Shannon M MacDonald, FASTRO, FACRO
Southwest Florida Proton Center
Introduction
Radiotherapy has long played a significant curative role in the management of breast cancer. Proton therapy, an advanced form of radiotherapy, offers the potential to reduce radiation exposure to the heart and other nearby tissues compared to traditional photon therapy. This reduction in incidental radiation may lessen the morbidity associated with radiation treatment for breast cancer.
Patient Population and Rationale for Proton Therapy
Each year, over 200,000 women in the United States are diagnosed with localized breast cancer. Of these, approximately one-third present with locally advanced disease or lymph node involvement, making them candidates for comprehensive nodal irradiation. Including the internal mammary lymph nodes (IMNs) in the radiation field is especially beneficial for these patients, as the proximity of the IMNs to the heart and lungs increases the risk of collateral exposure. Proton therapy may mitigate this risk by minimizing radiation dose to these critical organs, making this population more likely to benefit from proton therapy.
Historical Context and Clinical Trials
The first reported case of breast cancer treatment including regional and internal mammary lymph nodes with proton therapy occurred in 2010, coinciding with the launch of the first prospective clinical trial in this area. A major milestone was reached with the initiation of a randomized controlled trial, RadComp (Radiation Therapy Comparative Effectiveness Trial), in February 2016. By March 2024, the trial had successfully accrued 1,239 patients. In contrast, proton therapy for prostate cancer began much earlier, with the first treatment documented in 1979. Despite this head start, the first phase three randomized trial comparing proton and photon therapy for prostate cancer only recently concluded, enrolling 450 patients.
Comprehensive Nodal Irradiation and IMN Inclusion
Comprehensive nodal irradiation for breast cancer encompasses the axilla, supraclavicular nodes, and internal mammary lymph nodes. Multiple clinical guidelines recommend including the IMNs in the treatment volume, and several randomized controlled trials have demonstrated improved disease-free survival and reduced breast cancer mortality with this approach. However, the decision to include the IMNs is often individualized, as IMN irradiation can increase cardiac and pulmonary toxicity due to higher doses to the heart and lungs. Notably, the RadComp trial included only women whose treatment fields incorporated the IMNs, focusing on patients with locally advanced disease or lymph node involvement.
Design and Findings of the RadComp Trial
The RadComp trial was designed to provide high-quality evidence on whether proton therapy could reduce side effects while maintaining the effectiveness of photon therapy. Researchers enrolled 1,239 patients with non-metastatic breast cancer across 32 U.S. centers, randomizing them to proton (624 patients) or photon therapy (615 patients). The median age was 50, with most patients having undergone mastectomy, having few cardiovascular risk factors, and presenting with left-sided or bilateral cancer. All received radiation to the IMNs.
Participants completed validated quality-of-life questionnaires before treatment, at the end of radiation, and at one and six months post-treatment, covering physical, social, emotional, and functional well-being, as well as side effects and satisfaction. Both groups reported similarly high quality of life and satisfaction, including cosmetic outcomes.
Patients treated with protons were somewhat more likely to recommend their treatment or choose it again, report that the treatment was right for them, and were satisfied, feeling that the treatment was effective. However, since patients were aware of their treatment type, this may reflect perceptions of newer or more expensive therapies. No shortness of breath versus any shortness of breath favored the proton arm, but this difference was not statistically significant after correction for multiplicity. RADCOMP will further investigate shortness of breath and the relationship for protons, photons and dose delivered to the lungs.
Quality-of-life research, including patient-reported outcomes, is a key endpoint in modern clinical trials. Such data illustrate not only the effectiveness of treatment but also patients’ lived experiences and satisfaction.
These results were presented at the American Society for Radiation Oncology (ASTRO) Annual Meeting.
Individualizing the Use of Proton Therapy
Proton therapy is typically considered for women with non-metastatic breast cancer who require IMN irradiation or have tumors situated close to the heart, particularly those located medially in the left breast or chest wall. The benefit of proton therapy is highly individualized, depending on anatomical factors and the effectiveness of photon-based plans. Some patients, due to favorable anatomy or heart-displacing techniques, can achieve excellent coverage and organ sparing with photons. For others, protons can further reduce heart and lung doses, thereby lowering the risk of long-term cardiac and pulmonary side effects. Additional candidates for proton therapy include patients unable to raise their arms, those with genetic predispositions to radiation-induced malignancy, very young women, women with severe cardiac risk factors, and those with permanent bilateral implants or bilateral breast cancer. Like pediatric patients for whom proton therapy is considered standard for most curable childhood malignancies, young women have more years in survivorship to develop the most devastating side effects of radiation, including radiation-induced malignancy and cardiac morbidity. The higher cost and limited availability of proton therapy, as well as the potential financial burden on patients, must also be considered. Most breast cancer patients can receive excellent care with modern photon therapy, making the decision for proton therapy highly individualized.
Future Directions
Ultimately, the RadComp trial will assess long-term cancer control and cardiac outcomes between proton and photon therapies to determine whether protons reduce the risk of cardiac events while maintaining cure rates. Primary endpoint results are expected to be reported between 2028 and 2032 when statistical endpoints are met. Until this time, the decision of the best treatment modality should be individualized and based on patient, tumor characteristics, financial and emotional burden, and access to a proton center.
