Remmes, Nicholas B.

Abstract Objective. Proton minibeam radiation therapy (pMBRT) is a novel spatially fractionated radiation therapy technique that offers improved tumor control and reduced normal tissue toxicity. However, its clinical translation has been hindered in part by limited field sizes, low dose rates, and complex manufacturing. This work describes the design, manufacturing, and commissioning of a novel divergent pMBRT collimator along with accessory components to maximize its versatility and facilitate clinical implementation. Approach. The dosimetric outcomes for pMBRT collimator geometry, including slit width, center-to-center (CTC) spacing, thickness, divergence, and field size, were evaluated using TOPAS Monte Carlo (MC) to maximize surface peak-to-valley dose ratio (PVDR) while maintaining uniform target coverage. The collimator was constructed using brass plates held by aluminum side holders. Commissioning measurements with a PTW Bragg peak chamber and EBT4 radiochromic film were compared to TOPAS and an in-house fast GPU-based MC simulation. Ancillary equipment consisting of lead foils, range shifters, custom apertures, and secondary pMBRT collimators were characterized in tandem. Main results. An optimized divergent pMBRT collimator with 0.5 mm slit width, 2.0 mm CTC distance, and 40 mm thickness produced a surface PVDR of 4.8 while preserving quasi-homogeneous dose in the 6–14 cm depth region. Measured dose profiles demonstrated valley dose agreement within 3% for both TOPAS and GPU-based MC predictions after the simulated collimator geometry was refined to match Bragg-peak chamber average dose measurements. The onset of the quasi-homogeneous dose region was shifted toward shallower depths by using thin lead foils, without significantly impacting entrance PVDR. Apertures sharpened penumbra and enhanced peripheral PVDR. A dual collimator approach produced 2D pinhole dose arrays that resulted in valley doses from MC simulations and film measurements agreeing within ∼5%. Significance. We demonstrated a practical low-cost, large-area divergent physical pMBRT collimation system with validated MC modeling. In addition, we introduce complementary accessories that substantially expand system versatility to facilitate clinical implementation.

Abstract Background Proton therapy offers precise tumor targeting while minimizing damage to surrounding healthy tissue, making it especially valuable for treating tumors near critical organs and in pediatric patients. However, its success depends on accurate beam delivery, requiring rigorous quality assurance (QA) to maintain treatment precision and effectiveness. Purpose This study aims to standardize the measurement of key aspects of proton therapy delivery, such as gantry and couch isocentricity, spot position accuracy, and spot size consistency. The goal is to enhance the delivery accuracy of proton therapy across various clinical settings, improving patient outcomes. Methods The QA framework uses the Octopoint phantom, Gafchromic film, and spot position monitor (SPM) log data to evaluate proton beam isocentricity, spot position, and spot size. The Octopoint phantom, made from acrylic, was used with Gafchromic films at various gantry and couch angles to measure isocentricity. MATLAB tools were used to analyze spot positions, and SPM logs provided verification. Sensitivity tests were conducted to assess the system's response to intentional shifts and errors, ensuring alignment with clinical QA standards. Results The Octopoint phantom's stepwise two‐dimensional (2D) fitting process, validated against film‐measured dose profiles, accurately identified beam and ball bearing (BB) centroid locations. Isocentricity tests conducted over 8 months across four gantries demonstrated consistent beam‐to‐BB radial offsets. The phantom showed excellent repeatability, with a maximum standard deviation of 0.1 mm across various couch‐gantry combinations. Sensitivity testing across all axes revealed a strong alignment between intended shifts and measured values. Over the course of a year, film measurements tracked spot position and size consistency, with deviations remaining within acceptable clinical limits. Comparisons with SPM data further confirmed the system's reliability in maintaining beam accuracy across different gantry angles and energy levels. Conclusions This study presents a reliable QA framework for ensuring precision in proton therapy delivery. By combining the Octopoint phantom, Gafchromic film analysis, and SPM log file evaluation, we effectively measured isocentricity, spot position accuracy, and spot size stability. The framework demonstrated adaptability across various clinical QA tasks, enhancing the accuracy and safety of proton therapy treatments.

Abstract Poly ADP ribose polymerase inhibitors (PARPi) are being investigated in combination with photon and proton radiotherapy in clinical trials of pediatric and adult malignancies. The precise mechanisms of PARPi radiosensitization, and whether differences in photon and proton-mediated relative efficacy exist, have not been fully elucidated. To study mechanisms of PARPi radiosensitization we investigated the effects of PARPi in combination with photons and two different ionizing densities of protons delivered at the entrance (ENT) or the Bragg peak (BP) of the profile (dose-averaged LET [LETd] 2.2 and 7.0 keV/µm, respectively) of a 76.8 MeV proton beam after observing an extreme tumor and normal tissue response in an 18-year-old female patient with high grade glioma treated veliparib and proton therapy in a Children’s Oncology Group clinical trial. BRCA1/2 wild-type hTERT RPE-1, U2OS, and MDA-MB-231 cells were hypersensitive to the combination of veliparib and proton BP, with enhanced relative biological effectiveness (RBE) at 2 Gy values of 1.7, 1.4, and 1.3, respectively. Similar findings were observed with talazoparib and olaparib, suggesting that PARP trapping efficiency was not a major influence on the proton BP RBE. Further, we did not observe differences in transcription replication conflict between the different proton ionizing densities. Unexpectedly, DNA fiber assays revealed more elongated replication fork tracks in PARPi treated cells 60 minutes after proton BP compared with proton ENT, indicative of accelerated replication fork progression. To assess gap formation in the vicinity of nascent DNA we treated cells with the ssDNA-specific S1 nuclease and found that the lengths of CldU-labeled tracks were significantly reduced in cells treated with the PARPi/proton BP combination, suggestive of greater gap formation at replication forks. We postulated that more ssDNA gaps were being converted to DSBs during replication as we further observed that PARPi/proton BP resulted in increased γH2AX foci at 4- and 24-hours after treatment. Consistent with increased DSB formation, a higher proportion of cells arrested in the G2/M phase of the cell cycle at 24 hours following PARPi/proton BP. Despite being arrested in G2/M when homologous recombination is active, there was a significant increase in 53BP1 and a decrease in RAD51 recruitment, indicative of upregulated repair by more error-prone non-homologous end-joining (NHEJ) repair pathway. The enhanced proton BP RBE in PARPi treated cells was abrogated upon knockdown of XRCC4, a critical component of NHEJ repair pathway, suggesting that toxic NHEJ may be contributing to the enhanced proton BP RBE. In conclusion, PARPi renders cells hypersensitive to high LET BP proton irradiation. Enhancing the LET in combination with PARPi warrants further investigation to overcome therapeutic resistance. Citation Format: Yiqun Han, Qin Zhou, Anna Olson, Cameron M. Callaghan, Bin Chen, Nicholas B. Remmes, Meng Xu Welliver, Zheming Wu, Daniel K. Ebner, Jake A. Kloeber, Zhenkun Lou, Robert W. Mutter. Poly ADP ribose polymerase inhibitors potentiate proton therapy end-of-range relative biological effective dose by increasing replication stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4689.

Abstract Ataxia Telangiectasia–mutated (ATM) inhibitors are being developed as radiosensitizers to improve the antitumor effects of radiotherapy, but ATM inhibition can also radiosensitize normal tissues. Therefore, understanding the elevated risk of normal tissue toxicities is critical for radiosensitizer development. This study focused on modeling the relationship between acute mucosal toxicity, radiation dose, fractionation schedule, and radiosensitizer exposure. The ATM inhibitor WSD0628 was combined with single or fractionated doses of radiation delivered to the oral cavity or esophagus of Friend Leukemia virus B (FVB) mice. The potentiation by WSD0628 was quantified by a sensitizer enhancement ratio (SER), which describes the changes in radiation tolerance for radiation combined with WSD0628 relative to radiation-only regimens. WSD0628 profoundly enhanced radiation-induced acute oral and esophageal toxicities. For oral mucosal toxicity, the enhancement by WSD0628 with 3 fractions of radiation resulted in an SER ranging from 1.3 (0.25 mg/kg) to 3.1 (7.5 mg/kg). For the 7.5 mg/kg combination, the SER increased with increasing number of fractions from 2.2 (1 fraction) to 4.3 (7 fractions) for oral toxicity and from 2.2 (1 fraction) to 3.6 (3 fractions) for esophageal toxicity, which reflects a loss of the normal tissue sparing benefit of fractionated radiation. These findings were used to develop a modified biologically effective dose model to determine alternative radiation schedules with or without WSD0628 that result in similar levels of toxicity. Successful radiosensitizer dose escalation to a maximally effective therapeutic dose will require careful deliberation of tumor site and reduction of radiation dose volume limits for organs at risk.

Abstract Purpose/Objectives: Proton therapy is under investigation in breast cancer as a strategy to reduce heart and lung exposure, which is associated with late cardiopulmonary adverse events and secondary malignancy. To date, studies investigating postmastectomy radiotherapy (PMRT) with protons have used conventional fractionation. We hypothesized that condensing treatment to 15 fractions would be safe based on evidence that breast cancer is more sensitive to higher dose fractions than surrounding normal tissues. Materials/Methods: We conducted a randomized non-inferiority phase II trial comparing conventional and hypofractionated proton PMRT with primary endpoint of 24-month complication rate (defined as grade 3 or higher late adverse events using CTCAE, v 4.0 and/or unplanned surgical intervention in patients undergoing mastectomy with reconstruction). With a 10% non-inferiority margin the study ensured 80% power and had a one sided-type I error rate of 0.05. Cardiotoxicity was assessed with serial transthoracic conventional and 2-dimensional speckle tracking echocardiography (2D-STE). Eligibility included age ≥ 18 years with non-inflammatory breast cancer resected by mastectomy with indications for PMRT. Assignment of treatments was balanced with respect to immediate breast reconstruction (IBR). Conventional fractionation group received 50 Gy in 25 fractions of 2 Gy, and hypofractionation group received 40.05 Gy in 15 fractions of 2.67 Gy (RBE 1.1). Target volume included the chest wall and axillary, supraclavicular, and internal mammary lymph nodes. All patients were treated with multi-field optimized pencil beam scanning (intensity modulated proton therapy). Results: Between 2016 and 2018, 82 patients were enrolled and randomized (41 conventional, 41 hypofractionation). Median patient age was 52 years. 32.9% were staged T3-T4 and 79.3% node positive at diagnosis. 57 of 82 patients (69.5%) elected IBR. The median mean heart dose was 0.49 Gy and the median ipsilateral lung volume receiving 40% of prescription or greater (V40%) was 13.6%. No significant changes on conventional or 2D-STE at end-of-treatment or 3-month follow-up compared to baseline were observed. The rate of ≥ grade 2 acute dermatitis was lower with hypofractionation (44% vs 15%, p = 0.006). Other ≥ grade 2 acute adverse events including esophagitis (0 vs 5%), infection (5% vs 2.4%) and skin hyperpigmentation (7.3% vs 4.8%) were not significantly different between the two arms. With a median follow-up of 38.3 months, the 24-month complication rate was conventional 14.6% vs hypofractionation 17.1% (absolute difference 2.4%, p=0.17, 95% CI [-, 15.7%]). In patients with IBR, 6 of 28 (21.4%) conventional and 7 of 29 (24.1%) hypofractionated patients developed complications (p =0.80). There was no significant difference in 3-year disease-free survival between the conventional (89.4%; 95% CI 80.0 – 99.8%) and hypofractionated (92.4%, 95% CI 84.5 – 100.0%) arms (p = 0.91). One local recurrence occurred in the hypofractionated arm simultaneous with regional and distant relapse. The remaining 6 recurrences were isolated distant events. Conclusions: Proton PMRT provided excellent locoregional control and normal tissue sparing. There were no subclinical echocardiographic changes indicative of radiation-induced cardiac dysfunction. Hypofractionation resulted in comparable disease control, tolerability and reconstruction outcomes as conventional fractionation. Although non-inferiority of hypofractionation could not be established based on the upper bound of the 95% confidence interval for complication rate being greater than 10%, both conventional and hypofractionation may be considered appropriate regimens for ongoing phase 3 randomized trials comparing photon and proton radiotherapy. Citation Format: Robert Mutter, Sharmila Giri, Briant Fruth, Nicholas Remmes, Aman Anand, Kathryn Ruddy, Hector Villarraga, Sebastian Santos Patarroyo, Elizabeth Yan, Kenneth Merrell, Lisa McGee, Tamara Vern-Gross, Bradley Stish, Robert Gao, Judy C. Boughey, Sean Park, Kimberly Corbin, Carlos Vargas. Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy [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 GS4-05.

Abstract Background: Partial breast irradiation (PBI) is an established option for selected patients with early stage breast cancer. The optimal technique, target volume and dose/fractionation for PBI has yet to be defined. The most studied regimen in North America (38.5 Gy in 10 fractions twice daily) has been associated with cosmetic deterioration. We hypothesized that condensing treatment and reducing the total administered dose could improve the therapeutic ratio in luminal breast cancer and DCIS based on emerging evidence that breast cancer is more sensitive than surrounding normal tissues to high dose fractions. Herein, we report cosmetic, tolerability, disease control, and patient reported outcomes of a novel ultra-accelerated PBI regimen. Methods: We conducted a single arm, three cohort trial of photon, proton, and brachytherapy PBI. Technique was selected at physician and patient discretion. Eligible women were age ≥ 50 years with estrogen receptor positive (ER+), sentinel lymph node negative invasive or in-situ breast cancer measuring ≤ 2.5 cm. The regimen was designed to have comparable biologically equivalent effect as 40 Gy in 15 fractions, assuming an α/β ratio of 3.5. Intracavitary brachytherapy target volume was lumpectomy cavity plus 1 cm and prescribed 21 Gy in 3 fractions. Photon and proton target volumes were post-operative tumor bed plus 1 cm and a 3 mm setup uncertainty margin, prescribed 21.9 Gy (RBE) in 3 fractions, and delivered with image guidance. The primary outcome was the percentage difference in patients with adverse cosmesis (defined as fair or poor cosmesis) at 3 years compared to baseline pre-PBI, as assessed by trained nurses using the 4-point Harvard breast cosmesis scale. Patients also completed quality of life surveys and self-reported cosmesis using the 4-point scale. Locoregional and distant recurrence-free survival was determined using the Kaplan-Meier method. Adverse events were assessed using CTCAE, v 4.0. Results: Between 2015 and 2017, 163 patients were treated: photons in 58, protons in 48, and brachytherapy in 57. Median patient age was 66 years. 129 (79%) patients had invasive breast cancer (all ER+) and 34 (21%) had DCIS (83% ER+). Median tumor size was 1.1 cm. Grade was 2-3 in 102 (63%). The median mean heart/ipsilateral lung doses were photons 0.1/1.6 Gy, protons <0.001/0.1 Gy, and brachytherapy 0.5/0.9 Gy. Median follow-up was 4.1 years (IQR 3.9-5.0). The proportion of patients with adverse cosmesis (by RN assessment) was 14.3% at baseline and 3.8% at 3 years, with four patients (1 photon, 1 proton, 2 brachytherapy) experiencing cosmetic deterioration at 3 years from baseline. The proportion with adverse cosmesis by self-report at 3 years was 2.4%, with three patients (1 photon, 1 proton, 1 brachytherapy) reporting cosmetic deterioration. Four patients developed locoregional recurrence (1 photons, 2 protons, 1 brachytherapy); three were local only and one was local and distant. 4-year locoregional recurrence and distant metastasis-free survival were 97.9% and 97.4%, respectively. There were 2 treatment related ≥ grade 2 late events (grade 2 fibrosis and grade 2 seroma, both brachytherapy associated), and no evidence of deterioration in patient-reported pain, fatigue, breast related or overall quality of life, as assessed by the patient reported outcomes version of the CTCAE, 10-point linear analog scales, and the breast cancer treatment outcomes scale. Conclusions: Ultra-accelerated 3-fraction PBI exquisitely spared normal tissues and was associated with favorable cosmetic outcomes, disease control, and excellent long-term tolerability. This ‘precision-radiotherapy’ approach may optimize the therapeutic ratio over more aggressive radiotherapy options as well as radiotherapy omission, particularly in patients with long life expectancies. Citation Format: Robert Mutter, Tina Hieken, Todd DeWees, Arslan Afzal, Stephanie Kenison, Laura Vallow, Christopher Deufel, Nicholas Remmes, Kathryn Ruddy, Judy Boughey, Keith Furutani, Amy Degnim, James Jakub, Tamara Vern-Gross, Dean Shumway, William Wong, Samir Patel, Lisa McGee, Minetta Liu, Carlos Vargas, Daniel Visscher, Bradley Stish, Deanna Pafundi, Mark Waddle, Michael Golafshar, Michele Halyard, Kimberly Corbin, Sean Park. Ultra-accelerated photon, proton, and brachytherapy partial breast irradiation: Primary results of the Mayo 3-fraction trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD7-03.

Abstract The clinical use of surface imaging has increased dramatically, with demonstrated utility for initial patient positioning, real‐time motion monitoring, and beam gating in a variety of anatomical sites. The Therapy Physics Subcommittee and the Imaging for Treatment Verification Working Group of the American Association of Physicists in Medicine commissioned Task Group 302 to review the current clinical uses of surface imaging and emerging clinical applications. The specific charge of this task group was to provide technical guidelines for clinical indications of use for general positioning, breast deep‐inspiration breath hold treatment, and frameless stereotactic radiosurgery. Additionally, the task group was charged with providing commissioning and on‐going quality assurance (QA) requirements for surface‐guided radiation therapy (SGRT) as part of a comprehensive QA program including risk assessment. Workflow considerations for other anatomic sites and for computed tomography simulation, including motion management, are also discussed. Finally, developing clinical applications, such as stereotactic body radiotherapy (SBRT) or proton radiotherapy, are presented. The recommendations made in this report, which are summarized at the end of the report, are applicable to all video‐based SGRT systems available at the time of writing.

Abstract Proton Bragg peak irradiation has a higher ionizing density than conventional photon irradiation or the entrance of the proton beam profile. Whether targeting the DNA damage response (DDR) could enhance vulnerability to the distinct pattern of damage induced by proton Bragg peak irradiation is currently unknown. Here, we performed genetic or pharmacologic manipulation of key DDR elements and evaluated DNA damage signaling, DNA repair, and tumor control in cell lines and xenografts treated with the same physical dose across a radiotherapy linear energy transfer spectrum. Radiotherapy consisted of 6 MV photons and the entrance beam or Bragg peak of a 76.8 MeV spot scanning proton beam. More complex DNA double-strand breaks (DSB) induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ataxia-telangiectasia mutated (ATM) inhibitor, AZD0156, but not an inhibitor of ATM and Rad3-related, rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more DSBs to processing by toxic ligation through nonhomologous end-joining, whereas loss of DNA ligation via XRCC4 or Lig4 knockdown rescued resection and abolished the enhanced Bragg peak cell killing. Proton Bragg peak monotherapy selectively sensitized cell lines and tumor xenografts with inherent HR defects, and the repair defect induced by ATM inhibitor coadministration showed enhanced efficacy in HR-proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR-proficient tumors selectively enhances the relative biological effectiveness of proton Bragg peak irradiation. Significance: Coadministration of an ATM inhibitor rewires DNA repair machinery to render cancer cells uniquely hypersensitive to DNA damage induced by the proton Bragg peak, which is characterized by higher density ionization. See related commentary by Nickoloff, p. 3156

AbstractBackgroundA proton therapy system with 190° gantries uses robotic couch rotations to change the treatment beam laterality. Couch rotations are typically validated clinically with post‐rotation radiographic imaging.AimsThis study assesses the specificity and sensitivity of a commercial 3D surface imaging system, AlignRT (Vision RT, London UK) for validating couch rotations.Materials & MethodsIn clinical operation, a reference surface image of the patient is acquired after radiographic setup with couch at 270°, perpendicular to the gantry axis of rotation. The couch is then rotated ±90° to a typical treatment angle, and AlignRT reports a 3D displacement vector. Patient motion, changes in patient surface, non‐coincidence between AlignRT and couch isocenter, and mechanical couch run‐out all contribute to the 3D vector magnitude. To assess AlignRT sensitivity in detecting couch run‐out, volunteers were positioned orthogonal to the proton gantry and reference surface images were captured without x‐ray localization. Subjects were repeatedly rotated ±90⁰ to typical treatment angles and displacement vectors were recorded. Additionally, measurements were performed in which intentional translations of 2, 4, 6, and 8 mm were combined with the intended isocentric rotations. Data sets were collected using a phantom; subjects with a thoracic isocenter and no immobilization; and subjects with a cranial isocenter and thermoplastic immobilization. A total of 300 rotations were measured.ResultsDuring isocentric rotations, the mean AlignRT displacement vectors for the phantom, immobilized, and non‐immobilized volunteers were 0.1 ± 0.1 mm, 0.8 ± 0.1 mm, and 1.1 ± 0.2 mm respectively. 95% of the AlignRT measurements for the immobilized and non‐immobilized subjects were within 1 mm and 2 mm of the actual displacement respectively.DiscussionAfter characterizing the accuracy using phantoms and volunteers, we have shown that a three‐pod surface imaging system can be used to identify gross non‐isocentric patient rotations. Significant positional deviations, either due to improper couch rotation or patient motion, should be followed by radiographic imaging and repositioning.ConculsionAlignRT can be used to verify patient positioning following couch rotations that are applied after the initial x‐ray guided patient setup. Using a three‐pod AlignRt system, positional deviations exceeding 4 mm were flagged with sensitivity and specificity of 90% and 100% respectively.