Introduction

Cancer remains one of the leading causes of death worldwide, prompting ongoing research into novel therapeutic strategies. The repurposing of existing medications—off-label use—has emerged as a promising approach in oncology. Among the drugs being explored are ivermectin, traditionally an antiparasitic agent, and metformin, a first-line treatment for type 2 diabetes. Both have shown potential in preclinical studies and early-phase clinical trials, leading to increased interest in their off-label use in cancer treatment.

What Is Off-Label Drug Use?

Off-label drug use refers to the prescription of a drug for an indication, dosage, route, or patient population not included in the approved labeling by regulatory authorities (such as the FDA). While legal and often based on emerging scientific evidence, off-label use requires careful consideration of existing data, clinical judgment, and ethical oversight.

Ivermectin: Investigating Its Potential in Oncology

Mechanisms of Action

Ivermectin has been studied for its potential anticancer properties through various mechanisms:

Inhibition of WNT/β-catenin signaling: This pathway is often dysregulated in cancers like colorectal and breast cancer.
Induction of apoptosis and autophagy: These processes can lead to programmed cell death and the degradation of dysfunctional cellular components.
Suppression of cancer stem cell properties: Targeting cancer stem cells may reduce tumor recurrence and metastasis.
Enhancement of sensitivity to chemotherapy and radiation: Ivermectin may potentiate the effects of conventional cancer therapies.

Clinical Evidence

Despite promising preclinical findings, clinical evidence supporting ivermectin's efficacy in cancer treatment remains limited. A recent review highlighted that while ivermectin has demonstrated anticancer effects in laboratory settings, there is insufficient data from randomized clinical trials to confirm its effectiveness in humans. Additionally, concerns regarding appropriate dosing and potential side effects underscore the need for further research before considering its use in oncology.

Metformin: A Repurposed Diabetes Drug with Anticancer Potential

Mechanisms of Action

Metformin's anticancer effects are thought to arise from several mechanisms:

Activation of AMPK (AMP-activated protein kinase): This leads to inhibition of the mTOR pathway, a central regulator of cell growth and metabolism.
Reduction of insulin and IGF-1 levels: Both are implicated in tumor growth and progression.
Inhibition of cancer stem cells: Metformin may reduce the population of cells responsible for tumor initiation and recurrence.

Clinical Evidence

Breast Cancer

The MA.32 trial, a phase III randomized controlled trial, investigated the effect of metformin on invasive disease-free survival in patients with early-stage breast cancer. The study found no significant improvement in outcomes with metformin compared to placebo, suggesting limited benefit in this population.

Colorectal Cancer

A meta-analysis indicated that metformin use was associated with a 37% reduction in the risk of developing colon cancer in individuals with type 2 diabetes. Additionally, laboratory studies have shown that metformin may slow the growth of colon cancer cells by altering cellular energy use, potentially making cancer cells less likely to develop and divide.

Ovarian Cancer

A phase II clinical trial explored metformin as a cancer stem cell–targeting agent in ovarian cancer. The study met its primary endpoint by demonstrating a reduction in cancer stem cell markers and reported favorable progression-free and overall survival rates. However, the trial's nonrandomized design and small sample size limit the generalizability of these findings.

Lung Cancer

The OCOG-ALMERA trial, a phase II randomized clinical trial, examined the addition of metformin to chemoradiotherapy in patients with locally advanced non–small cell lung cancer. Preliminary results suggested potential benefits, including improved survival rates, warranting further investigation in larger studies.

Safety and Tolerability

Metformin is generally well-tolerated, with a long-established safety profile. However, gastrointestinal side effects, such as diarrhea, can occur, particularly at higher doses. These side effects may impact patient adherence to treatment regimens.

Ethical and Clinical Considerations

While the off-label use of ivermectin and metformin in oncology presents potential benefits, several ethical and clinical considerations must be addressed:

Evidence-Based Practice: Clinicians should base treatment decisions on robust clinical evidence to ensure patient safety and efficacy.
Informed Consent: Patients should be fully informed about the potential risks and benefits of off-label treatments.
Monitoring and Reporting: Close monitoring for adverse effects and reporting of outcomes contribute to the broader understanding of these treatments' efficacy and safety profiles.

Conclusion

The exploration of off-label medications like ivermectin and metformin in oncology is an exciting frontier. While metformin has shown promise in certain cancer types, particularly in diabetic patients, ivermectin's role remains largely speculative due to limited clinical data. Ongoing and future clinical trials are essential to determine the safety and efficacy of these drugs in cancer treatment. Until then, their use should be approached with caution, guided by the principles of evidence-based medicine and patient-centered care.