Eric Stanton Diffenderfer
· Ph.D.VerifiedUniversity of Pennsylvania · Rehabilitation Medicine
Active 2002–2025
About
Eric Stanton Diffenderfer, Ph.D., is an Associate Professor of Radiation Oncology at the Hospital of the University of Pennsylvania. His research expertise includes FLASH radiotherapy, proton SARRP development, proton and neutron microdosimetry, and machine learning applications in Radiation Oncology. He serves as the Proton Research Room Technical Director for the Proton SARRP research facility, and is the Physics Lead for the Thoracic Group within the Department of Radiation Oncology at the University of Pennsylvania. His clinical expertise encompasses proton and X-ray therapy physics and dosimetry. Dr. Diffenderfer holds a B.S. and M.S. in Physics from The Evergreen State College and Florida State University respectively, and earned his Ph.D. in Nuclear Physics from Florida State University. His work focuses on advancing radiotherapy techniques, including FLASH radiotherapy and proton therapy, with significant contributions to the development of proton research tools and the understanding of radiation physics.
Research topics
- Internal medicine
- Medicine
- Computer Science
- Physics
- Biology
- Nuclear physics
- Cancer research
- Medical physics
- Nuclear engineering
- Pathology
- Engineering
- Optics
Selected publications
Medical Physics · 2025-04-01 · 3 citations
articleOpen accessSenior authorCorrespondingBACKGROUND: Ultra-high dose rate radiotherapy elicits a biological effect (FLASH), which has been shown to reduce toxicity while maintaining tumor control in preclinical radiobiology experiments. FLASH depends on the dose rate, with evidence that higher dose rates drive increased normal tissue sparing. The pattern of dose delivery also has significance for conformal proton FLASH delivered via pencil beam scanning (PBS) given its unique spatio-temporal distribution of dose deposition. PURPOSE: In PBS, the machine-generated log file contains information on the spatio-temporal pattern of PBS delivery measured by the segmented ionization chambers in the treatment nozzle. The spot position and monitor unit (MU) obtained from log files have previously been used to reconstruct the treatment dose by Monte Carlo (MC) simulations. The incorporation of spot timing allows reconstruction of the 3D temporal dose distribution. The log-based dose and dose rate can have a role in quality assurance (QA) and FLASH treatment verification if the reconstruction can be shown to be accurate in spatial and temporal domains of dose deposition. Thus, the objective of this study is to validate the accuracy of dose rate reconstruction using input data from machine log files of PBS delivery. By analyzing the delivered spot timing, position, and MU extracted from the logs, we aim to evaluate the reliability and precision of the log data for dose and dose rate reconstruction. METHODS: FLASH PBS spread-out Bragg peak (SOBP) treatment fields were delivered using a cyclotron accelerated proton beam. This method involves a patient and field-specific conformal energy modulator (CEM) to achieve a SOBP at the tumor site. Log files record spot positions and the delivered MU with timing information at 250 µs resolution. To validate timing information, a 9.9 mm diameter parallel plate ionization chamber was positioned at various locations within the SOBP. An electrometer sampling at 20 kHz recorded the time-resolved ionization current collected by the ionization chamber. These measurements were used to determine spot dose, dose rate, duration, and transition times. Disparities between the measured and logged spot map MU and timing were determined. Dose average and PBS dose rates were compared between the measurement and log-based MC simulations. RESULTS: There was a good agreement between the measured dwell time and transition time and the logged information across various detector positions. The median disparities for inter-spot dwell time range from -0.041 to 0.024 ms. Differences between logged and planned spot positions are minimal, measuring less than 1.08 mm in the x direction and 1.15 mm in the y direction, consistent with prior studies and the spatial resolution of the PBS nozzle ionization chamber. Delivered MU were within 1.9% of the planned MU. Measured dose and dose rates are consistent with simulated outcomes derived from MC simulation. CONCLUSION: We validated the precision and accuracy of PBS log file data through measurements and MC simulations. These findings support the use of log files in MC calculations as one part of patient-specific quality assurance (PSQA) and dose rate delivery verification for conformal proton FLASH radiotherapy with SOBP.
Nature Cancer · 2025-02-05 · 57 citations
articleFROM THE DESIGN TO THE COMMISSIONING OF A PROTON CONFORMAL FLASH SYSTEM FOR CLINICAL TRIALS
International Journal of Particle Therapy · 2025-11-25
articleOpen accessSenior authorRadiotherapy and Oncology · 2025-05-01
articleAdvancing Proton FLASH Radiation Therapy: Innovations, Techniques, and Clinical Potentials
International Journal of Radiation Oncology*Biology*Physics · 2025-06-11 · 8 citations
reviewRadiotherapy and Oncology · 2025-01-27 · 22 citations
articleOpen accessBACKGROUND AND PURPOSE: The normal tissue sparing afforded by FLASH radiotherapy is being intensely investigated for potential clinical translation. Here, we studied the effects of FLASH proton radiotherapy (F-PRT) in the reirradiation setting, with or without hypofractionation. Chronic toxicities in three murine models of normal tissue toxicity including the intestine, skin, and bone were investigated. MATERIALS AND METHODS: In studies of the intestine, single-dose irradiation was performed with 12 Gy of standard proton RT (S-PRT), followed by a second dose of 12 Gy of F-PRT or S-PRT. Additionally, a hypofractionation scheme was applied in the reirradiation setting (3 x 6.4 Gy of F-PRT or S-PRT, given every 48 hrs). In studies of skin/bone of the murine leg, 15 Gy of S-PRT was followed by hypofractionated reirradiation with F-PRT or S-PRT (3 x 11 Gy). RESULTS: Compared to reirradiation with S-PRT, F-PRT induced less intestinal fibrosis and collagen deposition that was accompanied by significantly increased survival rate, demonstrating its protective effects on intestinal tissues in the reirradiation setting. In previously irradiated leg tissues, reirradiation with hypofractionated F-PRT created transient dermatitis that fully resolved in contrast to reirradiation with hypofractionated S-PRT. Lymphedema was also alleviated after a second course of radiation with F-PRT, along with significant reductions in the accumulation of fibrous connective tissue in the skin, compared to mice reirradiated with S-PRT. The delivery of a second course of fractionated S-PRT induced tibial fractures in 83.3% of the mice, whereas only 20% of mice reirradiated with F-PRT presented with fractures. CONCLUSION: These studies provide the first evidence of the sparing effects of F-PRT in the setting of hypofractionated reirradiation. The results support FLASH as highly relevant to the reirradiation regimen where it exhibits significant potential to minimize chronic complications for patients undergoing RT.
International Journal of Radiation Oncology*Biology*Physics · 2025-01-05 · 4 citations
articlePhysics in Medicine and Biology · 2025-07-29
articleOpen accessAbstract Objective. Ultra-high dose rate (UHDR) proton pencil beam scanning (PBS) delivery results in irregular temporal-varying dose accumulation. It is difficult to establish a dose rate standard for the indication of proton PBS FLASH effect. In this work, we adopted a published physicochemical approach and investigated the impact of proton PBS UHDR parameters on the formation and downstream reactions of reactive oxygen species (ROS). Approach. From the ROS physicochemical model, the dose-rate dependent alkyl hydroperoxide (ROOH) formation was validated against published lipid peroxide absorbance data and correlated with mice skin damage data. For proton PBS delivery with specified beam current, voxelized temporal dose and ROS accumulation was calculated at the plateau region to simulate a shoot-through FLASH delivery. The ROS were obtained mimicking the irradiation of hypoxic skin. We examine the ROS-volume histogram in relation to the proton PBS delivery parameters. Main results. ROOH production clearly indicates sparing effects under UHDR. For PBS deliveries of 10 Gy to a 100 × 100 mm 2 field at 8 mm depth, the ROOH yield at 500 nA FLASH beam current is equivalent to a 8.78 Gy delivery at 1nA CONV delivery. The yield of ROOH depends strongly on the dose and beam current but has minimal dependency on the field size and spot spacing. Introducing inter-beam intervals of two minutes reduces the FLASH reduction in ROOH, consistent with reduced FLASH effect in murine experiment. Significance. The volumetric statistics of the ROOH yield showed consistent indication of FLASH effects in preclinical observations and correlated with the lipid peroxidation damage in tissue. Using simulated ROOH production metrics can potentially indicate the FLASH sparing effect under various PBS delivery parameters. Our simulations indicate that the shoot-through PBS FLASH effect depends mainly on the total dose and the pencil beam current, and is relatively independent of field sizes and spot spacings.
3D PRINTING OF STACKABLE VARIABLE DENSITY RANGE MODULATORS FOR FLASH PROTON THERAPY
International Journal of Particle Therapy · 2025-11-25
articleOpen access2025-02-03
book-chapterSenior authorUltra-high-dose-rate (UHDR) radiotherapy has been investigated for the potential to induce the FLASH effect. Pre-clinically, UHDR beams have demonstrated increased normal tissue sparing with equivalent tumor control compared to the same dose delivered at conventional dose rates. Protons are of particular interest due to the physical properties of protons to reach deep-seated targets and the capability of various proton acceleration systems to deliver UHDR beams with minimal impact to existing clinical infrastructure. This chapter will discuss such accelerators and the differences they harbor when generating UHDR beams. Dosimetry and quality assurance (QA) for UHDR proton beams will be discussed briefly to highlight the challenges compared to conventional proton radiotherapy. Finally, recent advances in proton FLASH treatment planning will be reviewed, including differences between shoot-through transmission FLASH and conformal FLASH delivery. Proton FLASH radiotherapy is a continuously evolving research field with much knowledge to be gained from upcoming clinical trials. The interdisciplinary research community has been reinvigorated by the interest in FLASH radiotherapy and will continue to focus on rigorous treatment planning, dosimetry, treatment machine QA, and patient-specific QA to ensure safe and robust clinical translation.
Recent grants
Frequent coauthors
Education
- 2007
PhD, Physics
Florida State University
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