Abstract Background FLASH therapy is a treatment technique in which radiation is delivered at ultra-high dose rates (≥ 40 Gy/s). The first-in-human FAST-01 clinical trial demonstrated the clinical feasibility of proton FLASH in the treatment of extremity bone metastases. The objectives of this investigation are to assess the toxicities of treatment and pain relief in study participants with painful thoracic bone metastases treated with FLASH radiotherapy, as well as workflow metrics in a clinical setting. Methods This single-arm clinical trial is being conducted under an FDA investigational device exemption (IDE) approved for 10 patients with 1–3 painful bone metastases in the thorax, excluding bone metastases in the spine. Treatment will be 8 Gy in a single fraction administered at ≥ 40 Gy/s on a FLASH-enabled proton therapy system delivering a single transmission proton beam. Primary study endpoints are efficacy (pain relief) and safety. Patient questionnaires evaluating pain flare at the treatment site will be completed for 10 consecutive days post-RT. Pain response and adverse events (AEs) will be evaluated on the day of treatment and on day 7, day 15, months 1, 2, 3, 6, 9, and 12, and every 6 months thereafter. The outcomes for clinical workflow feasibility are the occurrence of any device issues as well as time on the treatment table. Discussion This prospective clinical trial will provide clinical data for evaluating the efficacy and safety of proton FLASH for palliation of bony metastases in the thorax. Positive findings will support the further exploration of FLASH radiation for other clinical indications including patient populations treated with curative intent. Registration ClinicalTrials.gov NCT05524064.

High grade neurologic events were common in patients with predominantly active, unresected high grade gliomas receiving ReRT. Though ascertainment and survival bias are significant limitations, pseudoprogression and necrosis appeared to be more prominent in patients receiving protons. These results contribute to ongoing efforts to both optimize ReRT for high grade glioma and investigate biologic effects of proton therapy.

Purpose: The purpose of this trial was to assess the patient and physician-reported toxicity in anal cancer patients undergoing definitive chemoradiation with intensity-modulated proton therapy (IMPT). Methods: Patients with stage II and III anal cancer were treated with IMPT. All patients received 2 cycles of 5-fluorouracil and mitomycin concurrently with radiation. Toxicity was assessed at baseline, weekly during chemoradiation, and in follow-up using physician-graded common terminology criteria for adverse events (CTCAE) v 4.0 and PRO-CTCAE. The primary endpoint was to define point estimates and 95% CI for acute ≥ grade 2/3 gastrointestinal (GI), genitourinary (GU), dermatologic, and hematologic toxicity. The proportion of PRO-CTCAE questions scored ≥3 for each domain was compared with the baselinse. The proportion of ≥ grade 2 and ≥ grade 3 toxicities were compared with historic intensity-modulated radiotherapy patients treated on RTOG 0529. Results: Fourteen patients were enrolled from 2017 to 2020. Rates of physician-reported GI, GU, dermatologic, and hematologic toxicity were not significantly different between patients treated with IMPT compared with patients treated with intensity-modulated radiotherapy. Rates of patient-reported dermatologic and GU toxicity were low at baseline with a peak at week 6 (91% and 58% PRO-CTCAE items ≥ grade 3, respectively) and normalization to baseline 3 months after IMPT. In contrast, the proportion of high-grade PRO-CTCAE GI scores was 40% at baseline, which persisted through 1-year posttreatment. Conclusions: Clinician-reported toxicity was not improved with IMPT in the context of this underpowered trial. High-grade GI symptoms persisted for 12 months and were similar to baseline. Additional measures are needed to minimize acute and chronic toxicity related to chemoradiation.

Purpose/Objective(s)FLASH radiotherapy (RT) is delivered at ultra-high dose rates (>40 Gy/s), with preclinical animal data suggesting less toxicity to normal tissues. FAST-01 was a prospective, first-in-human study that evaluated the feasibility of a clinical workflow for proton FLASH RT in the treatment of painful extremity bone metastases. The treatment workflow was hypothesized to be feasible. In addition, this study intended to generate preliminary results regarding the safety and efficacy of this FLASH treatment.Materials/MethodsFAST-01 was a single institution study under an FDA investigational device exemption (IDE) approved for 10 patients with >2 month life expectancy and 1-3 painful bone metastases in the extremities. Exclusion criteria included patients with fractures or prior RT in the treatment site(s), or lesions of the feet, hands, or wrists. Treatment was 8 Gy (RBE = 1.0) in a single fraction delivered at ≥40 Gy/s via a FLASH-enabled proton therapy system employing a single transmission proton beam. Primary study endpoints were workflow feasibility (time on the treatment table and FLASH-related treatment delays) and toxicity, and secondary endpoint was efficacy (validated pain questionnaires). Pain flare questionnaires were completed for 10 consecutive days post-RT. Pain response at each treatment site was evaluated at 3 months post-RT using the methodology of RTOG 9714. Pain, pain medication use, and adverse events (AEs) were evaluated on the day of treatment and at 15 days, 1, 2, and 3 months post-RT, and every 2 months thereafter. AEs were graded using CTCAE v5. Safety analysis included all events that were physician-attributed to be at least “possibly related” to FLASH. Photos of skin in the treatment site areas supported AE evaluations.ResultsTen subjects aged 27-81 years received FLASH RT to 12 metastatic sites. No FLASH-related technical issues or delays occurred. Average time on the treatment table was 15.8 min per treated site (range 11-33 min). Follow-up ranged from 2.3-13 months (median 4.8 months). Transient pain flares occurred in 4 of 12 treated sites. Complete or partial pain relief following FLASH radiotherapy was seen in 8 of 12 sites (7 of the 10 subjects) for an overall response rate of 66.7%. Complete pain responses were 50% (6/12 sites), and partial responses were 17% (2/12 sites). AEs were mild: skin hyperpigmentation (G1, n=4), skin discoloration (G1, n=1), limb edema (G1, n=2), pruritis (G1, n=2), fatigue (G1, n=1), erythema (G1, n=1), and extremity pain (G2, n=1).ConclusionThis first-in-human trial establishes the feasibility of FLASH proton radiotherapy. The treatment efficacy and the profile of AEs were favorable and were comparable to the published literature for conventional dose rate photon RT. AE and pain data collection continues for the evaluation of long-term results. These findings support the further exploration of FLASH radiation treatments for other clinical indications.

Glioblastoma is a malignant brain tumor of the central nervous system that has median survival of 15-16 months. Radiation therapy is one of the major pillars of the current standard of care. However, radiation therapy may lead to serious sequelae such as endocrinopathies and cognitive impairment resulting from dose deposition in surrounding tissue. Ultra-high dose rate radiation therapy (FLASH) is a new method of radiation therapy that is thought to spare normal tissue while maintaining activity against tumor cells. We asked whether delivery of protons via FLASH would show comparable anti-tumor activity in a mouse model of glioma compared to standard dose rate proton therapy. We induced formation of primary glioblastomas of the proneural subtype by a retroviral vector carrying PDGFB and dominant negative p53 into the white matter of adult wildtype mice. This experiment (n = 7 mice per group) included two irradiation groups and a control. Both irradiation groups received a single fraction of 10Gy but at different dose rates – 1Gy/s (conventional) and 100Gy/s (FLASH). The whole brain irradiations were performed on the plateau region of a high energy proton Bragg peak (100Gy/s at 250MeV, 1Gy/s at 244MeV). We found that FLASH and conventional therapy both provided a statistically equivalent survival benefit in our endogenous glioblastoma model as compared to untreated animals. Following the initial tumor regression, we observed tumor relapse and re-growth for FLASH and conventional proton radiation based on MRI imaging. Dose escalation studies are ongoing to compare the curative potential of FLASH vs conventional irradiation in an endogenous glioma model. To understand the mechanisms by which tumors respond to FLASH vs conventional proton irradiation, we performed single-cell transcriptomic profiling on relapsed tumors treated with FLASH or conventional proton therapy and compared with untreated tumors. We found that proton radiation induced striking changes in the tumor microenvironment, specifically through an increase in myeloid derived suppressor cells. We have further characterized cell proliferation, apoptosis and tumor stem cell populations in relapsed tumors compared to untreated tumors and explored the differences in cellular responses with respect to FLASH or conventional proton irradiation. We will discuss transcriptomic profiling changes between pre- and post-proton treatment in the mouse glioma models. Our present work indicates that FLASH proton radiotherapy shows similar efficacy compared to conventional proton radiotherapy in an endogenous glioma model in immune-competent mice, and that tumor microenvironmental changes may contribute to tumor relapse.

The use of proton therapy over photons for the treatment of non-small cell lung cancer (NSCLC) has been increasingly favored in recent years. Previous work suggests that there may be a relationship between dose rate and treatment efficacy. The purpose of the current study was to compare the efficacy of 18 Gy proton radiation delivered at different dose rates on the eradication of NSCLC in a syngeneic, orthotopic mouse model. We hypothesized that ultra-high dose rate proton FLASH therapy improves treatment efficacy and decreases tumor sizes compared to conventional proton therapy. Lewis Lung Carcinoma (LLC) cells were inoculated into the left lung of C57Bl/6J mice. Both male and female mice were used. Two weeks after tumor cells inoculation, CT scan was performed to measure the pre-radiation size of lung tumors. Mice were randomly assigned to four different groups: untreated control, conventional, FLASH and Pulsed-FLASH groups. The whole lungs of tumor-bearing mice were irradiated with a dose of 18 Gy using a clinical pencil beam scanning proton system at different dose-rate modes of conventional (.5 nA beam current), FLASH (40 Gy/s), and Pulsed-FLASH (40 Gy/s with a 10% duty cycle). The delivered dose was monitored and verified using different ionization chambers, as well as gafchromic EBT2 film. One week after proton treatment, the tumor sizes were measured using CT scan. Ten days after proton treatment, mice were sacrificed and tumor sizes were measured using caliper. Lung tumors and tissues were harvested for histological and molecular analysis. Immunofluorescent staining was performed on tumor sections using antibodies for CD3, CD4, and CD8. Tumor cells were visualized with mCherry antibodies. Mice treated with FLASH or Pulsed-FLASH dose-rate modes had significantly smaller lung tumors than mice treated with proton radiation delivered at conventional dose-rate. The results of CT scan analysis for tumor sizes were consistent with the tumor measurements at tissue harvest. Compared to conventional proton radiation, Pulsed-FLASH and FLASH radiation increased recruitment of CD3+ T lymphocytes from the peripheral tumor edge into the tumor core. Among CD3+ cells, both CD4+ and CD8+ cells were increased in the tumor core. These data indicate that improved lung tumor control by ultra-high dose rate FLASH proton radiation can be the result of improved recruitment of CD3+ cells into the tumor. Ultra-high dose rate proton FLASH induced more efficient lung-tumor eradication compared to conventional proton and improved recruitment of T lymphocytes into the tumor microenvironment. Thus, ultra-high dose rate proton FLASH represents a promising new alternative to conventional proton treatment.

Transplantable murine tumor models are critical for radiobiological studies of proton and photon radiation, and immobilization devices are essential for accurate tumor (often <1 cm) targeting in these models. We utilized three-dimensional (3D) printing technology to design and produce an immobilization device for this purpose. All procedures were approved by the institutional animal care committee. CT imaging of a C57BL/6 mouse was performed, and the Blender software package was used to generate a surface contour. A clamshell device was designed with a negative impression of the animal surface contour, and a lateral aperture for flank tumors. A brass block was affixed to reduce beam penumbra. The device was printed from polylactic acid polymer using an Ultimaker 2 3D printer and tested on a mouse harboring a subcutaneous flank tumor (EL4 Thymoma). Tumor motion was tracked in the x, y, and z planes using video monitoring over 15 minutes. Animals (n=3) were safely immobilized with no signs of trauma or distress. Minimal tumor movement was observed in the x, y, and z planes. Proton and photon treatment plans were generated using Eclipse software, demonstrating uniform targeting of the tumor with <10% of the prescribed dose delivered to the abdominal or thoracic cavity. We present the rapid and cost-effective design and production of an immobilization device using 3D printing for the treatment of experimental murine tumors with photon or proton beam radiotherapy.

Prior studies of accelerated partial breast irradiation (APBI) with passive scatter proton therapy have demonstrated promising dosimetric and clinical results. Disadvantages of passive scatter therapy include the use of multiple proton beams and higher skin doses, leading to an increase in clinically apparent skin toxicity. Scanning beam Intensity Modulated Proton Therapy (IMPT) has potential advantages over passive scatter proton therapy in regards to field selection, treatment duration, dose homogeneity, and normal tissue sparing. This retrospective review represents our clinical experience using IMPT technique for treatment of breast cancer with APBI. Between March 2014 and February 2015, 5 patients with IDC or DCIS underwent IMPT treatment. All patients underwent CT based simulation and treatment planning and were setup supine on a breast board or in the prone position. Daily setup and localization was accomplished with 4-6 skin surface fiducial markers tracked with orthogonal x-ray pairs. Treatment was administered while free breathing in 10 M-F daily fractions over a 2 week period, with 3800-4000 cGy prescribed to the gross operative cavity and 3400-3850 cGy prescribed to the clinical target volume which was defined as 10-15 mm expansion of the operative cavity respecting anatomical boundaries. Treatment was delivered with a single enface scanning proton beam. Normal organs were contoured and skin was defined as the volume within 3 mm of the exterior body contour. Clinical outcomes were monitored during and after treatment and later abstracted from the EMR. Mean total patient time in treatment room was 17 minutes. Enface proton beam setups included LAO, AP, LL and RAO. Maximum and mean doses are as follows: cardiac 531.4 cGy/4.3 cGy, ipsilateral lung 2610 cGy/55.3 cGy, chest wall 3682 cGy/692.2 cGy and skin 3 mm of 3966 cGy/889 cGy. All patients experienced grade 1 dermatitis of skin overlying the treatment area, grade 1 fatigue and no other acute toxicity. With a mean follow-up time of 7 months, 2 patients had minor dry skin in the treatment area and no other late toxicities. All patients self-reported ‘good to excellent’ cosmetic outcomes at time of most recent follow-up. No patients had evidence of local failure at the time of most recent follow up. Single field scanning beam IMPT is a feasible and effective approach for treating APBI. Improved treatment time and use of a single scanning beam helps to reduce delivery uncertainties and reduce intra-fractional motion and respiratory variance. IMPT delivers superior skin sparing when compared with passive scatter proton therapy. IMPT provides excellent normal tissue sparing dosimetry and good acute toxicity profile.

Due to significant cost of proton gantry systems, many proton therapy facilities install one or more fixed beamline systems. Using only traditional supine or prone patient setups limits the available treatment ports in fixed beamlines, thereby limiting the sites treatable. In this study, lateral decubitus immobilization techniques are investigated to increase the gantry-equivalent angle options in fixed beamline (FBL) and inclined beamline (IBL) proton treatment rooms. The FBL has one standard gantry angle of 90o; the IBL has two standard gantry angles of 30o and 90o. Each treatment room has a 6-degree of freedom robotic patient positioner. Several treatment sites were identified as potential candidates for lateral decubitus immobilization based on the ability to yield the same gantry-equivalent angle as a standard treatment technique. Currently, there is no commercially available product that offers whole-body lateral decubitus immobilization for external beam radiotherapy. However, several commercially available were assembled in-house with a custom designed frame. The final design was tested for robustness, reproducibility, comfort and compatibility with 80cm bore CT Scanner. For immobilization, a foam-based mold is made of the patient, lying in the lateral decubitus position, in a custom frame designed in-house. A head rest, hip rest and knee rest are placed in the mold to improve patient comfort and reduce discomfort of pressure points. After the foam sets, the mold becomes rigid and durable. A large 46cm x 56cm thermoplastic sheet is wrapped over the foam mold and secured to the frame, giving reproducibility to arm position and reducing any patient roll. By complementing the standard supine with the lateral decubitus position and robotic patient positioner, the FBL increases its gantry-equivalent angle to 0o, 90o, 180o, and 270o. The IBL increases its gantry-equivalent angles to 0o, 30o, 90o, 150o, 180o, 210o, 270o, 330o. This significantly increases the number of beam delivery options for the treatment room, expanding the sites treatable. The immobilization is also compact enough to fit inside the field of view of CT Scanner. Infrared, surface contour tracking equipment was used to quantify the setup uncertainty, which is shown to be equivalent to the conventional supine and prone immobilization techniques. The lateral decubitus immobilization is required to expand the sites treatable on a FBL or IBL delivery system. This immobilization technique provides a stable and reproducible patient position, adequate patient comfort and a durable mold.