Health-related quality-of-life analyses for proton radiation therapy and photon radiation therapy in patients with nonmetastatic breast cancer showed similar impacts on quality of life with both treatments, according to findings from the phase III RadComp consortium trial. Shannon M. MacDonald, MD, FASTRO, Medical Director, Southwest Florida Proton Center, Fort Myers, presented these results during the plenary session of the 2025 American Society for Radiation Oncology (ASTRO) Annual Meeting.1 The study is ongoing, and efficacy findings will be presented in approximately 5 years.
Shannon M. MacDonald, MD, FASTRO
“In this first randomized study comparing proton with photon radiation for breast cancer, health-related quality of life was excellent and similar between treatment arms through 6 months,” Dr. MacDonald said.
Background and Study Objectives
Even with associated adverse effects, radiation therapy can play a significant curative role in the treatment of patients with breast cancer. Proton therapy, however, may potentially reduce the morbidity of photon radiation therapy, as it reduces the volume of radiation to the heart and other exposed tissues. Previous studies, though, of proton therapy for breast cancer have been small, nonrandomized, and with short follow-up.
The RadComp trial sought to assess the effectiveness of proton therapy in comparison with photon therapy in reducing major cardiac events among patients with locally advanced breast cancer. The investigators hypothesized that proton therapy would reduce the 10-year incidence rate for major cardiac events after radiation from 6.3% to 3.8%. Dr. MacDonald commented that this primary objective was decided upon by patients, patient advocates, and physicians and required a concerted effort given the lengthy follow-up.
Additionally, the consortium wanted to determine whether proton therapy was noninferior to photon therapy in reducing local-regional recurrence or any recurrence in patients with ipsilateral breast cancer. It also wanted to assess the effectiveness of the two radiation modalities in terms of improvement in patient-reported body image and function, fatigue, and other health-related quality-of-life measurements. Further, the investigators sought to create predictive models for understanding the association between radiation dose distribution to the heart and major cardiac events as well as their impact on health-related quality-of-life outcomes.
Study Design
The study enrolled 1,239 patients who all had to have approval for proton radiation therapy from their insurance provider before completing enrollment. Patients in the study were stratified by age, cardiovascular risk, surgery type, and treatment laterality; they were then randomly assigned to receive either photon or proton radiation therapy. Treatment included breast or chest wall and nodal radiation with internal mammary node treatment, and the standard dose in both arms ranged from 45 to 50.4 Gy in 1.8 to 2 Gy/fraction with or without a tumor bed boost.
Eligible patients had invasive mammary carcinoma of the breast that was nonmetastatic or locally recurrent. Patients had to have undergone mastectomy or lumpectomy with any axillary surgery or sampling. Those who had received prior radiotherapy to the ipsilateral breast or chest wall, or who had scleroderma were excluded from participation in the study.
The primary health-related quality-of-life endpoints were PROMIS fatigue, satisfaction with breast cosmetic outcomes, BREAST-Q patient-reported outcomes on adverse effects of radiotherapy, and Functional Assessment of Cancer Therapy–Breast (FACT-B) general and breast cancer–specific quality-of-life measurements. Secondary health-related quality-of-life endpoints focused on the Functional Assessment of Chronic Illness Therapy–General Treatment Satisfaction (FACIT-TS-G) measurement system for reports of effectiveness of treatment and willingness to recommend treatment or choose it again (among others) plus the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) questionnaire. These endpoints were all previously validated in the RadComp consortium.
Health-related quality-of-life measurements were collected at baseline, at the end of radiotherapy, and at 1 and 6 months, and 1, 2, and 3 years after radiotherapy. Results through 6 months after radiotherapy were reported.
Health-Related Quality-of-Life Findings
At 6 months, the completion rate for patient-reported health-related quality-of-life outcomes was 86.5%. No clinically meaningful differences were observed between the two treatment arms across the studied time period for PROMIS fatigue, satisfaction with breast cosmetic outcomes, BREAST-Q score, and FACT-B index score.
PRO-CTCAE questionnaires demonstrated that the severity of shortness of breath significantly favored proton therapy when scores were categorized as 0 vs 1 to 4 (odds ratio [OR] = 0.74; 95% confidence interval [CI] = 0.59–0.93). When scores were categorized as 0 to 2 vs 3 to 4, though, no significant difference was observed between treatment arms. Multiplicity adjustment was performed to address the risks for false-positive results, and thus no PRO-CTCAE items retained their significance.
Five FACIT-TS-G items were statistically significantly in favor of proton therapy, including “willingness to recommend treatment” (OR = 0.13; 95% CI = 0.08–0.22; P < .001) and “willingness to choose treatment again” (OR = 0.11; 95% CI = 0.07–0.18; P < .001). These items retained their significance after multiplicity adjustment. However, Dr. MacDonald noted, “these [differences] must be interpreted in the context of an unblinded study, as we could not blind patients to whether they were receiving proton therapy or photon therapy.”
DISCLOSURE: The research was funded through a Patient-Centered Outcomes Research Institute Award, the National Cancer Institute, the David and Leslie Clarke Outcomes Research Fund, the Gant Family Foundation Fund, and the Alan and Louise Reed Cancer Outcomes Research Fund at the Raymond and Ruth Perelman School of Medicine of the University of Pennsylvania. Dr. MacDonald has received consulting and travel expenses from ICOTEC (carbon fiber hardware) and the Dana-Farber Cancer Institute; and has received travel expenses from Ion Beam Applications.
REFERENCE
1. MacDonald SM, Pugh S, Paulus R, et al: Phase III randomized trial of proton vs. photon therapy for patients with non-metastatic breast cancer receiving comprehensive nodal radiation: A radiotherapy comparative effectiveness (RadComp) consortium trial: Health-related quality of life outcomes. 2025 ASTRO Annual Meeting. Abstract LBA 01. Presented September 29, 2025.
EXPERT POINT OF VIEW
“The RadComp investigators should be congratulated for conducting this pragmatic, randomized clinical trial of proton vs photon regional nodal radiation,” said invited discussant Simona F. Shaitelman, MD, EdM, Professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center, Houston. Dr. Shaitelman provided further insight into the significance of the study and its findings for patients with breast cancer, with a particular focus on chest pain, shortness of breath, and patient satisfaction.
Patient Treatment Context
“The question of cosmesis and breast satisfaction is highly relevant on a trial comparing proton and photon breast radiotherapy,” Dr. Shaitelman said. She noted that the BREAST-Q questionnaires about looks and feels of the cosmetic surgery were the same for patients regardless of whether they underwent mastectomy or lumpectomy, “although the implications of these questions for a patient who has undergone mastectomy are distinct from those patients who have undergone lumpectomy.”
Simona F. Shaitelman, MD, EdM
“Contemporary proton cohort studies show that radiation dermatitis is a common adverse effect, with grade 2 or 3 radiation dermatitis seen in up to three-quarters of patients.1,2 Many efforts have been made to reduce skin toxicities for patients undergoing proton radiotherapy to the breast, including intensity-modulated proton therapy (IMPT), Mepitel, and hypofractionation.3-4 Use of IMPT with pencil beam scanning has not been defined in the study, however. Understanding these details, though, is important to understanding the equivalent breast cosmetic outcome and BREAST-Q scores,” Dr. Shaitelman said.
There were no significant differences between the treatment arms in terms of chest pain either. Dr. Shaitelman said this was notable, since patients in the proton therapy arm may receive higher doses to the skin. “It remains unclear if the biologic impact of proton therapy higher-dose deposition to the skin may or may not impact health-related quality of life in the same way as hotspots seen with older photon therapy plans,” Dr. Shaitelman said.
“Overall, short-term health-related quality of life and adverse event outcomes were comparable for photon and proton breast radiotherapy. Thus, the long-term primary outcomes and even longer-term health-related quality-of-life outcomes will be even more critical to understand if there is a benefit for protons for [patients with] breast cancer,” Dr. Shaitelman said. “Dosimetric information will be critical to contextualize the RadComp trial and to enable appropriate application off study.”
Shortness of Breath
Dr. Shaitelman explained that the investigators of the RadComp trial created their own RADCOMP Breast Atlas to assist with guiding contouring for the trial patients to ensure appropriate targets were not missed or underdosed when using protons, as protons have an enhanced ability to shape radiotherapy dose.5 When considering the shortness of breath that patients reported in the study, one should also consider the radiation dose to the lungs and whether or not it varied by technique and contours. The study allowed a loose dose constraint of ipsilateral lung V20 (volume of the lung receiving 20 Gy or more) of up to 50%, she added.
“One could imagine if photons were used to cover targets outlined in the RADCOMP Atlas, lung exposure to radiotherapy could potentially have been higher than in traditional photon therapy plans,” Dr. Shaitelman noted. “Though there was no difference in shortness of breath between protons and photons on this pragmatic study...dosimetric information on the actual dose delivered to the lungs will be highly relevant, as will longer follow-up.”
More than 10% of patients reported moderate, severe, or very severe shortness of breath, and more than 25% reported mild shortness of breath. Additionally, no notable changes were observed in reported shortness of breath from baseline through 6 months after radiation therapy.
“These numbers are much higher than what has historically been seen using Common Toxicity Criteria, a reporting of pulmonary toxicities for [patients with] breast cancer,” she said. “The PRO-CTCAE may be a very important tool to understand the lived experiences of our patients and may also point to the unmet needs of our patients who are coming in daily for breast radiotherapy.”
Patient Satisfaction
Dr. Shaitelman flagged a possible bias in the unblinded study for the use of protons over photons in questions about patient satisfaction, as proton therapy has more excitement behind it. The extent of hope for receiving proton therapy in joining the trial may have contributed to this patient satisfaction as well. Of interest, 46% of patients noted that one factor contributing to their trial participation was their desire to help future patients, whereas 17% noted that their doctor’s support was more important to their participation.
FACIT-TS-G significantly favored proton therapy for five of six tested measures of satisfaction and willingness to recommend treatment or choose it again. “It will be worthwhile for us to further delve into [the drivers of] patient satisfaction with treatment choice to better understand how, or if, we can improve these results,” Dr. Shaitelman said.
DISCLOSURE: Dr. Shaitelman has received research support from ARTIDIS, Exact Sciences, and the National Cancer Institute.
REFERENCES
1. Sayan M, Kilic S, Zhang Y, et al: Early toxicity and patient-reported cosmetic outcomes in patients treated with adjuvant proton-based radiotherapy after breast-conserving surgery. Clin Breast Cancer 23:176-180, 2023.
2. Gao RW, Mullikin TC, Aziz KA, et al: Postmastectomy intensity modulated proton therapy: 5-Year oncologic and patient-reported outcomes. Int J Radiat Oncol Biol Phys 117:846-856, 2023.
3. Mutter RW, Giri S, Fruth BF, et al: Conventional versus hypofractionated postmastectomy proton radiotherapy in the USA (MC1631): A randomised phase 2 trial. Lancet Oncol 24:10-83-1093, 2023.
4. Corbin K, Lee M, Roberts K, et al: Mepitel film for the reduction of radiation dermatitis in post-mastectomy radiation therapy: Results from Alliance A221803: A multicenter phase III randomized clinical trial. Clin Cancer Res 31:(12_Supplement): Abstract RF3-06, 2025.
5. NRG Oncology: RADCOMP Breast Atlas. Available at nrgoncology.org/About-Us/Center-for-Innovation-in-Radiation-Oncology/Breast-Cancer/RADCOMP-Breast-Atlas. Accessed October 29, 2025.
