In a groundbreaking advancement in breast cancer therapy, researchers have initiated the first-in-human clinical trial exploring the safety and tolerability of Plasma Adjuvant INtra-operative Treatment (PAINT), utilizing non-thermal plasma (NTP) technology. This innovative approach aims to confront the persistent challenge of local recurrence in breast cancer patients following breast conservation therapy, a domain where conventional treatments have plateaued. Non-thermal plasma, characterized as an ionized gas composed of charged particles and highly reactive agents, has demonstrated potent anticancer properties in both laboratory and animal studies, but its translation to clinical practice marks a pivotal moment in oncological treatment strategies.
Breast cancer remains one of the most prevalent malignancies worldwide, with lumpectomy—a surgery to remove the tumor followed by radiation therapy—emerging as a standard breast conservation approach. Despite these interventions, a concerning 15–20% of patients experience local recurrence within 10 years, underscoring the pressing need for supplementary therapies targeting residual cancerous cells in the tumor bed. The application of NTP during surgery offers a novel intra-operative adjuvant strategy designed to eradicate microscopic disease and potentially reduce the risk of local recurrence without the added toxicities typically associated with systemic chemotherapy or additional radiation doses.
The trial, recently registered under ClinicalTrials.gov (NCT06222788), adopts a meticulous dose-escalation design to systematically explore the safety profile of NTP administered directly to the tumor bed immediately following lumpectomy. This study innovatively segments patients into three cohorts to examine different treatment paradigms: ex vivo plasma treatment on excised tumor bed tissues, in situ plasma exposure with complete tissue excision for analytical purposes, and in situ treatment with partial tissue retention aimed at real-world application scenarios. This stratified approach allows the investigators to robustly evaluate both safety measures and preliminary biological responses within normal and cancerous tissues.
Non-thermal plasma technology exploits physical and chemical mechanisms unique from traditional cancer therapies. The reactive oxygen and nitrogen species generated by NTP induce oxidative stress selectively in malignant cells, triggering apoptosis and inhibiting proliferation. Critically, NTP achieves these effects at ambient temperature, mitigating collateral thermal damage to the surrounding healthy tissue. This precise mode of action, combined with its potential for intra-operative use, positions NTP as a highly promising modality for localized tumor control within the breast, where cosmetic and functional outcomes are paramount.
The study’s primary endpoint focuses on determining the maximum tolerable dose of plasma delivered during surgery, a crucial step before expansive efficacy trials can commence. Researchers will meticulously monitor dose-limiting toxicities, treatment-emergent adverse events, and changes in laboratory parameters over a three-month follow-up period. All adverse events will be assessed and coded based on the Common Terminology Criteria for Adverse Events (CTCAE v5.0), ensuring standardized reporting and facilitating cross-trial comparisons. Beyond safety, the study also evaluates cosmetic outcomes, recognizing the importance of quality of life and aesthetic satisfaction among breast cancer survivors.
One of the fascinating aspects of this trial is the integration of quality of life questionnaires and photographic documentation to capture subtle changes in breast texture and appearance post-treatment. These patient-centered measures represent a comprehensive approach to assessing the broader implications of NTP therapy, providing insights beyond traditional clinical endpoints. Since survival rates for breast cancer have markedly improved, prioritizing cosmetic outcomes represents an ethical and clinical imperative that this trial addresses head-on.
Laboratory analysis of treated tissues will play a pivotal role in elucidating the biological impact of NTP within both diseased and adjacent healthy cells. By comparing histological and molecular changes between plasma-exposed samples and untreated controls, researchers aim to understand the mechanisms through which NTP mediates tumor cytotoxicity and its potential effects on wound healing. These findings could pave the way for optimizing treatment parameters to maximize efficacy while preserving normal tissue integrity.
Importantly, this study reflects a broader shift in oncology toward integrating novel physical sciences technologies to complement traditional cancer treatments. Plasma medicine, though still emergent, intersects disciplines including physics, chemistry, and biology, promising fresh therapeutic avenues previously unexplored in clinical settings. If shown to be safe and tolerable, NTP could revolutionize intra-operative cancer care, offering oncologists a new tool to combat microscopic residual disease without extending surgery time or increasing patient risk.
The investigators have designed the dose escalation phase according to the “3 + 3 design,” a widely accepted method in early-phase clinical trials to efficiently and safely determine dosing limits. Beginning with small patient cohorts, doses are carefully escalated while closely monitoring individuals for adverse reactions. This conservative approach prioritizes patient safety, a non-negotiable criterion given the novelty of NTP application in human subjects, particularly within the delicate and functionally important breast tissue.
As a first-in-human trial, the Breast Cancer PAINT study inherently carries the excitement and uncertainty of exploring new scientific territory. Yet, it is grounded in solid preclinical evidence demonstrating that NTP can disrupt cancer cell viability through oxidative mechanisms without inducing thermal injury. Previous research has validated NTP’s efficacy against a variety of tumor types in vitro and in animal models, making this clinical translation a highly anticipated step toward potentially reshaping breast cancer management.
Moreover, the localized nature of NTP application during surgery offers a distinct advantage over systemic therapies by minimizing exposure of distant organs to toxic agents, thereby reducing adverse systemic effects. This localized therapy aligns well with the principles of precision medicine, targeting the tumor bed microenvironment precisely when and where it is most susceptible to eradication. If successful, the approach could significantly decrease the rates of local relapse, a persistent obstacle in improving long-term breast cancer outcomes.
The implications of this trial extend beyond breast cancer. Successful demonstration of NTP safety and tolerability could stimulate investigations into its applicability across other solid tumors where surgical excision is standard, providing a versatile adjuvant strategy. The concept of leveraging physical plasma during oncologic surgeries could open entirely new frontiers in intra-operative cancer care, blending cutting-edge technology with established surgical procedures.
Patient recruitment for the Breast Cancer PAINT study reflects careful ethical consideration, ensuring informed consent and rigorous safety protocols. Trials of this nature bear great responsibility as they bring experimental therapies directly into patient care with the hope of advancing standards but also the need to protect participants from unforeseen harms. Transparent reporting of outcomes, both positive and adverse, will be essential to build trust and guide future development.
This clinical investigation also contributes to the growing field of plasma medicine, which explores therapeutic applications of plasma for dermatology, wound healing, and now cancer therapy. Each success story in this rapidly evolving domain bolsters momentum toward integrating plasma technologies into everyday clinical use, transforming the way physicians approach disease eradication and tissue repair.
Looking forward, the data generated from this trial will inform larger Phase II and III studies designed to evaluate efficacy endpoints such as reduction in local recurrence rates, overall survival improvements, and long-term cosmetic outcomes. The translational potential of NTP as an adjuvant modality combined with standard treatments could present a paradigm shift in comprehensive breast cancer care.
In conclusion, the Breast Cancer PAINT trial represents a pioneering effort to harness the unique properties of non-thermal plasma in a clinical oncology setting. By systematically assessing safety, tolerability, and cosmetic impacts while exploring biological effects in treated tissues, this study paves the way for establishing plasma technology as a viable adjuvant treatment for breast cancer and potentially other malignancies. The scientific and medical communities eagerly await the outcomes of this innovative investigation, poised to potentially revolutionize cancer surgery and patient quality of life.
Subject of Research: Use of non-thermal plasma (NTP) as an intra-operative adjuvant treatment to reduce local recurrence in breast cancer patients after lumpectomy.
Article Title: Breast cancer PAINT: a first-in-human, dose-escalation study to determine the safety of Plasma Adjuvant INtra-operative Treatment in breast cancer patients.
Article References:
Glory, A., Patocskai, E. & Wong, P. Breast cancer PAINT: a first-in-human, dose-escalation study to determine the safety of Plasma Adjuvant INtra-operative Treatment in breast cancer patients. BMC Cancer 25, 748 (2025). https://doi.org/10.1186/s12885-025-14153-5
Image Credits: Scienmag.com
