Sharifzadeh, Yasamin

Background/Objectives: We performed a systematic review of preclinical literature on the use of high-LET particle therapy, DDRi, and/or immunotherapy specifically in pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, and carbon) or X-ray radiation either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICIs) in pMMR colorectal cancer models. Results: In total, 131 studies met the inclusion criteria, including 70 preclinical studies. These studies consistently demonstrate that high-LET radiation amplifies immunogenic cell death, increases cGAS-STING pathway activation, and enhances tumor antigen presentation, thereby fostering greater immune infiltration and systemic antitumor responses. Concurrent irradiation with DDRi enhances persistent DNA damage and cytosolic DNA accumulation. In murine models, high-LET therapies show excellent local control, with manageable toxicity profiles. Combination regimens with ICIs exhibit improved local control and elicit systemic antitumor immune responses. Conclusions: High-LET particle radiation and/or the use of concurrent DDRi with ICI have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increased response rates to immunotherapy. The clinical evidence will be reviewed in the companion manuscript.

Background/Objectives: We performed a systematic review of the current clinical and preclinical literature on the use of particle therapy, DDRi, and/or immunotherapy, specifically for pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, carbon) either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICI), or X-ray radiotherapy (XRT) in combination with DDRi/ICI. Results: In total, 133 studies met the inclusion criteria, including 62 clinical studies. Clinically, particle therapies show excellent local control and normal tissue sparing, with manageable toxicity profiles. Trials with any form of radiation and DDRi are few, potentially owing to toxicity concerns. ICI combinations showed promising efficacy with XRT, with no randomized trials comparing them to particle radiation. Conclusions: Particle radiation and/or DDRi have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increase response rates to immunotherapy (presented in the companion manuscript). Despite strong preclinical evidence and rationale, clinical trials including all three modalities are scarce. Existing evidence suggests a potential benefit based on extrapolation from photon-based studies and supports prospective evaluation with careful attention to treatment-related toxicity, which remains a concern.

98 Background: Prior authorization (PA) purports to control costs and ensure adherence to evidence-based guidelines but negatively impacts cancer care. Radiation oncology (RO) represents a minority of overall cancer spending yet bears a disproportionately high PA burden. Limited research exists on the effects of PA on patient outcomes and administrative workload within RO clinics. Methods: From 9/2024 to 10/2024, an online survey was open to U.S. members of the American Society for Radiation Oncology assessing experiences with PA including disposition (approval/denial/appeal including peer-to-peer [P2P] review) and perceived impact on patient care and administrative workload. Outcomes included treatment delays, changes from recommended treatment, and patient event including hospitalization, ED visits, permanent disability, or death. Descriptive statistics evaluated responses. Results: Of 736 responding radiation oncologists (16% response rate), 83% reported a rise in PA over the past three years, with 58% noting the burden has increased greatly. In the past year, 50% reported that more than half of their cases required PA, with a median approval rate of 75% and median overturn rate of 82% for denials. For more than half of their cases, nearly half of physicians (43%) noted that P2P was a futile effort to overturn PA denials due to insurance policies. Most (75%) reported that PA resulted in their practice needing to reallocate staff; 91% reported worsening burnout due to PA. P2P reviews were particularly burdensome, averaging 1.65 hours per week. A third (30%) reported that PA requirements had caused serious complications for their patients, including 7% who reported PA had contributed to patient death. Almost all (91%) reported PA-related treatment delays for some of their patients, with 58% indicating average delays of ≥5 days. Most (81%) reported that at times they had to use radiation techniques they considered less optimal due to PA, including 58% who were forced to deviate from national guidelines. The most common reasons for not appealing a PA denial were anticipated delays (73%), perceived futility based on prior PA experiences (62%), and administrative burden (45%). Conclusions: The administrative and clinical burdens associated with PA have significant implications for patient care, physician well-being, and healthcare resource allocation in RO. Treatment delays, compromised therapies, and adverse patient outcomes are commonly reported and underscore the need for PA reform to improve patient outcomes, reduce physician burnout, and improve efficiency.

PURPOSE Over 50% of households in the United States have at least one musician—many musicians are also breast cancer survivors. This group has not been well studied, and given the level of fine sensory-motor skill required for musicianship, we hypothesized that musicians experience unique manifestations of breast cancer treatment toxicities. METHODS A nine-item Musical Toxicity Questionnaire (MTQ) was distributed to patients who had consented to participate in the Mayo Clinic Breast Cancer Registry. The MTQ screened participants by asking if they played a musical instrument or sang in the last 10 years: questions populated for those who answered yes. Respondents were asked if they noticed difficulty with their musical endeavor during or after breast cancer treatment, defined as acute musical toxicity (AMT). The questionnaire asked which side effect and cancer-directed therapy most influenced musical ability, what musical attributes were affected, and the timeline of resolution. Multivariable and classification tree analyses assessed relationships between AMT and treatment characteristics. RESULTS Of 1,871 survey respondents, 29% (535/1,871) self-identified as musicians. Over a quarter (27%, 144/535) reported AMT, and for 57% (82/144), AMT had not resolved at the time of survey. Of the treatments each participant received, chemotherapy was most often reported as most negatively impactful (63/89 who received chemotherapy, 71%). Decreased endurance was the most common musical difficulty (64% of those with AMT, 92/144), followed by decreased accuracy, trouble playing/singing quickly, and difficulty using proper technique. Multivariable and classification tree analyses revealed that receipt of chemotherapy was most strongly correlated with AMT. CONCLUSION These results will help oncology care teams counsel musicians, answer questions about impacts on musicality, and provide a timeline for resolution of musical symptoms.

12048 Background: Playing music has been an important part of human culture for millennia. Today more than half of American households have at least one person who plays music, and in the UK 43% of adults play an instrument. Despite the overlap between musicians and people diagnosed with cancer, the effect of cancer treatment on musicianship has not been well-studied. We previously reported that 26% of a musician breast cancer survivor cohort reported difficulty with musicianship after treatment, and here we conduct further analysis to identify treatment and disease factors associated with this difficulty, termed acute musical toxicity (AMT). Methods: The Musical Toxicity Questionnaire was distributed to participants who had previously enrolled in the Mayo Clinic Breast Cancer Registry. PROMIS (Patient-Reported Outcomes Measurement Information System) scores were available through the Registry and treatment details were collected retrospectively. Due to the inter-dependency and high correlation between treatment and disease-related variables, a classification tree analysis (CTA) was performed to identify the combination of variables that most accurately classified patients by AMT. Sixteen variables were analyzed by the algorithm. Logistic regression was utilized for examining associations between AMT and continuous variables. Results: Of the 4075 surveys distributed, 1871 were returned and 535 respondents identified as musicians. Median time from diagnosis was 5.2 years, respondents were mostly stage I or II (71%), and 32% were node positive (N+). Over a quarter (26% or 144 respondents) reported AMT. In the final CTA model, being N+ was strongly associated with AMT (42% of those N+ had AMT, 20% of those not N+ had AMT). For respondents who were N+, those who received endocrine therapy were more likely to have AMT than those who did not (46% vs 21% respectively). Subsequent leaves identified not undergoing axillary lymph node dissection (ALND) and receiving chemotherapy as associated with AMT. For respondents who did not receive chemotherapy, breast reconstruction was associated with AMT (60% vs 19%). Variables such as mastectomy, radiation volume, specific chemotherapies, and stage of disease were not selected by the algorithm. The odds of having AMT decreased by 9.7% and 17% with each additional point in the composite mental health (p=0.003) and physical health (p<0.001) PROMIS scores, respectively. The odds of having AMT increased by 3.5% with each lymph node removed (p=0.001). Conclusions: The final model suggests that the group with the largest proportion of AMT was N+, received endocrine therapy, did not have ALND, and received chemotherapy. Both physical and mental health PROMIS scores were associated with AMT, although the directionality of this relationship requires more study. Care teams should counsel patients on potential musical toxicity and engage in shared decision making with musical patients.

PURPOSE The COVID-19 pandemic led to rapid expansion of telemedicine. The implications of telemedicine have not been rigorously studied in radiation oncology, a procedural specialty. This study aimed to evaluate the characteristics of in-person patients (IPPs) and virtual patients (VPs) who presented to a large cancer center before and during the pandemic and to understand variables affecting likelihood of receiving radiotherapy (yield) at our institution. METHODS A total of 17,915 patients presenting for new consultation between 2019 and 2021 were included, stratified by prepandemic and pandemic periods starting March 24, 2020. Telemedicine visits included video and telephone calls. Area deprivation indices (ADIs) were also compared. RESULTS The overall population was 56% male and 93% White with mean age of 63 years. During the pandemic, VPs accounted for 21% of visits, were on average younger than their in-person (IP) counterparts (63.3 years IP v 62.4 VP), and lived further away from clinic (215 miles IP v 402 VP). Among treated VPs, living closer to clinic was associated with higher yield (odds ratio [OR], 0.95; P < .001). This was also seen among IPPs who received treatment (OR, 0.96; P < .001); however, the average distance from clinic was significantly lower for IPPs than VPs (205 miles IP v 349 VP). Specialized radiotherapy (proton and brachytherapy) was used more in VPs. IPPs had higher ADI than VPs. Among VPs, those treated had higher ADI ( P < .001). CONCLUSION Patient characteristics and yield were significantly different between IPPs and VPs. Telemedicine increased reach to patients further away from clinic, including from rural or health care–deprived areas, allowing access to specialized radiation oncology care. Telemedicine has the potential to increase the reach of other technical and procedural specialties.

Abstract Background: Sarcopenia, characterized by the loss of muscle mass, has emerged as a negative prognostic factor in cancer patients. It has been associated with poorer outcomes and increased treatment-related morbidity. Post-mastectomy breast radiation therapy (RT) increases the likelihood of reconstructive complication, with up to 20% of reconstructed women requiring implant removal. The factors that lead to these complications are poorly understood and likely multifaceted. We investigated the relationship between pre-radiation therapy sarcopenia and post-mastectomy reconstruction outcomes. Methods: Chart review was performed to determine demographic, medical, and treatment variables, including reconstruction complication events and failures in breasts treated with mastectomy, immediate reconstruction, and RT. Reconstruction failure was defined as tissue expander or implant removal, resulting in no final reconstruction or autologous reconstruction only. Reconstruction complications included surgical site infection, late infection (1 year post-RT), seroma development, flap necrosis, nipple necrosis, wound dehiscence, capsular contracture, hematoma, extrusion, leak, venous congestion, and unplanned reoperation. An axial slice at the L2 or L3 vertebral body from the radiation therapy planning CT scan was analyzed for skeletal muscle area using a previously validated algorithm, with manual review and adjustment as indicated. Sarcopenia was defined by skeletal muscle index (SMI, skeletal muscle area in cm2 divided by patient’s height squared) below 34.4 cm2/m2. Chi-square, Kaplan Meier, and univariate Cox regression tests were used for analysis. Results: Ninety-nine women with breast cancer who underwent mastectomy, reconstruction, and RT were included in this study. All women had immediate reconstruction: 93 women had tissue expander placement while six women had permanent implant placement. Mean age was 47.5 years (SD 10.6) at diagnosis and median BMI was 24.8. Seventy-six percent were non-smokers, 24% were former smokers, and only 16 (16.2%) and 3 (3.0%) had hypertension or diabetes, respectively. Median follow-up was 2.7 years. Median SMI was 38 cm2/m2 and 18 (18%) met criteria for sarcopenia (SMI &lt; 34.4 cm2/m2). Mastectomy was bilateral in 79 women, skin-sparing in 61, and nipple sparing in 31. Bilateral mastectomy was less frequent amongst women with sarcopenia (61%) compared to 84% of those without sarcopenia (p=0.03). After RT, twenty-three women required unplanned reoperation. Within these 23 women, there were 45 total complications. Complications included surgical site infection (n=18), capsular contracture (n=12), seroma (n=4), wound dehiscence (n=3), and others (n=8). However, only 8 women had reconstructive failure and none were sarcopenic at the time of the RT planning scan. Any complication or failure after RT occurred in similar proportions of patients with and without sarcopenia: 38% and 30%, respectively. Kaplan-Meier curves and univariate Cox regression models showed no significant difference in time to failure (p = 0.380) or time to any event (complication or failure) (p=0.53), between sarcopenic and non-sarcopenic patients. Conclusion: Sarcopenia, using SMI &lt; 34.4 cm2/m2 on pre-radiotherapy planning scans, was not associated with an increased risk of post-radiotherapy reconstructive complication or failure in this selected cohort of non-smokers. Few women had sarcopenia at the time of operation, and results should be validated in a larger series. Citation Format: Yasamin Sharifzadeh, Robert Gao, William S. Harmsen, Jason Klug, Panagiotis Korfiatis, Kimberly Gergelis, Dean A. Shumway, Robert Mutter, Kimberly Corbin. Sarcopenia and Post-Mastectomy Breast Reconstruction Outcomes after Radiation Therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-52.