tumor subregions and no atovaquone-related adverse events reported.
• Ovarian and pediatric indications: Phase II evaluation has also been pursued in platinum-resistant ovarian cancer, and atovaquone has been studied in combination with chemotherapy in pediatric acute myeloid leukemia (the ATACC-AML trial), which has since completed.

Mechanistically, atovaquone's mitochondrial inhibition and hypoxia-reducing effects position it as a potential radiosensitizer rather than a cytotoxic agent in its own right, which is a meaningfully different role from the other three drugs discussed in this review.

18. Niclosamide. Tier 2 · Phase I/II Trials

Niclosamide is a chlorinated salicylanilide anthelmintic first marketed for human tapeworm infections in the early 1960s and listed on the WHO Model List of Essential Medicines. The FDA approved it for tapeworm treatment in 1982 under the brand name Niclocide, but — unlike ivermectin, mebendazole, and atovaquone — niclosamide is no longer commercially marketed in the United States, even though the historical approval was never formally withdrawn. It remains available in other countries under brand names such as Yomesan.

Proposed Anticancer Mechanisms

Niclosamide is considered a "pleiotropic" repurposing candidate because it appears to interfere with several oncogenic pathways simultaneously, rather than a single target:

• Wnt/β-catenin inhibition: Niclosamide promotes degradation of LRP6, a Wnt co-receptor, blocking downstream β-catenin accumulation. This is the best-characterized mechanism and the basis for its testing in Wnt-driven cancers such as colorectal cancer and familial adenomatous polyposis (FAP).
• STAT3 inhibition: Niclosamide blocks STAT3 phosphorylation and nuclear translocation, downregulating anti-apoptotic targets such as Mcl-1 and survivin in models including hepatocellular carcinoma.
• NF-κB and Notch signaling: Several groups report that niclosamide impairs NF-κB activation (via TAK1/IKK) and Notch pathway signaling, though at least one early mechanistic study in colorectal cancer cell lines found no effect on NF-κB or mTOR, underscoring that niclosamide's mechanism appears to vary by cancer type and experimental model rather than acting uniformly across all pathways in all tissues.
• Mitochondrial uncoupling: As with its antiparasitic mechanism, niclosamide uncouples mitochondrial oxidative phosphorylation in cancer cells, impairing ATP production.
• Macropinocytosis and nutrient transport inhibition: More recent work (2023) describes niclosamide acting as a proton channel that blocks macropinocytosis and the amino acid transporter SLC38A5, effectively starving cancer cells of extracellular nutrients.
• Androgen receptor splice variant (AR-V) degradation: In prostate cancer specifically, niclosamide has been shown to degrade constitutively active AR splice variants such as AR-V7, a mechanism of resistance to standard androgen-receptor-targeted therapies like abiraterone and enzalutamide.

Clinical Trials

• Colorectal cancer — NIKOLO trial (NCT02519582, Charité Universitätsmedizin Berlin): A single-arm, open-label Phase II study testing niclosamide (2 g orally once daily) in patients with metastatic colorectal cancer progressing after standard therapy, designed around niclosamide's suppression of the Wnt target gene S100A4, a metastasis-associated marker.
• Familial adenomatous polyposis — chemoprevention (NCT04296851, Yonsei University, South Korea): A randomized, double-blind, placebo-controlled Phase II trial testing niclosamide 650 mg once daily for six months to assess its effect on colorectal and duodenal polyp burden in FAP patients, a population with a well-defined Wnt-pathway-driven cancer predisposition.
• Castration-resistant prostate cancer: Multiple early-phase combination trials have been conducted, including a Phase Ib study of reformulated niclosamide with abiraterone and prednisone (reaching a tolerated dose of 1,200 mg three times daily with plasma concentrations in the expected therapeutic range), a Phase I dose-escalation study combining niclosamide with enzalutamide (testing 500, 1,000, and 1,500 mg three-times-daily dose levels), and a Phase II trial of abiraterone plus niclosamide and prednisone (NCT02807805), which was listed as active but not recruiting as of this update.
• Preclinical combination strategies: Laboratory research has explored pairing niclosamide with metformin to more completely suppress Wnt and Hippo/YAP signaling in APC-mutated colorectal cancer models, aiming to overcome a limitation of niclosamide monotherapy in this genetic context.

The Bioavailability Problem

Niclosamide's biggest translational obstacle is not safety but pharmacokinetics. Because it was designed to act locally in the intestinal lumen against tapeworms, oral niclosamide is poorly absorbed systemically, and researchers have repeatedly noted this as the central barrier to using standard niclosamide tablets as a systemic anticancer agent. This has driven a substantial reformulation effort, including amorphous solid dispersion and nanoparticle-based oral formulations designed to improve dissolution and absorption, and the reformulated "PDMX1001" niclosamide product used in some of the prostate cancer trials above. Readers should understand that trial doses reported here — some considerably higher than the 2 g single-dose antiparasitic regimen — reflect attempts to overcome this bioavailability ceiling, not an established or standardized oncology dosing protocol.

Tier 3: Emerging Evidence (Clinical Series / Observational)

These interventions have meaningful human data — case series, observational studies, small clinical trials — combined with strong preclinical rationale. They lack large RCT confirmation but are being actively investigated.

19. Green Tea (EGCG). Tier 3 · Epidemiological + Mechanistic

A phase I clinical trial (NCT00516243) has been initiated that targets women with hormone receptor-negative stages I-III breast cancer and aims to explore the safety and effectiveness of EGCG. Concurrently, several clinical trials for CRC (NCT02321969 and NCT01360320) are also in progress. However, while these studies are promising, the potential therapeutic application of EGCG in cancer treatment is still restricted by its limited bioavailability.

⚠️ High-dose green tea extract may be hepatotoxic in individuals with underlying liver conditions — use with caution and monitor LFTs.

20. Curcumin (Nanocurcumin). Tier 2 · Small Clinical Trials

⚠️ Curcumin interacts with anticoagulants (warfarin, clopidogrel), some antibiotics, and antidepressants. Use nanocurcumin or phospholipid complexes for adequate bioavailability.

21. Berberine. Tier 3 · Small Clinical Trials

⚠️ Absolute contraindication with cyclosporine (raises levels dangerously). Monitor blood glucose when combining with metformin. May alter metabolism of warfarin, tacrolimus, sedatives, and losartan.

22. Glucose Management, Ketogenic Diet & GLP-1 Agonists. Tier 3 · Observational + Metabolic Oncology

• Cancer types: Multiple cancers (Warburg effect-dependent tumours); obesity-related cancers (GLP-1 data.
• Evidence: 2025 ASCO data: GLP-1 receptor agonists modestly reduce risk of 14 obesity-related cancers in diabetics; observational data for ketogenic diet in glioma and NSCLC; CGM studies showing post-meal glucose as tumour growth proxy.
• Approach: Limit carbohydrates <25 g/day (strict keto); post-meal glucose target <120 mg/dL via CGM; GKI (Glucose-Ketone Index) as metabolic monitoring tool.
• Mechanism: Reduces circulating glucose and insulin → starves Warburg-dependent tumour cells; ketone bodies cannot be efficiently metabolised by most cancer cells; reduced IGF-1 signalling; synergy with fasting-mimicking approaches.

🔗 Related: FLCCC Fasting and Healthy Eating Guide

23. Methylene Blue. Tier 3 · Systematic Review (PDT) + In Vivo

• Cancer types: Ovarian (platinum-resistant), colorectal, melanoma, glioblastoma.
• Evidence: Lim 2023 systematic review (PDT efficacy in colorectal, carcinoma, melanoma); Da Veiga Moreira 2024 (in vivo ovarian tumour restraint); Makis 2025 (post-surgical breast cavity clearance; GBM + TMZ synergy).
• Dosage: Not yet standardised for oncology use; PDT protocols are centre-specific.
• Mechanism: Mitochondrial Complex IV enhancer (electron carrier); photosensitiser for PDT → generates singlet oxygen to destroy tumour cells; inhibits mTOR; reduces mitochondrial ROS in normal cells while increasing it in cancer cells.

🔗 Read: Methylene Blue for Cancer: Mechanisms and Clinical Implications

Tier 4: Experimental / Primarily Preclinical

These interventions lack robust human clinical trial data. Some have strong biological rationale and emerging case report signals. They are listed here for completeness and to reflect current integrative oncology discussion — not as recommended treatments.

24. DMSO (Dimethyl Sulfoxide) Tier 4 · Preclinical + Anecdotal

Dr William Makis (April 2026) summarised the current status clearly: "DMSO's use in cancer is not documented. In comparison to DMSO, Ivermectin has 400+ publications, several human clinical trials coming, $60 million research backing... Would I support DMSO research in cancer? Absolutely." This captures where DMSO sits — promising biology, zero human trial evidence, warranting investigation rather than clinical use.

🔗 Read: DMSO and Cancer: The Overlooked Therapy (OneDayMD Substack)

25. Ashwagandha (Withania somnifera) Tier 4 · Preclinical

⚠️ May affect thyroid hormone levels — monitor if thyroid conditions present. Potential drug interactions with immunosuppressants and thyroid medications.

26. Gerson Therapy Tier 4 · Historical / No Robust Clinical Trials

The Gerson Therapy occupies a complex position: historically significant, patient communities report subjective benefits, but it lacks any rigorous clinical evidence and its intensive nature makes adherence difficult. Coffee enemas carry real risks including electrolyte disturbances and rare fatalities. If considered, it should be supervised by an experienced Gerson-trained practitioner.

27. Hydralazine (Glioblastoma) Tier 4 · Cell Studies Only

The press release from Memorial Sloan Kettering emphasises this is a starting point for drug repurposing, not a clinical treatment. As a blood-pressure drug already FDA-approved, it could enter trials faster than novel compounds — but human evidence is entirely absent at this stage.

Anticancer Nutrition: The Dietary Foundation

Why Diet Belongs in This Evidence Review
Pharmacological interventions — however promising — operate within a metabolic environment shaped entirely by what the patient eats. A repurposed drug cocktail administered alongside a diet of french fries, potato chips, and ice cream is working against itself. What follows is an evidence-ranked review of dietary interventions, applying the same rigour used for the drug and lifestyle therapies above.

⚠️ If Cancer Hospitals Are Still Serving French Fries and Cake, We Have a Problem

Cancer patients require carefully tailored nutrition to support treatment and recovery. Healthy diets for cancer patients emphasise whole foods rich in fibre, lean proteins, healthy fats, fruits, and vegetables — while avoiding ultra-processed foods, fried snacks, and excessive sugars. Although some high-calorie options like ice cream may occasionally be warranted to maintain weight in patients with poor appetite, regularly serving nutrient-poor, processed foods directly contradicts evidence-based nutritional practice in oncology.

Leading cancer centres and dietitians recommend diets that maintain strength, manage treatment side effects, support immune function, and reduce inflammation. This means avoiding deep-fried and ultra-processed foods, limiting processed red meats, and focusing on nutrient-dense, minimally processed meals. Ensuring cancer hospitals provide appropriate, evidence-based nutrition is not an optional upgrade — it is a fundamental obligation to patient outcomes.

1. ACS Guidelines: The Baseline Standard

In 2020, the American Cancer Society published updated diet and physical activity guidelines for cancer prevention. A healthy eating pattern, per the ACS, includes foods high in nutrients in amounts that maintain healthy body weight; a variety of vegetables (dark green, red and orange, legumes); whole fruits; and whole grains. It limits or excludes red and processed meats, sugar-sweetened beverages, and highly processed foods and refined grain products.

A 2024 literature review published in Nutrients updated the international evidence base, concluding that the Mediterranean diet reduces cancer risk; overnight fasting may contribute to cancer prevention but excessive fasting can harm quality of life; vegetarian and pescetarian diets are associated with lower risks of general and colorectal cancer compared to a carnivorous diet; high heme and total iron intake are linked to increased lung cancer risk; and coffee and tea have a neutral impact on cancer risk.

📌 The WCRF/AICR (World Cancer Research Fund / American Institute for Cancer Research) Cancer Prevention Recommendations (2018) represent the most comprehensive global synthesis. Greater adherence to these recommendations is associated with a reduced risk of all cancers combined (BMC Medicine, 2023).

2. Ultra-Processed Foods, Sugar, Preservatives & Insulin Resistance

The evidence linking ultra-processed food to cancer is now robust at the umbrella review level — the highest tier of epidemiological evidence.

🔑 Key Evidence Summary

Ultra-Processed Food (2026, AACR)	Linked ultra-processed foods to reduced survival after cancer. Sugar, starch, and saturated fat packed into UPF worsen cancer prognosis.
Ultra-Processed Food — Umbrella Review (BMJ 2024)	45 pooled analyses, 9,888,373 participants: direct associations between UPF and 32 health parameters, including cancer, all-cause mortality, and metabolic dysfunction.
Insulin Resistance (Nature Communications, Feb 2026)	Insulin resistance linked to a 25% higher risk across 12 cancer types. Strongest signal: uterine cancer (+134% risk). AI tool developed to predict insulin resistance and flag cancer risk.
Food Preservatives (BMJ 2026)	French NutriNet-Santé cohort (7.57-year follow-up): higher preservative intake associated with higher overall cancer and breast cancer rates, independent of confounders including age, BMI, activity, smoking, and alcohol.
Sugar — Umbrella Review (BMJ 2023)	8,000+ studies: supports limiting dietary sugar. Sugar-sweetened soft drinks linked to obesity-related cancers (Cambridge University Press, 2018). Cancer cells consume glucose at 200× the rate of normal cells.
MGO / Sugar Mechanism (Cell, 2024)	Findings on methylglyoxal (MGO) — a reactive sugar metabolite — support reducing sugar intake as a direct mechanism for mitigating cancer risk at the cellular level.

The food ecosystem is dominated by processed foods and sweetened beverages — see the Top 10 Food & Beverage Companies by Revenue for the scale of the problem. Poor diet quality is a root cause of chronic disease worldwide. Diets high in processed foods, sugars, and unhealthy fats contribute to inflammation and metabolic disorders, fuelling the same environments in which cancer thrives.

Key Takeaway: Avoid sugar, ultra-processed foods, and food preservatives where possible. This is not controversial — it is supported by the highest level of epidemiological evidence (umbrella reviews) and endorsed by every major cancer nutrition guideline.

3. Plant-Based & Mediterranean Diets

Certain plant compounds regulate cancer-protective pathways and activate detoxification systems: sulforaphane (cruciferous vegetables), flavonoids (citrus), polyphenol catechins (green tea), and curcumin (turmeric), according to a 2025 review in the Journal of Nutritional Oncology. A cancer-preventive diet does not need to be fully vegetarian — but it should be rich in colourful fruits and vegetables.

Diet / Food	Evidence	Key Cancers
Vegetarian / Vegan Diet	Umbrella review (PLOS One, 2024) — 48 reviews & meta-analyses: significantly reduces risk of gastrointestinal cancer and prostate cancer, and associated mortality.	GI, Prostate, Bowel
Healthy Plant-Based Diet	BMC Medicine 2022 (n=79,952 men): highest plant-based food intake = 22% lower bowel cancer risk. JAMA Oncology 2022: plant-enriched diet reduces cancer risk.	Colorectal, Bowel
Mediterranean Diet + Olive Oil	Meta-analysis of 45 studies (2022): daily olive oil consumption = 31% lower risk of any cancer. Mediterranean diet associated with reduced breast cancer risk.	Breast, Multiple
Cruciferous Vegetables	BMC Gastroenterology (2025): 17 studies, 639,539 participants, 97,595 colon cancer cases — 17% reduction in colon cancer risk. Optimal dose: 40–60g/day (½ cup cooked broccoli). Umbrella review (2022): protective for gastric, lung, endometrial cancers & all-cause mortality.	Colon, Gastric, Lung, Endometrial
Quality Matters	Am J Clin Nutr (2023): healthy plant-based diet = lower pancreatic cancer risk; unhealthy plant-based diet = higher pancreatic cancer risk. Not all plant-based eating is equivalent.	Pancreatic

⚠️ Nutrients of Concern for Vegetarians & Vegans: Vitamin B12 (only in animal products — deficiency causes anemia, neurological damage), Vitamin K2, Vitamin D, Omega-3 fatty acids, and minerals including iodine, selenium, iron, and zinc. Anyone on a vegan or largely plant-based diet should supplement with B12 and K2 at minimum.

4. Dietary Fiber

An umbrella review published in Nutrients (2023) examined 11 large-scale meta-analyses. The conclusion was consistent across cancer types: the more dietary fibre consumed, the lower the risk of several cancers — particularly gastric, oesophageal, ovarian, and endometrial tumours.

The mechanisms are clear. For endometrial and ovarian cancers, fibre reduces the reabsorption and bioavailability of circulating oestrogens — reducing hormonal stimulation of cancer growth. For breast cancer, higher fibre intake tracked closely with fewer tumour incidences, particularly in postmenopausal women, via the same oestrogen recirculation pathway. Across multiple analyses, fibre also moderates inflammation — a known driver of malignant cell growth.

📌 Optimal intake: A 2019 Lancet publication found risk reduction was greatest when daily dietary fibre intake was between 25–29g/day. Most people in high-income countries consume fewer than 20g daily. Practical sources: legumes, whole grains, broccoli, berries, apples, oats, lentils, and chia seeds.

5. Fasting, Calorie Restriction, Low-Carb & Ketogenic Diet (Controversial)

⚠️ Label: Controversial — The evidence remains mixed and inconclusive. This topic is included because of its growing interest within integrative oncology, while emphasizing the limitations of the available evidence and the need for appropriate clinical caution.

A 2024 Nutrients literature review concluded that overnight fasting and carbohydrate restriction may contribute to cancer prevention, but excessive fasting may harm patients' quality of life. A Japanese study (cited in Korean gastric cancer guidelines) found low-carbohydrate diets are associated with higher risk of colorectal and lung cancer but reduce risk of gastric cancer — illustrating why blanket recommendations are inadequate.

Patient selection matters critically. If you are underweight, fasting, low-carb, calorie restriction, and ketogenic diets are not suitable for you. For overweight patients, short-term strategies may be considered — but long-term safety evidence remains mixed. Extreme caloric restriction and high-intensity workouts increase cortisol and should be avoided in cancer patients.

The biological case for ketogenic diets rests on the metabolic theory of cancer, most prominently advanced by Prof. Thomas Seyfried (Boston College): cancer cells have defective mitochondria and impaired metabolism — they can only ferment glucose and glutamine for energy. Ketone bodies cannot be fermented by cancer cells, making a ketogenic metabolic environment theoretically hostile to tumour growth (Nature, 2019). A 2021 review (Curr Issues Mol Biol) highlights that the ketogenic diet produces an unfavourable metabolic environment for cancer cells and represents a promising adjuvant in therapy.

Important distinction: Do not conflate reducing added sugars and ultra-processed foods with calorie restriction; these are distinct dietary strategies and should not be treated as interchangeable. Limiting added sugars and highly processed foods is generally consistent with established principles of healthy dietary patterns, whereas deliberate calorie restriction requires appropriate patient selection and further study in the context of cancer treatment. For many patients, dietary diversity and metabolic flexibility—the ability to shift between carbohydrate- and fat-derived fuels—may be more practical and sustainable than maintaining a strict ketogenic diet. Time-restricted eating or carefully implemented periods of fasting may be potential approaches for supporting metabolic flexibility, although their safety, feasibility, and clinical benefits in people with cancer require individualized assessment and further clinical research.

* Note on glutamine: Red meat has one of the highest sources of glutamine (1.2g per 100g serving). For glutamine-driven tumours, berberine is the most promising intervention once delivery issues are resolved (Onco, 2025). 

🔗 IMA/FLCCC Dietary Guidance: Dietary Interventions in Cancer (imahealth.org)

6. Meat: Cooking, Processing & Cancer Risk

The cancer risk associated with meat is not simply about how much you eat — it is significantly shaped by how it is processed and cooked.

Processed meat is classified as a Group 1 carcinogen by the International Agency for Research on Cancer. Hot dogs, bacon, sausage, deli meat, pepperoni, salami, and jerky contain nitrates and nitrites — preservatives that prevent bacterial growth but trigger the formation of N-nitroso compounds (NNOCs): carcinogens that promote DNA damage, oxidative stress, and inflammation in the colonic mucosa (GeroScience meta-analysis). Despite this, nearly half of 2,202 American adults recently polled were unaware that processed meat increases cancer risk. Two-thirds supported warning labels on packaging.

High-heat cooking of any meat — charring, burning, grilling, smoking, or pan-searing at high temperatures — generates heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). These compounds cause genetic mutations in colon and rectal lining cells, and a study in Nutrients found they increase oral cancer risk by the same mechanism.

The broader red meat–cancer link is less settled. One study in the Annals of Internal Medicine noted low certainty of evidence, small effect sizes, and confounding factors (physical inactivity, low fibre, gut dysbiosis, obesity). Isolating meat as a direct cause remains methodologically difficult.

💡 "Ristoceutics" — a practical strategy: eating fibre-rich vegetables alongside red meat attenuates cancer risk. A Nutrients study found that a diet high in red meat but low in fruits and vegetables was associated with increased risk of 15 cancers, while combining lower meat intake with higher vegetable and fruit consumption showed far less consistent cancer association. The side dish matters.

There is also a protective side to meat. Carnosine — found in high concentrations in animal muscle, especially red meat — reduces the viability and growth of colorectal cancer cells by acting as an antioxidant (Oncology Letters). The highly bioavailable haem iron in meat delivers oxygen in ways plant sources cannot efficiently replicate. The immune and detoxification systems — both critical for cancer defence — depend on protein, and animal foods remain among the richest sources.

Bottom line: Avoid processed meat and high-heat-charred meat. Limit unprocessed red meat to moderate quantities. Pair all meat with ample vegetables and fibre. Food quality and preparation method matter more than the binary "meat vs no meat" framing.

7. Coffee & Cancer

Coffee is the most studied dietary compound in oncology — PubMed indexes more than 2,500 research studies on coffee and cancer — and the news is largely positive.

Evidence	Finding
Umbrella review (Nature, 2021)	Coffee consumption is inversely associated with liver cancer and skin basal cell carcinoma.
Review of 1,000+ coffee compounds (PMID: 36769029, 2023)	Consistent associations between regular coffee intake and reduced risks of liver, endometrial, thyroid, and colorectal cancers.
JAMA Oncology (2020)	Regular coffee consumption associated with improved outcomes in non-metastatic colorectal cancer patients (large observational study nested in clinical trial).
Systematic review (2019, 4 studies)	Coffee has a weak-to-strong inverse association with liver cancer; Japanese populations likely to experience a decrease in primary liver cancer risk from regular consumption.
ACS 2024 update (Nutrients)	Coffee and tea have a neutral impact on overall cancer risk (confirms safety; no increased risk).

☕ Practical implication: 3–4 cups of coffee daily is associated with the most consistent cancer risk reduction signals. There is no current evidence to restrict coffee in cancer patients. Avoid adding sugar or high-sugar flavoured syrups, which would offset any benefit.

🥦 Anticancer Nutrition: Practical Priority Summary

✅ Do prioritise	Cruciferous vegetables (≥40g/day); colourful whole fruits; legumes and whole grains; oily fish; olive oil; 3–5 cups green tea or coffee daily; 25–29g dietary fibre/day
✅ Do adopt	Mediterranean diet pattern; healthy plant-based diet with quality animal protein; B12 + K2 supplementation if plant-based; organic where possible to reduce preservative load
⛔ Avoid strictly	Ultra-processed foods; sugar-sweetened beverages; food preservatives (especially nitrates/nitrites); charred or smoked meats; excessive red meat without vegetable pairing
⚠️ Use with caution	Fasting / ketogenic diet (not for underweight patients; mixed evidence; requires medical supervision); calorie restriction (patient selection critical)
📌 Key principle	Food quality and preparation method matter more than strict dietary categories. A processed vegan diet is worse than a whole-food omnivorous diet. Pair all meals with abundant vegetables.

Lifestyle Foundation: Stress Reduction, Sleep & Sunshine (Tier 4)

• Cancer types: Most cancer types.
• Evidence: Strong indirect evidence linking chronic stress, sleep deprivation, and low vitamin D to cancer incidence and progression; no direct RCTs testing stress reduction as cancer treatment.
• Techniques: Meditation, deep breathing, mindfulness, nature exposure — 15+ minutes outdoors daily.
• Dosage: 7–9 hours restorative sleep; sleep disruption suppresses melatonin and NK cell activity.
• Mechanism: Chronic cortisol elevation → immunosuppression → reduced tumour surveillance; sleep deprivation → reduced melatonin → loss of apoptotic signalling; sunshine → vitamin D synthesis → VDR-mediated cancer suppression pathways

Although ranked Tier 4 due to lack of direct RCT evidence for oncology outcomes, these three lifestyle factors represent the essential non-negotiable foundation of any integrative cancer protocol. Their indirect evidence is compelling and their risk profile is almost zero. They should be considered prerequisites, not additions.

Discussion: Where the Field Is Heading

Several clear themes emerge from this evidence-ranked review:

The Tier 1 story is already compelling. Aspirin (for PIK3CA-mutant CRC), metformin, statins, cimetidine; and diet, exercise and lifestyle (foundational) are supported by meta-analyses and guideline updates. These are not "fringe" therapies — they are data-supported, low-cost interventions that most oncology teams do not actively prescribe. The ALASCCA trial has already moved aspirin into NCCN guidelines. Cimetidine's Cochrane HR of 0.53 in CRC is more impressive than many approved drugs.

The perioperative window is critically underutilised. Propranolol and cimetidine both show their strongest signals in the perioperative context — the days around cancer surgery when immune suppression and stress-hormone surges create metastatic opportunity. Addressing this pharmacologically is low-risk and supported by trial data.

Repurposed antiparasitics are advancing. Ivermectin and benzimidazoles are moving from Tier 3 towards Tier 2. The $60 million Florida Cancer Innovation Fund, the Cedars-Sinai TNBC trial, and growing Phase I/II pipeline mark a genuine inflection point. Within two to three years, RCT data will either confirm or challenge the case-series signals.

Metabolic oncology is maturing. Metformin, statins, berberine, glucose restriction, and GLP-1 agonists are converging around a coherent framework: disrupt cancer cell metabolic dependencies while preserving normal cell function. The 2025 ASCO GLP-1 cancer data and the insulin/cancer evidence base are strengthening this approach.

DMSO and Tier 4 interventions warrant monitored investigation, not dismissal. As Dr Makis noted, the biology is interesting and the compounds are available. What is needed is documentation — peer-reviewed case series, then formal trials. The same trajectory that took ivermectin from anecdote to $60 million in funded research is available to DMSO if clinicians document and publish their cases.

Mistletoe evidence is real — but more limited than originally stated in this article. The strongest recent clinical data is from the Johns Hopkins Phase I IV mistletoe trial (Paller et al., Cancer Research Communications, 2023, PMID 36860652): 21 patients, disease control rate 23.8%, meaningful QoL improvement, Phase II dose established. The subcutaneous RCT evidence base consistently supports QoL benefits during chemotherapy but has not demonstrated survival benefit in rigorous placebo-controlled trials. 

Low Dose Naltrexone is the most overlooked Tier 2 intervention. At USD $30–50/month, with a 30-year mechanistic research base, a 2024 systematic review, an active Phase II RCT, and an exceptional safety profile, LDN's absence from standard oncology practice is difficult to justify on evidence grounds. The opioid-cancer intersection — and specifically the OGF/OGFr cell cycle regulation axis — represents a legitimate therapeutic target that deserves significantly more clinical attention than it currently receives.

Diet is not optional — it is pharmacological. The 2026 data on insulin resistance (25% increased cancer risk across 12 types), the umbrella review linking ultra-processed foods to reduced cancer survival, and the BMJ 2026 preservative study collectively make the case that what a patient eats is not a "lifestyle nicety" — it is a primary intervention. Cancer hospitals that continue to serve french fries and sugary desserts as standard patient meals are undermining every other treatment on this list. The policy and systems implications of this evidence deserve urgent attention from hospital administrators, not just oncologists.

Conclusion

Theoretically, repurposed drugs can partially alleviate the shortage of new drugs and resistance to existing chemotherapeutic drugs. For patients with advanced disease or chemotherapy resistance who lack alternative treatment options, combination therapy is a promising and valuable treatment option. Combining repurposed therapeutic drugs with approved anticancer drugs can achieve synergy and improve therapeutic effectiveness and safety.

Due to the multiple mechanisms of resistance and complex oncogenic signaling pathways of cancers, monotherapy may be relatively ineffective for cancer patients. This may explain why few repurposed drugs can be used in cancer treatment as monotherapy, and why, in the era of precision medicine, drug combination therapies are a more promising strategy. Drug combination therapies typically target multiple mechanisms, including downstream off-target, parallel pathways, or compensatory signaling. Concurrently, with the rapid development of molecular profiling, the use of non-oncological drugs that have the potential to target multiple hallmarks of cancer and specialized TME could be a vital complement to personalized/precision treatment in the near future. Furthermore, combining repurposed drugs with first-line anticancer drugs will offer cancer patients new treatment opportunities.

This review presents a framework for that possible combination opportunities. Start with Tier 1: aspirin for PIK3CA-mutant CRC, exercise, metformin, statins, cimetidine for colorectal cancer, and BCG for bladder cancer. These are evidence-backed, low-cost, and underutilized. Add Tier 2 interventions — BCG (bladder cancer), Mistletoe, LDN, propranolol, ivermectin, mebendazole, vitamin D, omega-3, IV vitamin C, melatonin — guided by cancer type and patient context. Consider Tier 3 repurposed drugs under physician supervision, with clear biomarker monitoring. Treat Tier 4 interventions as experimental — potentially valuable, currently unproven in humans.

Underpin all of this with an anticancer nutritional foundation: eliminate ultra-processed foods, sugar-sweetened beverages, and processed meats; emphasise cruciferous vegetables, dietary fibre (25–29g/day), olive oil, and whole plant foods; and apply ketogenic or fasting strategies only under appropriate clinical supervision. The evidence for diet quality in cancer outcomes is now at umbrella-review level — the same tier as the strongest pharmacological evidence. It deserves the same clinical priority.

To find integrative oncologists who might guide this process, see our Integrative Oncologist Directory. 

⚠️ Medical Disclaimer: This content is for educational purposes only. Nothing in this article should be used as the basis for initiating, modifying, or discontinuing any cancer treatment without guidance from your treating oncologist or physician. The interventions described here are not approved cancer treatments unless explicitly stated.

Key References & Further Reading

1. ALASCCA Trial — Aspirin in PIK3CA-mutant CRC. NEJM, September 2025. [Summary]
2. Cochrane Review — Cimetidine adjuvant therapy in colorectal cancer. 2012 (6 RCTs, 1,229 patients).
3. ESHO Multicenter Trial — Hyperthermia + radiotherapy in metastatic melanoma. [Source]
4. COMPIT Trial — Perioperative propranolol + etodolac in CRC. Eur J Surg Oncol. 2023.
5. Propranolol systematic review (31 studies, 7 RCTs). PMC. 2025. [Source]
6. NCT05318469 — Ivermectin + Balstilimab in metastatic TNBC. Cedars-Sinai. 2025 ASCO results. [Trial]
7. De Castro et al. Ivermectin in refractory paediatric AML. Anticancer Res. 2020. [PubMed]
8. Ishiguro et al. Ivermectin case series. 2022. [PubMed]
9. Cardiff University — Aspirin and cancer mortality. Br J Cancer. 2023. [Source]
10. Aspirin and digestive tract cancers meta-analysis. Annals of Oncology. 2020.
11. High-dose vitamin C review (150+ studies). J Pharmacol Sci. 2026. [Source]
12. Fan et al. IV Vitamin C dosing (1.5g/kg/day). 2023.
13. Lim. MB-mediated PDT — systematic review. 2023. [PMC]
14. Da Veiga Moreira et al. Methylene blue in ovarian cancer. 2024. [PMC]
15. Matsumoto et al. Cimetidine 10-year survival in CRC. Br J Cancer. 2002.
16. Marik PE. Cancer Care: 2nd Edition. FLCCC/IMA Health. [imahealth.org]
17. Integrative naturopathic treatment + mEHT in CRC (n=131). Integrative Medicine and Health. 2025.
18. Nature — Drug repurposing in cancer. 2024. [Source]
19. Top 10 Cancer Fighting Supplements — Cancer Advisor
20. Fenbendazole vs Mebendazole for Cancer
21. Enhanced Ivermectin + Mebendazole 16-Week Protocol (OneDayMD Substack)
22. ACS Diet and Physical Activity Guidelines for Cancer Prevention. 2020.
23. ACS Nutrition and Physical Activity Guideline for Cancer Survivors. 2022.
24. Nutrients literature review — International cancer dietary guidelines update. 2024.
25. AACR — Ultra-Processed Foods linked to Reduced Survival after Cancer. 2026.
26. Nature Communications — Insulin resistance and 12 cancer types (+25% risk). University of Tokyo / Taichung Veterans General Hospital. February 2026.
27. BMJ — Food preservatives and cancer risk. NutriNet-Santé cohort (n=large; 7.57-year follow-up). 2026.
28. BMJ Umbrella Review — Ultra-processed food and 32 adverse health parameters. 45 pooled analyses, 9,888,373 participants. 2024.
29. BMJ Umbrella Review — Dietary sugar and cancer risk. 8,000+ studies. 2023.
30. Cell — Methylglyoxal (MGO) and sugar-driven cancer risk mechanisms. 2024.
31. PLOS One — Vegetarian/vegan diet and cancer risk reduction. 48 reviews, 2024.
32. JAMA Oncology — Plant-enriched diet and cancer risk. 2022.
33. BMC Medicine — Healthy plant-based diet and bowel cancer (n=79,952). 2022.
34. Am J Clin Nutr — Healthy vs unhealthy plant-based diet and pancreatic cancer risk. 2023.
35. BMC Gastroenterology — Cruciferous vegetables and colon cancer risk: 17 studies, 639,539 participants, 17% risk reduction. 2025.
36. Umbrella Review — Cruciferous vegetable intake: gastric, lung, endometrial cancer. 2022.
37. Meta-analysis — Olive oil consumption and 31% lower risk of any cancer. 45 studies. 2022.
38. Nutrients — Dietary fibre and cancer risk: umbrella review of 11 meta-analyses. 2023.
39. The Lancet — Dietary fibre intake 25–29g/day and cancer risk reduction. 2019.
40. Nutrients — Low-carbohydrate diet and cancer risk (Japanese study). 2024.
41. Curr Issues Mol Biol — Ketogenic diet antitumour mechanisms. 2021.
42. Nutrients — Red meat, cooking methods, and cancer risk. 2024.
43. GeroScience — Nitrates, nitrites, and N-nitroso compounds in processed meat (meta-analysis).
44. Oncology Letters — Carnosine in red meat and colorectal cancer cell viability.
45. Annals of Internal Medicine — Red meat and cancer: low certainty of evidence review.
46. Nature — Coffee umbrella review: liver cancer and basal cell carcinoma. 2021.
47. JAMA Oncology — Coffee and non-metastatic colorectal cancer outcomes. 2020.
48. Systematic review — Coffee and primary liver cancer (4 studies). 2019.
49. PMID: 36769029 — 1,000+ coffee compounds: liver, endometrial, thyroid, colorectal cancer risk reduction. 2023.
50. Journal of Nutritional Oncology — Plant compounds and cancer-protective pathways review. 2025.
51. IMA Health — Dietary Interventions in Cancer. [imahealth.org]
52. BMC Medicine — WCRF/AICR adherence and reduced cancer risk. 2023.
53. LDN — Systematic review: low dose naltrexone in cancer (16 studies). Cureus. 2024. PMID: 38966634
54. NCT04401579 — Phase II RCT: Low dose naltrexone + alpha-lipoic acid in pancreatic cancer. [ClinicalTrials.gov]
55. Zagon IS, McLaughlin PJ. Opioid growth factor (OGF) and the OGFr receptor axis in cancer biology. Penn State University. 30+ years of mechanistic research.
56. LDN Research Trust — Clinical evidence database. [ldnresearchtrust.org]
57. EF-14 Trial — Tumor Treating Fields + temozolomide in newly diagnosed GBM. JAMA. 2015; 5-year OS update 2017. PMID 26670971
58. STELLAR Trial — TTF + pemetrexed/cisplatin/carboplatin in malignant pleural mesothelioma (n=80, Phase 2 single-arm). Median OS 18.2 vs 12.1 months (historical control). The Lancet Oncology. 2019/2020. NCT02397928.
59. EF-11 Trial — TTF vs chemotherapy in recurrent GBM (non-inferior, superior tolerability). JAMA. 2012.
60. Novocure — PANOVA-3 (pancreatic), LUNAR (NSCLC), INNOVATE-3 (ovarian) trial data. [novocure.com]
61. Paller CJ, Wang L, Fu W, et al. Phase I Trial of Intravenous Mistletoe Extract in Advanced Cancer. Cancer Research Communications. 2023;3(2):338–346. doi:10.1158/2767-9764.CRC-23-0002. PMID 36860652
62. STELLAR Phase 2 trial — Tumor Treating Fields + pemetrexed/cisplatin/carboplatin in malignant pleural mesothelioma (n=80). Median OS 18.2 vs 12.1 months (historical control). The Lancet Oncology. Published 2019–2020. NCT02397928. [Annals of Oncology final results]
63. Systematic review — Mistletoe extracts in cancer (30 datasets from 26 publications). BMC Complement Med Ther. 2020. PMC7370416