Future Directions in Alpha-Emitter Therapy for Metastatic Ovarian Cancer

Purpose: Ovarian cancer (OC) is often diagnosed at an advanced stage and characterized by high rates of recurrence despite aggressive cytoreductive surgery and chemotherapy. Relapse is driven by microscopic residual tumors disseminated throughout the peritoneal cavity which poses significant challenges with conventional therapy. Targeted-alpha particle therapy (TAT) combines molecular targeting of cancer with alpha-emitting radionuclides to deliver highly potent and localized cellular damage, uniquely suited for the eradication of small tumor clusters within the peritoneal cavity.

Methods/Materials: An extensive literature search for clinical trials (clinicaltrials.gov) and pre-clinical studies (PubMed, Scopus, Google Scholar) was conducted. Four clinical trials were identified to critically evaluate early treatment outcomes in terms of efficacy, safety, and feasibility. The 19 pre-clinical studies identified targeting strategies against a variety of tumor-associated antigens.

Results: TAT is positioned to evolve into a broadly applicable modality for patients with advanced stage peritoneal malignancies who currently have limited therapeutic options with continued advancements in ligand engineering, reliable imaging/dosimetry, expanded generator production pipelines to stabilize global isotope supply, and efficient regulatory pathways. Integration of TAT into clinical practice as an adjuvant therapy or primary strategy for minimal residual disease has the potential to reshape the standard of care in the management of gynecological cancers and transform a historically deadly diagnosis into a therapeutically addressable target. Several challenges remain including heterogenous antigen expression, delivery and retention within the peritoneal cavity, off-target toxicity, radiation resistance, radionuclide availability, dosimetry uncertainties, and clinical trial design limitations.

Conclusions: Looking forward, the TAT platform for OC will naturally extend to other solid tumor malignancies where microscopic implants remain major drivers of mortality, including that of endometrial, cervical, gastric, and colorectal cancers. TAT with immunotherapy is also a likely combination.