Improving Treatment Options for Patients with Breast Cancer

Written by: Akash Gupta

Edited by: Kristine Chung and Michelle Kwon

Illustrated by: Ariel Brown-Ogha

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For decades, conventional external beam radiotherapy, referred to as EBRT, has been the standard approach for treating early-stage breast cancer. This process requires patients to undergo multiple radiation sessions over several weeks. While effective, this method can be time-consuming, physically demanding, and pose risks to surrounding healthy tissues. A more specific and efficient alternative has emerged to address these challenges: Targeted Intraoperative Radiotherapy (TARGIT IORT). TARGIT IORT is a revolutionary approach to cancer treatment, specifically targeting early-stage breast cancer. Unlike traditional radiotherapy, which requires multiple sessions over several weeks, TARGIT IORT delivers a single, targeted dose of radiation directly to the tumor bed during surgery. This technique minimizes radiation exposure to surrounding healthy tissues and organs and offers an efficient, convenient, and patient-friendly alternative to conventional radiation therapy.

Before a patient decides to pursue the course of TARGIT IORT, they must understand some key terminology related to breast cancer treatment. First, breast cancer refers to the uncontrolled growth of cells in the breast, often forming a tumor. It can be detected through various screening methods, such as mammograms (an X-ray test to diagnose breast cancer), and is staged based on tumor size, lymph node involvement, and whether cancer has spread to other parts of the body. Breast cancer can develop due to a combination of genetic, environmental, and lifestyle factors, affecting both women and men. A lumpectomy is a standard surgical procedure for early-stage breast cancer, where only the tumor and a small margin of surrounding tissue are removed, leaving the rest of the breast intact. Following a lumpectomy, most patients require additional treatments, such as radiation therapy, which aims to remove any remaining cancer cells and reduce the risk of recurrence [1]. This is where TARGIT IORT differs from the standard whole-beam radiation therapy (WBRT). 

Traditional radiotherapy requires multiple treatment sessions over several weeks, making it a time-consuming and burdensome process for patients. Moreover, it may lead to incomplete treatments due to challenges of accessibility for some patients because of the number of treatments required. Using a linear accelerator machine called LINAC, a beam of radiation is aimed at a marked area on the breast, which prevents the cancer cells from growing and dividing. This radiation breaks the sugar-phosphate backbone of the cancer cells’ DNA molecules, which then prevents the cells from continuing to grow and divide, eventually leading to cellular death. While this may seem extremely effective, radiation is not limited to just the cancerous cells, as there have been many cases of nearby non-cancerous cells suffering the same fate [2]. DNA damage done to healthy cells can result in a multitude of consequences, ranging from acute side effects such as tissue inflammation to chronic conditions such as fibrosis and even the risk of secondary cancer [3]. Although this treatment only lasts around twenty minutes, multiple sessions are necessary, creating a significant burden on patients who may be experiencing side effects from the radiation therapy. Daily treatments for up to six weeks are essential in achieving the best results, but incomplete treatments may occur due to the inability of patients to maintain a rigorous schedule [4]. 

In contrast, the process of TARGIT IORT is administered during a lumpectomy procedure, immediately after the tumor has been surgically removed. A specialized, spherical applicator is placed in the tumor cavity, delivering a precise radiation dose directly to the affected area. The applicator's size is carefully matched to fit perfectly within the excised tumor bed. It is then inserted into the tumor cavity, ensuring it is in direct contact with the surrounding tissues, where small, microscopic cancer cells may still exist. The surrounding tissues are gently positioned around the applicator to distribute uniform radiation. Another key difference in TARGIT IORT’s process is its localization. This approach only affects the immediate area, reducing exposure to deeper tissues such as the heart and lungs beneath the breast. While the radiation requires a more extended administration, it is completed in a single session during surgery, reducing treatment time, hospital visits, and associated costs that occur with daily radiation treatments seen in EBRT.

A prospective open-label randomized clinical trial called TARGIT-A was conducted to investigate the effectiveness of TARGIT IORT; a participant population of 2298 women from 32 centers in 10 countries qualified with early-stage breast cancer. Patients were randomized 1:1 to the TARGIT IORT group and the EBRT group to assess the non-inferiority of the novel strategy within a 2.5% margin [5]. Non-inferiority trials are used when the benefit is a safer and less burdensome treatment for the patient. Instead of showing that a new treatment might provide more promising results, it aims to confirm that it works almost as well or, at the very least, not worse than a predefined margin. After extensive observations and calculations, there can be three separate interpretations of the results at the end of the trials. If the new treatment’s effect lies within the non-inferiority margin (in this case: 2.5%), it is denoted as non-inferior, meaning that the new treatment offers the same results as the preexisting treatment while potentially coming with less risk. If the new treatment proved to be better than the standard, then it would be declared superior. Finally, if the new treatment was worse than the margin, it would be labeled as inferior and thus would not be an acceptable replacement for what is already being used [6]. TARGIT IORT is more convenient than EBRT and does not have the concerns surrounding patient compliance to complete the full treatment, thus justifying a non-inferiority trial design. The study spanned over twelve years with a primary endpoint of demonstrating no local recurrence at the surgical site during this period. 

The primary findings of the study were that the TARGIT IORT was non-inferior to the standard EBRT treatment (2.11% vs. 0.95%) local recurrence at five-year follow-up, which was within the pre-assigned non-inferiority bounds. The bounds were pre-specified before the start of the trial as to what was considered similar to the existing EBRT treatment. TARGIT IORT was found to be advantageous for patients as it significantly reduced radiation-related side effects. This included, but was not limited to, skin burns, formation of scar tissue, and internal heart and lung damage. This advantage of the novel treatment likely led to significantly fewer non-cancer-related deaths. Additionally, patients who received the new treatment avoided the long treatment schedules of EBRT, thus allowing many women to complete their whole cancer journey in a single surgery. The investigators also note that in long-term follow-up of a median of 8.6 years, IORT produced around the same, if not better, results in comparison to EBRT with regards to local recurrence-free survival, mastectomy-free survival, distant disease-free survival, and overall survival. This confirmed IORT was non-inferior to EBRT, making it a viable alternative treatment strategy. 

The non-inferiority design for this trial accounts for the fact that IORT offers patients a higher rate of compliance, less risk for incomplete radiation treatment, and lower complication rates. Given that there was no statistical difference between EBRT and IORT concerning the primary endpoint of local recurrence at the surgical site within five years, the study demonstrates the viability of IORT as an alternative treatment for patients undergoing lumpectomy for breast cancer. Moreover, by including multiple countries and investigator sites, the broader applicability of the results can likely be applied to the general population. 80% of patients in the TARGIT IORT did not require further radiation treatment, and the treatment costs are far less expensive than the standard six-week radiation strategy employed with EBRT. TARGIT IORT is thus non-inferior to EBRT in preventing local recurrence of early breast cancer at 5-year follow-up post-surgical resection of the lesion. The treatment also offers a significantly lower chance of death from non-cancer-related causes and improved convenience, lower cost, and fewer complications. 

Despite its many advantages, TARGIT IORT is not suitable for all breast cancer patients. It is primarily recommended for individuals with early-stage breast cancer and low-risk tumor profiles. Patient eligibility is determined based on tumor size, type, and overall health condition, making consultation with a specialized oncology team essential. However, with the pace of technology evolving in recent years, TARGIT IORT or alternative strategies may be tested against EBRT in the future to see if it may be effective for more aggressive breast cancers. 

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References

[1] Łukasiewicz, S., Czeczelewski, M., Forma, A., Baj, J., Sitarz, R., & Stanisławek, A. (2021). Breast Cancer-Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies-An Updated Review. Cancers, 13(17), 4287. https://doi.org/10.3390/cancers13174287

[2] Hazout, S., Oehler, C., Zwahlen, D. R., & Taussky, D. (2025, April 29). Historical view of the effects of radiation on cancer cells. Frontiers. https://www.frontiersin.org/journals/oncology-reviews/articles/10.3389/or.2025.1527742/full 

[3] Radiological Society of North America (RSNA) and  American College of Radiology (ACR). (2023, May 1). Linear accelerator. Radiologyinfo.org. https://www.radiologyinfo.org/en/info/linac 

[4] Winstead, E. (2021, September 30). Breast cancer surgery’s impact on quality of life. Breast Cancer Surgery’s Impact on Quality of Life - NCI. https://www.cancer.gov/news-events/cancer-currents-blog/2021/breast-cancer-mastectomy-quality-of-life 

[5] Vaidya, J. S., Bulsara, M., Baum, M., Wenz, F., Massarut, S., Pigorsch, S., Alvarado, M., Douek, M., Saunders, C., Flyger, H. L., Eiermann, W., Brew-Graves, C., Williams, N. R., Potyka, I., Roberts, N., Bernstein, M., Brown, D., Sperk, E., Laws, S., … Tobias, J. S. (2020). Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (Targit-IORT) for early breast cancer: Targit-A randomised clinical trial. BMJ, m2836. https://doi.org/10.1136/bmj.m2836 

[6] Cuzick, J., & Sasieni, P. (2022). Interpreting the results of Noninferiority Trials—a review. British Journal of Cancer, 127(10), 1755–1759. https://doi.org/10.1038/s41416-022-01937-w