Mendenhall, Nancy P.

LBA5012 Background: There is a critical evidence gap on the relative benefits and harms of proton therapy (PT) compared with photon-based intensity-modulated radiation therapy (IMRT) in prostate cancer. Herein we report early results from COMPPARE, a non-randomized comparative study of outcomes with PT and IMRT in prostate cancer. Methods: Between 2018-2022, 2524 patients from 51 facilities (28 PT and 23 IMRT) enrolled in COMPPARE, including 1501 treated with PT and 1023 treated with IMRT, and were followed prospectively. Treatment naïve patients with localized prostate cancer except those with very high-risk disease were eligible. Treatment was pragmatic with daily standard fractionation (1.8-2.1 Gy) and moderate hypofractionation (2.4-3.1 Gy) permitted. Use of rectal spacers and androgen deprivation were at physician discretion. Patient-reported quality of life data and treatment team-reported toxicity and disease control outcomes were collected at baseline and pre-specified time intervals via VisionTreeOptimalCare; treatment planning and delivery data were collected via the Advanced Treatment Consortium. We analyzed 1404 PT patients and 939 IMRT patients. We report the early primary endpoint of the study, a comparison of patient reported bowel urgency and bowel frequency at 2-years using the EPIC tool, and the secondary endpoints of 2-year CTCAE v5 ≥ grade 2 gastrointestinal toxicity outcomes and 3-year freedom from biochemical progression (FFBP) results reported by the study teams. Results: Study sample size was targeted at 1,500 PT patients and 1,000 IMRT patients, and median follow-up time was 4.0 years. The primary endpoint and secondary toxicity 2-year endpoints focused on the alternative hypothesis of PT superiority. All results include inverse probability of treatment weighting. Using generalized linear mixed effects models, we found there to be no significant difference in EPIC bowel urgency scores (p = 0.324) or bowel frequency scores (p = 0.514) between PT and IMRT cohorts over time up to the 2-year endpoint. For grade 2 gastrointestinal toxicity, the 2-year cumulative incidence was 5.2% for PT and 5.6% for IMRT. Gray’s Test for competing risks showed a hazard ratio (HR) of 0.91 [95% confidence interval (CI): 0.65-1.28, p = 0.6] for PT versus IMRT. The exploratory non-inferiority endpoint of 3-year FFBP was 98.0% for PT and 97.9% for IMRT, and Gray’s Test showed a HR of 0.95 (95% CI: 0.52-1.71, p = 0.90). Conclusions: Analysis of early results of COMPPARE show no significant differences between PT and IMRT in patient reported bowel frequency and urgency, grade ≥2 gastrointestinal toxicity, or FFBP. Assessment of long-term disease control, late toxicity and secondary malignancy will require longer follow-up. Clinical trial information: NCT03561220 .

AbstractBackgroundWe sought to characterize and compare late patient‐reported outcomes (PROs) after moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) for localized prostate cancer (PC).MethodsThis multi‐institutional analysis included low‐ or intermediate‐risk group PC patients treated with moderately hypofractionated radiation to an intact prostate stratified by treatment modality: IMRT or PBT. The primary outcomes were prospectively collected patient‐reported late gastrointestinal (GI) and genitourinary (GU) toxicity assessed by International Prostate Symptom Score (IPSS) and Expanded PC Index Composite (EPIC). Multivariable regression analysis (MVA) controlling for age, race, and risk group tested the effect of time, treatment, and their interaction.Results287 IMRT and 485 PBT patients were included. Intermediate risk group (81.2 vs. 68.2%; p < 0.001) and median age at diagnosis (70 vs. 67 years; p < 0.001) were higher in the IMRT group. On MVA, there was no significant difference between modalities. PBT IPSS did not differ from IMRT IPSS at 12 months (odds ratio [OR], 1.19; p = 0.08) or 24 months (OR, 0.99; p = 0.94). PBT EPIC overall GI function at 12 months (OR, 3.68; p = 0.085) and 24 months (OR 2.78; p = 0.26) did not differ from IMRT EPIC overall GI function. At 24 months, urinary frequency was no different between PBT and IMRT groups (OR 0.35; p = 0.096).ConclusionsThis multi‐institutional analysis of low‐ or intermediate‐risk PC treated with moderately hypofractionated PBT and IMRT demonstrated low rates of late patient‐reported GI and GU toxicities. After covariate adjustment, late GI and GU PROs were not significantly different between PBT or IMRT cohorts.

Abstract Purpose: To determine the rate of rib fracture in a cohort of patients with breast cancer treated with proton therapy and enrolled on a prospective registry. In series investigating photon therapy for breast cancer, the rib fracture rate ranges from 0.3-13% Methods: From a prospective database, we identified patients treated with proton therapy for breast cancer at our institution between January 1, 2012 and December 31, 2020. Clinical and dosimetric data was extracted from the electronic medical record. The cumulative incidence method assessed rib fracture rate; the Fine-Gray test statistic assessed prognostic significance select variables. Results: 225 patients were identified, 223 women and 2 men. Median age at the time of radiation was 57.8 years (range, 25 – 87). 26% of patients were black, 69% white and 5% were other races or race not disclosed. 5% were Hispanic. 74% of patients had left-sided breast cancer, 5% bilateral, and 21% right-sided. DEXA scan was normal in 20%, showed osteopenia in 34%, osteoporosis in 6%, and not performed in 40%. 57% of patients received antiendocrine therapy with an aromatase inhibitor. For 16% of patients, the breast +/- internal mammary nodes (IMN) were treated, while 32% underwent proton therapy to treat the breast and comprehensive regional lymphatics. 1% of patients had chest wall +/- IMN treated, while 51% underwent proton therapy to treat the chest wall and comprehensive regional lymphatics. 41% of patients were treated with passive scatter proton therapy (n=92); 52% of these had mastectomy. 58% of patients received treatment with pencil beam scanning (PBS) proton therapy (n=131); 53% of these had mastectomy. A combination of passive scatter and PBS was used for 2 patients (1%). 85% of patients received a boost. Median follow-up was 3.1 years (range, 0.2 – 9.1). 97% of patients had &gt; 12 months of follow-up. The 3 year cumulative incidence of in-field rib fracture was 3.7% (95%CI: 1.6%-7.1%). In total, 8 patients developed in-field rib fractures, one symptomatic and 7 identified incidentally on surveillance imaging, for a 0.4% rate of symptomatic rib fracture. Median time from completion of radiation to identification of rib fracture was 1.8 years (range, 0.4-7.4 years). Rib fractures occurred within 2.2 years from radiotherapy completion for seven of the eight patients who experienced this side effect. Three patients developed rib fractures outside of the radiation field, for a cumulative incidence of out-of-field rib fracture of 0.9% (95%CI: 0.2-3.0%). No variables were associated with rib fracture on univariate analysis. Of those with in-field rib fractures, 3 had low and 3 had normal bone density while 2 had not undergone testing; of those with out-of-field rib fractures, 2 had osteopenia and 1 did not have testing. Conclusions: Although a proton beam has higher biological dose deposition at end-of-range than the assumed constant RBE=1.1, the 3 year rate of any in-field rib fractures in our series remains low at 3.7%, with a 0.4% rate of symptomatic rib fracture. Contouring ribs as an OAR and establishing a dose constraint warrants further investigation as a means to maintaining a low rate of rib fracture with proton therapy. Citation Format: Julie Bradley, Xiaoying Liang, Raymond Mailhot Vega, Chunbo Liu, Eric Brooks, Teena Burchianti, Emma Viviers, Roi Dagan, Oluwadamilola Oladeru, Christopher Morris, Nancy Mendenhall. Incidence of rib fracture following treatment with proton therapy for breast cancer [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 P1-10-08.

AbstractPurposeTo evaluate the relative biological effectiveness (RBE)‐weighted dose to the heart and to estimate RBE uncertainties when assuming a constant RBE of 1.1, for breast cancer patients receiving intensity‐modulated proton therapy (IMPT). Further, to study the impact of RBE uncertainties on the risk of an acute coronary event (ACE).Material and methodsWe analyzed 20 patients who received IMPT to either the left breast (n = 10) or left chest wall (n = 10) and regional lymph nodes. The Monte Carlo simulation engine, MCsquare, was used to simulate the dose‐averaged linear energy transfer (LETd) map. The RBE‐weighted dose to the heart and its substructures was calculated using three different RBE models. The risk of ACE was estimated per its linear relationship with mean heart dose (MHD) as established by Darby et al.ResultsThe median MHD increased from 1.33 GyRBE assuming an RBE of 1.1 to 1.64, 1.87, and 1.99 GyRBE when using the RBE‐weighted dose models. The median values (and ranges) of the excess absolute risk of ACE were 0.4% (0.1%–0.8%) when assuming an RBE of 1.1, and 0.6% (0.2%–1.0%), 0.6% (0.2%–1.1%), and 0.7% (0.2%–1.1%) with the RBE‐weighted models. For our patient cohort, the maximum excess absolute risk of ACE increased by 0.3% with the RBE‐weighted doses compared to the constant RBE of 1.1, reaching an excess absolute ACE risk of 1.1%. The interpatient LETd variation was small for the relevant high‐dose regions of the heart.ConclusionAll three RBE models predicted a higher biological dose compared to the clinical standard dose assuming a constant RBE of 1.1. An underestimation of the biological dose results in underestimation of the ACE risk. Analyzing the voxel‐by‐voxel biological dose and the LET map alongside clinical outcomes is warranted in the development of a more accurate normal‐tissue complication probability model.

AbstractData comparing outcomes in prostate cancer and factors affecting treatment choice are sparse. To inform the design of a comparative effectiveness clinical trial, we engaged patients in developing a 28‐question survey about decision making on treatment and research participation and dispersed it among men greater than or equal to 50 years of age. The 1046 respondents ranked long‐term clinical outcomes as most important in making treatment decisions, specific functional outcomes as slightly less important, and duration, location, and cost of treatment as least important. Treatment choice was strongly impacted by side effect profile. Responses to whether the subject would agree to participation in a randomized trial between two types of radiation with minimal differences in outcomes were “yes” in 15%, “no” in 39%, and “undecided” in 46%. Responses to whether the subject would agree to participation in a randomized trial between two treatment durations with similar outcomes were yes in 36%, no in 24%, and undecided in 40%. Findings suggest many potential patients have strong treatment preferences and are averse to randomization, particularly when outcomes of importance may be affected. Patient engagement in study design and novel nonrandomized trial designs may offer a path to increase clinical trial success.

Purpose: Radiotherapy (RT) is an effective treatment for localized gastric mucosa-associated lymphoid tissue (MALT) lymphomas unresponsive to antibiotic therapy; however, irradiating the stomach can result in significant radiation to the heart, a risk factor for cardiac disease. We analyzed the Surveillance, Epidemiology, and End Results database to evaluate outcomes related to cardiac disease among patients treated with RT for stage I gastric MALT. Materials and Methods: We identified adult patients treated between 1993 and 2014. The relationship between treatment modality (RT, chemotherapy, combination, and no treatment) and overall survival (OS), mucosa-associated lymphoid tissue-specific survival (MSS), non-mucosa-associated lymphoid tissue-specific survival (non-MSS), and cardiac-specific survival (CSS) was assessed using the Kaplan-Meier estimator and Cox proportional hazards analyses. Results: A total of 2996 patients (median follow-up, 5.6 y) were analyzed: 27.5% had received RT alone, 12.1% chemotherapy alone, 3.9% chemoradiotherapy, and 56.5% no/unknown treatment (including antibiotic therapy). Compared with RT alone, patients who received chemotherapy alone exhibited worse OS (hazard ratio [HR]: 1.67; 95% confidence interval [CI]: 1.32-2.10; P<0.001) and MSS (HR: 2.10; 95% CI: 1.36-3.23; P=0.001). Although CSS appeared worse in patients who received chemotherapy (HR: 1.56; 95% CI: 0.92-2.66; P=0.10), it was not statistically significant. When comparing orbital and gastric MALT patients, there was no significant difference in CSS (HR: 0.80; 95% CI: 0.49-1.31; P=0.38). Conclusions: RT improved survival among patients with stage I gastric MALT without increasing the risk of cardiac death. Those with gastric MALT exhibited similar CSS to those with orbital MALT. Although we cannot analyze nonfatal cardiac toxicity, these results suggest that, absent antibiotic therapy, RT should remain first-line treatment for early-stage gastric MALT.

e16555 Background: The ProtecT trial underscores the importance of treatment in men with prostate cancer and life expectancies > 10 years and the validity of radiation therapy (RT). RT can be given with photons or protons (PT). To address the controversy of which is better, clinical outcomes of photon-based intensity modulated RT (IMRT) and PT cohorts from 2 institutions were directly compared. Methods: Under respective IRB approvals, data from 2 cohorts were analyzed. The first was 301 men treated with ultrasound image guided IMRT from 2000-05 to 75.6 Gy in 42 fractions. The second was 1214 men treated with fiducial image guided PT from 2006-10 to 78 CGE in 39 fractions. Median age and followup were 74 y and 7.2 y for IMRT and 66 y and 5.6 y for PT. Hormone therapy (ADT) was used with IMRT and PT, respectively, in 3% and 7% of low-risk patients, 25% and 9.9% of intermediate-risk, and 91% and 57.8% of high-risk. Comparative endpoints were age-stratified 5-year (5Y) survival (OS), ≥ grade 3 gastrointestinal (GI) and urologic (GU) toxicity, and 5Y freedom from biochemical progression (FFBP). Results: There was a lower prevalence of GI (1.3% vs 0.1%, p = 0.0065) and GU (4.3% vs 0.1%, p < 0.0001) toxicity at last follow-up in the PT group. In the IMRT and PT cohorts, OS rates were 90.8% and 88.7% in men ≥75 (p = 0.4083). In men < 75, OS rates were 91.6% and 97.5% in the IMRT and PT low-risk patients (p = 0.003), 92.1% and 95.5% in the IMRT and PT intermediate-risk (p = 0.0535), and 92.0% and 90.0% (p = 0.4975) in the IMRT and PT high-risk. In the IMRT and PT cohorts, respectively, FFBP rates were 92.2% and 98.9% for low-risk patients (p < 0.0001), 87.3% and 94.5% for intermediate-risk patients(p = 0.0226), and 80.3% and 74.4% for high-risk patients (p = 0.5154). Conclusions: In this retrospective comparison of outcomes in cohorts of men treated with IMRT and PT for prostate cancer, FFBP rates were better with PT for men with low- and intermediate-risk disease and similar in men with high-risk disease despite longer and more frequent use of ADT in the IMRT cohort. This study underscores the difficulty of comparing retrospective series, with differences noted in age, RT dose, and ADT use between cohorts. However, the magnitude of improvement with PT is intriguing and warrants prospective testing.

326 Background: Review initial outcomes for patients enrolled on the University of Florida Proton Therapy Institute PC01 protocol for patients with unresectable pancreatic cancer. Methods: The protocol received Institutional Review Board (IRB) approval in 7/2007. The first patient was enrolled in 4/2010. The accrual target was 66 patients to test if the Serious Adverse Event (SAE) ratecould be reduced from 15% (expected) to less than 5%. Protocol therapy consisted of proton therapy to a planning target volume (PTV) dose of 59.4 Cobalt Gray Equivalent (CGE) at 1.8CGE per fraction with concomitant oral Capecitabine (1000mg PO BID 5 days/week on radiation treatment days). Only gross disease was targeted. Results: 12 patients were enrolled. 1 patient died of a gunshot wound 5 days after starting treatment so only 11 patients are reported. Median follow up from start of treatment: 13 months (range 2 to 21 months). Median age: 68 (range 51 to 86) years. Gender: Males 5, Females 6. Race/Ethnicity: 9 White, 2 Hispanic. Overall survival: 90% at 6 months and 60% at 12 months. Freedom from progression: 80% at 6 months and 53% at one year. Local control: 100% at 6 months and 86% at 12 months. Freedom from metastasis: 80% at 6 months and 67% at 12 months.No patient experienced any grade 3 or greater toxicity during treatment or the follow up period. Grade 2 toxicity was limited to a single patient experiencing grade 2 fatigue. Median weight loss over the course of treatment was 1.7 (range: loss of 5.7 to gain of 4.9) Kg. 4 patients were deemed to have had an adequate radiographic response to radiotherapy so as to justify surgical exploration. Conclusions: Proton therapy to 59.4 CGE with concomitant Capecitabine was well tolerated with no grade 2 or greater gastrointestinal toxicities. 4 of 11 patients achieved a radiographic response allowing for attempted surgical resection. The study was closed to accrual on 9/1/2013 due to recognition that slow accrual made achievement of the primary study endpoint unlikely. At the same time, the lack of any meaningful gastrointestinal toxicity suggests significant opportunities for treatment intensification when proton therapy is used in this setting. Clinical trial information: NCT00685763.