FLASH Dose Research Articles

FLASH Effects Induced by kV X-Rays in a Murine Skin Model

<h3>Purpose/Objective(s)</h3> Current research on FLASH dose rate radiotherapy is predominantly performed with advanced proton or electron accelerators of limited access to the laboratory researcher. Stationary anode orthovoltage x-ray irradiators would be desirable but are currently incapable of supporting the power requirements to operate at FLASH dose rates. In this study, we investigate the use of rotating anode x-ray tubes to overcome these limitations. We present the dosimetric characterization of a rotating anode x-ray system for laboratory FLASH research and its implementation for a pilot study of radiation skin toxicities in mice. <h3>Materials/Methods</h3> A high-capacity rotating anode x-ray tube was installed in our laboratory with a 75-kW generator, operating at 150 kVp with 0.025 mm Cu added filtration. Calibrated radiographic film was irradiated at varying depths in kV solid water to measure output, beam profiles, and depth-dose parameters (PDD). A variety of wild-type mice (GR/GRT, CMV) were irradiated to the hind flank to 38 or 48 Gy at the highest achievable dose rate (FLASH-IR). Conventional dose rate irradiations (CONV-IR) to the same doses were performed at 3 Gy/min using a 220 kVp x-ray irradiator. Visible skin toxicities were assessed weekly and quantified using a skin scoring scale for endpoints of hair loss, erythema, and ulceration (n= 7 per dose at each dose rate). At 8-weeks post irradiation, skin samples were harvested and stained with H&E to assess pathological changes from FLASH-IR or CONV-IR x-rays. <h3>Results</h3> Dose rates peaked at 101 Gy/s in the cathode side of the radiation field from anode heel effects. The total field size at 46 mm SSD was 20 × 20mm². A useable region of 10 × 20 mm² for FLASH studies was defined as the cathode-half of the field, with an average dose rate of 96.1 ± 2.8 Gy/s. The PDD within this region falls to 67% at 5mm depth in solid water and 51% at 10 mm. At 4 weeks post irradiation, CONV-IR mice saw hair loss and erythema in the entire irradiated region, while all FLASH-IR mice retained hair in-field with no change in skin condition. By 8 weeks post irradiation, skin effects in all FLASH-IR mice did not progress beyond hair loss in field, while all CONV-IR mice had progressed to more severe skin toxicities. Pathological assessments are ongoing. Early analysis shows higher frequency of ulceration, dermis hyperplasia, and fibrosis from CONV-IR than FLASH-IR. <h3>Conclusion</h3> This study presents the first observation of FLASH effects induced by a single pulse of kV x-rays in an animal skin toxicity model. FLASH dose rates requisite for preclinical research are achievable with kV x-rays using rotating anode technology. X-ray FLASH effects in skin occur at comparable doses to those published for FLASH electrons and protons. The use of a single x-ray pulse suggests that average dose rate is the necessary condition, in contrast to fine pulse structure, for the induction of FLASH effects.

A Novel Ultra-High Dose Rate Proton Therapy Technology: Spot-Scanning Proton Arc Therapy FLASH (SPLASH)

<h3>Purpose/Objective(s)</h3> The flash dose rate on the order of 40 Gy/s has the potential to spare normal tissue with iso-effective tumor growth delay. Meanwhile, the spot-scanning proton arc therapy (SPArc), demonstrated its superior dosimetric conformity and plan robustness compared to the conventional intensity modulated proton therapy (IMPT). To take the full advantage of flash dose rate and the high dose conformity, we introduce a novel optimization and delivery technique, SPArc FLASH (SPLASH). <h3>Materials/Methods</h3> SPLASH framework was implemented in an open-source proton planning platform (matRad). It optimizes the spot monitor unit (MU) weighting and cyclotron beam current per spot simultaneously. More specifically, it simultaneously optimized with the clinical dose-volume constraint based on dose distribution and optimized the dose-average dose rate by minimizing the monitor unit constraint on spot weight and maximum cyclotron beam current to minimize the cost function value combined by dose and dose rate. An intracranial target (volume = 20.8cc) case was used for testing purpose. Prescription is 50 Gy in 25 fractions. Dose-volume histogram, dose averaged dose rate histogram and dose rate map per spot were compared between SPArc and SPLASH. <h3>Results</h3> The dose-averaged dose rate histogram indicated that flash dose rate (40Gy/s) could not be achieved using the original SPArc with the current clinical beam current configuration. With a same plan quality, SPLASH improved dose-averaged dose rate of V<i>r</i> > 40 Gy/s (Volume of dose rate larger than 40Gy/s) in PTV, optic chiasm, optic nerve and brainstem from 0%, 0%, 0%, 0% in SPArc plan to 100%, 100%, 100%, 75%, respectively. The optimal cyclotron beam current per spot is simultaneously generated. <h3>Conclusion</h3> The SPLASH offers simultaneously optimizing dose distribution and dose rate. It could generate a treatment plan with a superior conformal dose distribution and ultra-high dose rate, which has never been demonstrated before.

FLASH vs. Conventional Dose Rate Proton Radiation in Mouse Abdomen

<h3>Purpose/Objective(s)</h3> The mechanisms underlying normal tissue toxicity sparing and survival benefits of ultra-high dose rate radiation (FLASH) are still unclear. We used a low-energy proton system (50 MeV) optimized for small animal radiobiological research to study the biological effects after FLASH and conventional dose rate (CONV) proton radiation to mouse abdomen. <h3>Materials/Methods</h3> We radiated the abdomen of 6–7-week-old female C57BL/6 mice using the plateau region of a continuous (unpulsed) cyclotron-generated 50 MeV preclinical proton beam, transmitting through the abdomen, with 1.5cm (for survival study) or 3cm (for EdU assay) width of beam via customized vertical and horizontal collimators. Mice survival and regenerated crypts in colon tissues using EdU assay were studied. Mice were stratified into 3 groups: 1) control/sham radiation (n=8 for survival, n=4 for EdU); 2) FLASH (20Gy at 48-93Gy/sec, n=22 for survival and n=13 for EdU); 3) CONV (20Gy at ∼1Gy/sec, n=19 for survival, n=11 for EdU). For survival study, mice were observed for survival post radiation. For EdU assay, the mice were injected with EdU 3-4 hours prior to euthanasia, and colon tissues were collected at 24 hours and 96 hours post-radiation for sectioning and then EdU staining. <h3>Results</h3> FLASH and CONV groups showed different survival: FLASH (13 days post radiation, 36.4% survival); CONV (15.6% survival, P = 0.04). FLASH group had more EdU staining than the CONV group, though both FLASH and CONV groups showed reduced EdU staining compared to the control group. <h3>Conclusion</h3> Preliminary results of mouse abdomen FLASH and CONV proton radiation from a 50 MeV beam suggest FLASH proton radiation leads to better survival and less normal tissue damage than CONV radiation.

Enhanced Radiation-Sparing Effects of Ultra-High Dose Rate Proton Radiation (FLASH-RT) in a Human Induced Pluripotent Stem Cell-Derived Cerebral Organoid Model

<h3>Purpose/Objective(s)</h3> Superior normal tissue sparing with similar antitumoral effectiveness has been observed in preclinical animal models following delivery of radiation at ultra-high dose rates (FLASH-RT), relative to conventional dose rates (CONV-RT). Clinical application of FLASH-RT could reduce devastating radiation-related side effects for patients with aggressive brain tumors such as glioblastoma; however, the FLASH effect must be established in representative models of human systems before its implementation in the clinic. Our objective is to measure relevant response outcomes to proton FLASH-RT using advanced cerebral organoid (CO) models of normal and diseased human brain tissue, correspondingly generated with human induced pluripotent stem cells and patient-derived glioma stem-like cells (GSCs). <h3>Materials/Methods</h3> Mature COs were irradiated to 9 Gy using conventional (CONV, 0.2 Gy/s) and FLASH (100 Gy/s) dose rates using a proton beam and prepared for histological analysis at 30 days post-irradiation. Spatial distribution of hypoxia was visualized in COs by incubating for 2 hours with pimonidazole prior to preparation for histologic analysis. Image analysis was performed with QuPath. Lactate dehydrogenase (LDH) release, a marker of cell death, was sequentially quantified. COs implanted with GSCs expressing a luciferase reporter were co-cultured for 14 days and irradiated as above. Tumor cell proliferation was tracked via luciferase expression. <h3>Results</h3> At 2- and 4-days post-irradiation, there was an increase in LDH release for CONV versus FLASH-radiated COs (p<0.01, p<0.01 respectively) which normalized after 9 days. At 30 days, when specific cell populations in FLASH-radiated COs were histologically compared to CONV-radiated COs, there were higher numbers of proliferating neural progenitor cells (SOX2+/Ki67+, p<0.01), mature neurons (NeuN+, p=0.03), and deep cortical surface layer neurons (SATB2+, p=0.01). The spatial distribution of neural progenitor cells and mature neurons overlapped with hypoxic regions of the CO (pimonidazole+). A trend towards lower expression of activated microglia (IBA1+/CD68+) in FLASH-irradiated COs compared to CONV-radiated COs was noted (p=0.12). A 48.6% versus 51.2% reduction in tumor proliferation in FLASH versus CONV-irradiated GSC-laden-COs was observed at 4d post-irradiation (p=0.98). <h3>Conclusion</h3> We report preliminary findings of normal tissue toxicity reduction and iso-effective tumor response in a human-derived brain model following proton FLASH-RT. Potential protective effects following FLASH-RT to be further validated include preservation of specific cell populations within hypoxic niches including progenitor and differentiated neurons with a corresponding reduction in chronic neuroinflammation.

Dose and dose rate objectives in Bragg peak and shoot-through beam orientation optimization for FLASH proton therapy.

The combined use of Bragg peak (BP) and shoot-through (ST) beams has previously been shown to increase the normal tissue volume receiving FLASH dose rates while maintaining dose conformality compared to conventional intensity-modulated proton therapy (IMPT) methods. However, the fixed beam optimization method has not considered the effects of beam orientation on the dose and dose rates. To maximize the proton FLASH effect, here, we incorporate dose rate objectives into our beam orientation optimization framework. From our previously developed group-sparsity dose objectives, we add upper and lower dose rate terms using a surrogate dose-averaged dose rate definition and solve using the fast-iterative shrinking threshold algorithm. We compare the dosimetry for three head-and-neck cases between four techniques: (1) spread-out BP IMPT (BP), (2) dose rate optimization using BP beams only (BP-DR), (3) dose rate optimization using ST beams only (ST-DR), and (4) dose rate optimization using combined BP and ST (BPST-DR), with the goal of sparing organs at risk without loss of tumor coverage and maintaining high dose rate within a 10mm region of interest (ROI) surrounding the clinical target volume (CTV). For BP, BP-DR, ST-DR, and BPST-DR, CTV homogeneity index and Dmax were found to be on average 0.886, 0.867, 0.687, and 0.936 and 107%, 109%, 135%, and 101% of prescription, respectively. Although ST-DR plans were not able to meet dosimetric standards, BPST-DR was able to match or improve either maximum or mean dose in the right submandibular gland, left and right parotids, constrictors, larynx, and spinal cord compared to BP plans. Volume of ROIs receiving greater than 40Gy/s ( was 51.0%, 91.4%, 95.5%, and 92.1% on average. The dose rate techniques, particularly BPST-DR, were able to significantly increase dose rate without compromising physical dose compared with BP. Our algorithm efficiently selects beams that are optimal for both dose and dose rate.

FLASH-Enabled Proton SBRT/SRS via Simultaneous Dose and Dose Rate Optimization (SDDRO)

<h3>Purpose/Objective(s)</h3> The availability of SBRT/SRS is often hindered by dose-limiting toxicities to organs at risk (OAR). This work investigates the clinical potential of FLASH-RT for improving high-dose sparing of OAR, to enable SBRT/SRS that could otherwise fail to meet dose constraints with CONV-RT. <h3>Materials/Methods</h3> CONV-RT (via Bragg peaks (BP)) and FLASH-RT (via transmission beams (TB)) are compared with pencil beam scanning proton therapy, i.e., CONV-RT planned with IMPT-BP, and FLASH-RT planned respectively with IMPT and SDDRO of TB. While IMPT only optimizes the dose distribution, SDDRO also optimizes the FLASH effect, i.e., to maximize the normal tissue volume receiving dose rate and dose thresholds pertinent to the FLASH effect, which was set to be 40Gy/s and 8Gy. The plan evaluation is based on the effective dose, i.e., the product of the physical dose and FLASH dose modifying factor, which was set to be 0.7 when normal tissues meet both dose rate and dose thresholds. <h3>Results</h3> CONV-RT (i.e., IMPT-BP) was compared with FLASH-RT (planned with IMPT and SDDRO respectively) for three clinical SBRT/SRS cases of lung, prostate, and brain. For fair comparison, all plans had the same clinical objectives and were after the same normalization of D95%=100% for PTV. The effective dose results are summarized in the table. (1) The CI values show that SDDRO had the best target dose conformality (note that 0.95 is optimal under D95%=100%). (2) The mean doses at PTV-10mm (10mm expansion of PTV) suggest that SDDRO had the fastest high-dose falloff for normal tissues adjacent to the target. (3) For the lung case, per RTOG 0618, the max dose constraint 27Gy for esophagus was only met by SDDRO (25Gy), not CONV-RT (35Gy) or IMPT (37Gy); the max dose constraint 30Gy for trachea and bronchus was substantially relaxed to 22Gy by SDDRO. (4) For the prostate case, SDDRO substantially decreased V32Gy to nearly 0cc. (5) For the brain case, compared to CONV-RT, SDDRO substantially decreased V12Gy from 44cc to 14cc; note that V12Gy≤15cc is required to reduce the likelihood of symptomatic radiation necrosis per HyTEC reports. <h3>Conclusion</h3> Compared to CONV-RT (i.e., IMPT-BP), FLASH-RT via SDDRO improved high-dose sparing of OAR, which can potentially enable proton SBRT/SRS that could otherwise fail to meet dose constraints, e.g., the reduction of V12Gy from 44cc to 14cc to meet V12Gy≤15cc for this case to be eligible for brain SRS.

Potential Molecular Mechanisms behind the Ultra-High Dose Rate "FLASH" Effect.

FLASH radiotherapy, or the delivery of a dose at an ultra-high dose rate (>40 Gy/s), has recently emerged as a promising tool to enhance the therapeutic index in cancer treatment. The remarkable sparing of normal tissues and equivalent tumor control by FLASH irradiation compared to conventional dose rate irradiation—the FLASH effect—has already been demonstrated in several preclinical models and even in a first patient with T-cell cutaneous lymphoma. However, the biological mechanisms responsible for the differential effect produced by FLASH irradiation in normal and cancer cells remain to be elucidated. This is of great importance because a good understanding of the underlying radiobiological mechanisms and characterization of the specific beam parameters is required for a successful clinical translation of FLASH radiotherapy. In this review, we summarize the FLASH investigations performed so far and critically evaluate the current hypotheses explaining the FLASH effect, including oxygen depletion, the production of reactive oxygen species, and an altered immune response. We also propose a new theory that assumes an important role of mitochondria in mediating the normal tissue and tumor response to FLASH dose rates.

Advanced pencil beam scanning Bragg peak FLASH-RT delivery technique can enhance lung cancer planning treatment outcomes compared to conventional multiple-energy proton PBS techniques

To investigate the dosimetric characteristics between an advanced proton pencil beam scanning (PBS) Bragg peak FLASH technique and conventional PBS planning technique in lung tumors. To evaluate the "FLASHness" of single-field in a multiple-field delivery scheme for a hypofractionation regimen and move a step forward to clinical application. Single-energy PBS Bragg peak FLASH treatment plans were optimized based on a novel Bragg peak tracking technique to enable Bragg peaks to stop at the distal edge of the target. Inverse treatment planning using multiple-field optimization (MFO) can achieve sufficient FLASH dose rate and intensity-modulated proton therapy (IMPT)-equivalent dosimetric quality. The dose rate of organs-at-risk (OARs) and the target were calculated under FLASH machine parameters. A group of 10 consecutive lung SBRT patients was optimized to 34Gy/fraction using a standard treatment of PBS technique with multiple energy layers as references to the Bragg peak plans. The dosimetric quality was compared between Bragg peak FLASH and conventional plans based on RTOG0915 dose metrics. FLASH dose rate ratios (V40Gy/s) were calculated as a metric of the FLASH-sparing effect. For higher dose thresholds, the Bragg peak plans achieved greater V40Gy/s FLASH coverage for all major OARs. The V40Gy/s was close to 100% for all OARs when the dose thresholds were>5Gy for full plan and single beam evaluations. The less "FLASHness" region was associated with a low dose distribution, mainly occurring in the PBS field penumbra region. The conventional IMPT treatment plans yielded slightly superior target dose uniformity with a D2%(%) of 108.02% versus that of Bragg peak 300 MU plans of 111.81% (p<0.01) and that of Bragg peak 1200 MU plans of 115.95% (p<0.01). No significant difference in dose metrics was found between Bragg peak and IMPT treatment plans for the spinal cord, esophagus, heart, or lung-GTV (all p>0.05). Hypofractionated lung Bragg peak plans can maintain comparable plan quality to conventional PBS while achieving sufficient FLASH dose rate coverage for major OARs for each field under the multiple-field delivery scheme. The novel Bragg peak FLASH technique has the potential to enhance lung cancer planning treatment outcomes compared to standard PBS treatment techniques.

Pencil beam scanning proton FLASH maintains tumor control while normal tissue damage is reduced in a mouse model.

Preclinical studies indicate a normal tissue sparing effect when ultra-high dose rate (FLASH) radiation is used, while tumor response is maintained. This differential response has promising perspectives for improved clinical outcome. This study investigates tumor control and normal tissue toxicity of pencil beam scanning (PBS) proton FLASH in a mouse model. Tumor bearing hind limbs of non-anaesthetized CDF1 mice were irradiated in a single fraction with a PBS proton beam using either conventional (CONV) dose rate (0.33-0.63Gy/s field dose rate, 244MeV) or FLASH (71-89Gy/s field dose rate, 250MeV). 162 mice with a C3H mouse mammary carcinoma subcutaneously implanted in the foot were irradiated with physical doses of 40-60Gy (8-14 mice per dose point). The endpoints were tumor control (TC) assessed as no recurrent tumor at 90days after treatment, the level of acute moist desquamation (MD) to the skin of the foot within 25days post irradiation, and radiation induced fibrosis (RIF) within 24weeks post irradiation. TCD50 (dose for 50% tumor control) was similar for CONV and FLASH with values (and 95% confidence intervals) of 49.1 (47.0-51.4) Gy for CONV and 51.3 (48.6-54.2) Gy for FLASH. RIF analysis was restricted to mice with tumor control. Both endpoints showed distinct normal tissue sparing effect of proton FLASH with MDD50 (dose for 50% of mice displaying moist desquamation) of <40.1Gy for CONV and 52.3 (50.0-54.6) Gy for FLASH, (dose modifying factor at least 1.3) and FD50 (dose for 50% of mice displaying fibrosis) of 48.6 (43.2-50.8) Gy for CONV and 55.6 (52.5-60.1) Gy for FLASH (dose modifying factor of 1.14). FLASH had the same tumor control as CONV, but reduced normal tissue damage assessed as acute skin damage and radiation induced fibrosis.

Cognitive and behavioral effects of whole brain conventional or high dose rate (FLASH) proton irradiation in a neonatal Sprague Dawley rat model.

Recent studies suggest that ultra-high dose rates of proton radiation (>40 Gy/s; FLASH) confer less toxicity to exposed healthy tissue and reduce cognitive decline compared with conventional radiation dose rates (~1 Gy/s), but further preclinical data are required to demonstrate this sparing effect. In this study, postnatal day 11 (P11) rats were treated with whole brain irradiation with protons at a total dose of 0, 5, or 8 Gy, comparing a conventional dose rate of 1 Gy/s vs. a FLASH dose rate of 100 Gy/s. Beginning on P64, rats were tested for locomotor activity, acoustic and tactile startle responses (ASR, TSR) with or without prepulses, novel object recognition (NOR; 4-object version), striatal dependent egocentric learning ([configuration A] Cincinnati water maze (CWM-A)), prefrontal dependent working memory (radial water maze (RWM)), hippocampal dependent spatial learning (Morris water maze (MWM)), amygdala dependent conditioned freezing, and the mirror image CWM [configuration B (CWM-B)]. All groups had deficits in the CWM-A procedure. Weight reductions, decreased center ambulation in the open-field, increased latency on day-1 of RWM, and deficits in CWM-B were observed in all irradiated groups, except the 5 Gy FLASH group. ASR and TSR were reduced in the 8 Gy FLASH group and day-2 latencies in the RWM were increased in the FLASH groups compared with controls. There were no effects on prepulse trials of ASR or TSR, NOR, MWM, or conditioned freezing. The results suggest striatal and prefrontal cortex are sensitive regions at P11 to proton irradiation, with reduced toxicity from FLASH at 5 Gy.

Pencil-beam Delivery Pattern Optimization Increases Dose Rate for Stereotactic FLASH Proton Therapy

FLASH dose rates >40 Gy/s are readily available in proton therapy (PT) with cyclotron-accelerated beams and pencil-beam scanning (PBS). The PBS delivery pattern will affect the local dose rate, as quantified by the PBS dose rate (PBS-DR), and therefore needs to be accounted for in FLASH-PT with PBS, but it is not yet clear how. Our aim was to optimize patient-specific scan patterns for stereotactic FLASH-PT of early-stage lung cancer and lung metastases, maximizing the volume irradiated with PBS-DR >40 Gy/s of the organs at risk voxels irradiated to >8 Gy (FLASH coverage). Plans to 54 Gy/3 fractions with 3 equiangular coplanar 244 MeV proton shoot-through transmission beams for 20 patients were optimized with in-house developed software. Planning target volume-based planning with a 5 mm margin was used. Planning target volume ranged from 4.4 to 84 cc. Scan-pattern optimization was performed with a Genetic Algorithm, run in parallel for 20 independent populations (islands). Mapped crossover, inversion, swap, and shift operators were applied to achieve (local) optimality on each island, with migration between them for global optimality. The cost function was chosen to maximize the FLASH coverage per beam at >8 Gy, >40 Gy/s, and 40 nA beam current. The optimized patterns were evaluated on FLASH coverage, PBS-DR distribution, and population PBS-DR-volume histograms, compared with standard line-by-line scanning. Robustness against beam current variation was investigated. The optimized patterns have a snowflake-like structure, combined with outward swirling for larger targets. A population median FLASH coverage of 29.0% was obtained for optimized patterns compared with 6.9% for standard patterns, illustrating a significant increase in FLASH coverage for optimized patterns. For beam current variations of 5 nA, FLASH coverage varied between -6.1%-point and 2.2%-point for optimized patterns. Significant improvements on the PBS-DR and, hence, on FLASH coverage and potential healthy-tissue sparing are obtained by sequential scan-pattern optimization. The optimizer is flexible and may be further fine-tuned, based on the exact conditions for FLASH.

Benefit of a flash dose of corticosteroids in digestive surgical oncology: a multicenter, randomized, double blind, placebo-controlled trial (CORTIFRENCH)

BackgroundThe modulation of perioperative inflammation seems crucial to improve postoperative morbidity and cancer-related outcomes in patients undergoing oncological surgery. Data from the literature suggest that perioperative corticosteroids decrease inflammatory markers and might be associated with fewer complications in esophageal, liver, pancreatic and colorectal surgery. Their benefit on cancer-related outcomes has not been assessed.MethodsThe CORTIFRENCH trial is a phase III multicenter randomized double-blind placebo-controlled trial to assess the impact of a flash dose of preoperative corticosteroids versus placebo on postoperative morbidity and cancer-related outcomes after elective curative-intent surgery for digestive cancer. The primary endpoint is the frequency of patients with postoperative major complications occurring within 30 days after surgery (defined as all complications with Clavien-Dindo grade > 2). The secondary endpoints are the overall survival at 3 years, the disease-free survival at 3 years, the frequency of patients with intraabdominal infections and postoperative infections within 30 days after surgery and the hospital length of stay. We hypothesize a reduced risk of major complications and a better disease-survival at 3 years in the experimental group. Allowing for 5% of drop-out, 1 200 patients (600 per arm) should be included.DiscussionThis will be the first trial focusing on the impact of perioperative corticosteroids on cancer related outcomes. If significant, it might be a strong improvement on oncological outcomes for patients undergoing surgery for digestive cancers.Trial registrationClinicalTrials.gov, NCT03875690, Registered on March 15, 2019, URL: https://clinicaltrials.gov/ct2/show/NCT03875690.

Use of single-energy proton pencil beam scanning Bragg peak for intensity-modulated proton therapy FLASH treatment planning in liver-hypofractionated radiation therapy.

The transmission proton FLASH technique delivers high doses to the normal tissue distal to the target, which is less conformal compared to the Bragg peak technique. To investigate FLASH radiotherapy (RT) planning using single-energy Bragg peak beams with a similar beam arrangement as clinical intensity-modulated proton therapy (IMPT) in a liver stereotactic body radiation therapy (SBRT) and to characterize the plan quality, dose sparing of organs-at-risk (OARs), and FLASH dose rate percentage. An in-house platform was developed to enable inverse IMPT-FLASH planning using single-energy Bragg peaks. A universal range shifter and range compensators were utilized to effectively align the Bragg peak to the distal edge of the target. Two different minimum MU settings of 400 and 800 MU/spot (Bragg-400 MU and Bragg-800 MU) plans were investigated on 10 consecutive hepatocellular carcinoma patients previously treated by IMPT-SBRT to evaluate the FLASH dose and dose rate coverage for OARs. The IMPT-FLASH using single-energy Bragg peaks delivered 50Gy in five fractions with similar or identical beam arrangement to the clinical IMPT-SBRT plans. NRG GI003 dose constraint metrics were used. Three dose rate calculation methods, including average dose rate (ADR), dose threshold dose rate (DTDR), and dose-ADR (DADR), were all studied. The novel spot map optimization can fulfill the inverse planning using single-energy Bragg peaks. All the Bragg peak FLASH plans achieved similar results for the liver-gross tumor volume (GTV) Dmean and heart , compared to SBRT-IMPT. The Bragg-800 MU plans resulted in 18.3% higher clinical target volume (CTV) compared with SBRT (p<0.05), and no significant difference was found between Bragg-400 MU and SBRT plans. For the CTV Dmax , SBRT plans resulted in 10.3% (p<0.01) less than Bragg-400 MU plans and 16.6% (p<0.01) less than Bragg-800 MU plans. The Bragg-800 MU plans generally achieved higher ADR, DADR, and DTDR dose rates than Bragg-400 MU plans, and DADR mostly led to the highest V40Gy/s compared to other dose rate calculation methods, whereas ADR led to the lowest. The lower dose rate portions in certain OARs are related to the lower dose deposited due to the farther distances from targets, especially in the penumbra of the beams. Single-energy Bragg peak IMPT-FLASH plans eliminate the exit dose in normal tissues, maintaining comparable dose metrics to the conventional IMPT-SBRT plans, while achieving a sufficient FLASH dose rate for liver cancers. This study demonstrates the feasibility of and sufficiently high dose rate when applying the Bragg peak FLASH treatment for a liver cancer hypofractionated FLASH therapy. The advancement of this novel method has the potential to optimize treatment for liver cancer patients.

Intra-Operative Electron Radiation Therapy: An Update of the Evidence Collected in 40 Years to Search for Models for Electron-FLASH Studies.

Simple SummaryFour decades ago, intraoperative electron radiation therapy (IOeRT) was developed to improve precision in local cancer treatment by combining real-time surgical exploration and resection with high-energy electron irradiation. The technology of ultra-high dose rate electron and other radiation beams known as FLASH irradiation sharply increases its interests, as data from preclinical experiments have proven a marked favorable effect on the therapeutic index: similar cancer control with a clearly improved tolerance of many normal tissues to high doses of irradiation. The knowledge and tools regarding technology, physics, biology, and preclinical results in heterogeneous cancers opens great opportunities towards the path of developing the first clinical applications of the emerging FLASH technology via clinical trials based on state-of-the-art medical practice with IOeRT.Introduction: The clinical practice and outcome results of intraoperative electron radiation therapy (IOeRT) in cancer patients have been extensively reported over 4 decades. Electron beams can be delivered in the promising FLASH dose rate. Methods and Materials: Several cancer models were approached by two alternative radiobiological strategies to optimize local cancer control: boost versus exclusive IOeRT. Clinical outcomes are revisited via a bibliometric search performed for the elaboration of ESTRO/ACROP IORT guidelines. Results: In the period 1982 to 2020, a total of 19,148 patients were registered in 116 publications concerning soft tissue sarcomas (9% of patients), unresected and borderline-resected pancreatic cancer (22%), locally recurrent and locally advanced rectal cancer (22%), and breast cancer (45%). Clinical outcomes following IOeRT doses in the range of 10 to 25 Gy (with or without external beam fractionated radiation therapy) show a wide range of local control from 40 to 100% depending upon cancer site, histology, stage, and treatment intensity. Constraints for normal tissue tolerance are important to maintain tumor control combined with acceptable levels of side effects. Conclusions: IOeRT represents an evidence-based approach for several tumor types. A specific risk analysis for local recurrences supports the identification of cancer models that are candidates for FLASH studies.

Ultrahigh dose rate pencil beam scanning proton dosimetry using ion chambers and a calorimeter in support of first in-human FLASH clinical trial.

PurposeTo provide ultrahigh dose rate (UHDR) pencil beam scanning (PBS) proton dosimetry comparison of clinically used plane‐parallel ion chambers, PTW (Physikalisch‐Technische Werkstaetten) Advanced Markus and IBA (Ion Beam Application) PPC05, with a proton graphite calorimeter in a support of first in‐human proton FLASH clinical trial.MethodsAbsolute dose measurement intercomparison of the plane‐parallel plate ion chambers and the proton graphite calorimeter was performed at 5‐cm water‐equivalent depth using rectangular 250‐MeV single‐layer treatment plans designed for the first in‐human FLASH clinical trial. The dose rate for each field was designed to remain above 60 Gy/s. The ion recombination effects of the plane‐parallel plate ion chambers at various bias voltages were also investigated in the range of dose rates between 5 and 60 Gy/s. Two independent model‐based extrapolation methods were used to calculate the ion recombination correction factors ks to compare with the two‐voltage technique from most widely used clinical protocols.ResultsThe mean measured dose to water with the proton graphite calorimeter across all the predefined fields is 7.702 ± 0.037 Gy. The average ratio over the predefined fields of the PTW Advanced Markus chamber dose to the calorimeter reference dose is 1.002 ± 0.007, whereas the IBA PPC05 chamber shows ∼3% higher reading of 1.033 ± 0.007. The relative differences in the ks values determined from between the linear and quadratic extrapolation methods and the two‐voltage technique for the PTW Advanced Markus chamber are not statistically significant, and the trends of dose rate dependence are similar. The IBA PPC05 shows a flat response in terms of ion recombination effects based on the ks values calculated using the two‐voltage technique. Differences in ks values for the PPC05 between the two‐voltage technique and other model‐based extrapolation methods are not statistically significant at FLASH dose rates. Some of the ks values for the PPC05 that were extrapolated from the three‐voltage linear method and the semiempirical model were reported less than unity possibly due to the charge multiplication effect, which was negligible compared to the volume recombination effect in FLASH dose rates.ConclusionsThe absolute dose measurements of both PTW Advanced Markus and IBA PPC05 chambers are in a good agreement with the National Physical Laboratory graphite calorimeter reference dose considering overall uncertainties. Both ion chambers also demonstrate good reproducibility as well as stability as reference dosimeters in UHDR PBS proton radiotherapy. The dose rate dependency of the ion recombination effects of both ion chambers in cyclotron generated PBS proton beams is acceptable and therefore, both chambers are suitable to use in clinical practice for the range of dose rates between 5 and 60 Gy/s.

Modeling the impact of spatial oxygen heterogeneity on radiolytic oxygen depletion during FLASH radiotherapy

Purpose. It has been postulated that the delivery of radiotherapy at ultra-high dose rates (‘FLASH’) reduces normal tissue toxicities by depleting them of oxygen. The fraction of normal tissue and cancer cells surviving radiotherapy depends on dose and oxygen levels in an exponential manner and even a very small fraction of tissue at low oxygen levels can determine radiotherapy response. To quantify the differential impact of FLASH radiotherapy on normal and tumour tissues, the spatial heterogeneity of oxygenation in tissue should thus be accounted for. Methods. The effect of FLASH on radiation-induced normal and tumour tissue cell killing was studied by simulating oxygen diffusion, metabolism, and radiolytic oxygen depletion (ROD) over domains with simulated capillary architectures. To study the impact of heterogeneity, two architectural models were used: (1) randomly distributed capillaries and (2) capillaries forming a regular square lattice array. The resulting oxygen partial pressure distribution histograms were used to simulate normal and tumour tissue cell survival using the linear quadratic model of cell survival, modified to incorporate oxygen-enhancement ratio effects. The ratio (‘dose modifying factors’) of conventional low-dose-rate dose and FLASH dose at iso-cell survival was computed and compared with empirical iso-toxicity dose ratios. Results. Tumour cell survival was found to be increased by FLASH as compared to conventional radiotherapy, with a 0–1 order of magnitude increase for expected levels of tumour hypoxia, depending on the relative magnitudes of ROD and tissue oxygen metabolism. Interestingly, for the random capillary model, the impact of FLASH on well-oxygenated (normal) tissues was found to be much greater, with an estimated increase in cell survival by up to 10 orders of magnitude, even though reductions in mean tissue partial pressure were modest, less than ∼7 mmHg for the parameter values studied. The dose modifying factor for normal tissues was found to lie in the range 1.2–1.7 for a representative value of normal tissue oxygen metabolic rate, consistent with preclinical iso-toxicity results. Conclusions. The presence of very small nearly hypoxic regions in otherwise well-perfused normal tissues with high mean oxygen levels resulted in a greater proportional sparing of normal tissue than tumour cells during FLASH irradiation, possibly explaining empirical normal tissue sparing and iso-tumour control results.

Oxygen Monitoring in Model Solutions and In Vivo in Mice During Proton Irradiation at Conventional and FLASH Dose Rates.

FLASH is a high-dose-rate form of radiation therapy that has the reported ability, compared with conventional dose rates, to spare normal tissues while being equipotent in tumor control, thereby increasing the therapeutic ratio. The mechanism underlying this normal tissue sparing effect is currently unknown, however one possibility is radiochemical oxygen depletion (ROD) during dose delivery in tissue at FLASH dose rates. In order to investigate this possibility, we used the phosphorescence quenching method to measure oxygen partial pressure before, during and after proton radiation delivery in model solutions and in normal muscle and sarcoma tumors in mice, at both conventional (Conv) (∼0.5 Gy/s) and FLASH (∼100 Gy/s) dose rates. Radiation dosimetry was determined by Advanced Markus Chamber and EBT-XL film. For solutions contained in sealed glass vials, phosphorescent probe Oxyphor PtG4 (1 µM) was dissolved in a buffer (10 mM HEPES) containing glycerol (1 M), glucose (5 mM) and glutathione (5 mM), designed to mimic the reducing and free radical-scavenging nature of the intracellular environment. In vivo oxygen measurements were performed 24 h after injection of PtG4 into the interstitial space of either normal thigh muscle or subcutaneous sarcoma tumors in mice. The "g-value" for ROD is reported in mmHg/Gy, which represents a slight modification of the more standard chemical definition (µM/Gy). In solutions, proton irradiation at conventional dose rates resulted in a g-value for ROD of up to 0.55 mmHg/Gy, consistent with earlier studies using X or gamma rays. At FLASH dose rates, the g-value for ROD was ∼25% lower, 0.37 mmHg/Gy. pO2 levels were stable after each dose delivery. For normal muscle in vivo, oxygen depletion during irradiation was counterbalanced by resupply from the vasculature. This process was fast enough to maintain tissue pO2 virtually unchanged at Conv dose rates. However, during FLASH irradiation there was a stepwise decrease in pO2 (g-value ∼0.28 mmHg/Gy), followed by a rebound to the initial level after ∼8 s. The g-values were smaller and recovery times longer in tumor tissue when compared to muscle and may be related to the lower initial endogenous pO2 levels in the former. Considering that the FLASH effect is seen in vivo even at doses as low as 10 Gy, it is difficult to reconcile the amount of protection seen by oxygen depletion alone. However, the phosphorescence probe in our experiments was confined to the extracellular space, and it remains possible that intracellular oxygen depletion was greater than observed herein. In cell-mimicking solutions the oxygen depletion g-vales were indeed significantly higher than observed in vivo.

A 2D strip ionization chamber array with high spatiotemporal resolution for proton pencil beam scanning FLASH radiotherapy.

Experimental measurements of two-dimensional (2D) dose rate distributions in proton pencil beam scanning (PBS) FLASH radiation therapy (RT) are currently lacking. In this study, we characterize a newly designed 2D strip-segmented ionization chamber array (SICA) with high spatial and temporal resolution and demonstrate its applications in a modern proton PBS delivery system at both conventional and ultrahigh dose rates. A dedicated research beamline of the Varian ProBeam system was employed to deliver a 250-MeV proton PBS beam with nozzle currents up to 215nA. In the research and clinical beamlines, the spatial, temporal, and dosimetric performances of the SICA were characterized and compared with measurements using parallel-plate ion chambers (IBA PPC05 and PTW Advanced Markus chamber), a 2D scintillator camera (IBA Lynx), Gafchromic films (EBT-XD), and a Faraday cup. A novel reconstruction approach was proposed to enable the measurement of 2D dose and dose rate distributions using such a strip-type detector. The SICA demonstrated a position accuracy of 0.12±0.02mm at a 20-kHz sampling rate (50μs per event) and a linearity of R2 >0.99 for both dose and dose rate with nozzle beam currents ranging from 1 to 215nA. The 2D dose comparison to the film measurement resulted in a gamma passing rate of 99.8% (2mm/2%). A measurement-based proton PBS 2D FLASH dose rate distribution was compared to simulation results and showed a gamma passing rate of 97.3% (2mm/2%). The newly designed SICA demonstrated excellent spatial, temporal, and dosimetric performances and is well suited for commissioning, quality assurance, and a wide range of clinical applications in proton PBS clinical and FLASH-RT.

Treatment planning for Flash radiotherapy: General aspects and applications to proton beams.

The increased radioresistence of healthy tissues when irradiated at very high dose rates (known as the Flash effect) is a radiobiological mechanism that is currently investigated to increase the therapeutic ratio of radiotherapy treatments. To maximize the benefits of the clinical application of Flash, a patient-specific balance between different properties of the dose distribution should be found, that is, Flash needs to be one of the variables considered in treatment planning. We investigated the Flash potential of three proton therapy planning and beam delivery techniques, each on a different anatomical region. Based on a set of beam delivery parameters, on hypotheses on the dose and dose rate thresholds needed for the Flash effect to occur, and on two definitions of Flash dose rate, we generated exemplary illustrations of the capabilities of current proton therapy equipment to generate Flash dose distributions. All techniques investigated could both produce dose distributions comparable with a conventional proton plan and reach the Flash regime, to an extent that was strongly dependent on the dose per fraction and the Flash dose threshold. The beam current, Flash dose rate threshold, and dose rate definition typically had a more moderate effect on the amount of Flash dose in normal tissue. A systematic estimation of the impact of Flash on different patient anatomies and treatment protocols is possible only if Flash-specific treatment planning features become readily available. Planning evaluation tools such as a voxel-based dose delivery time structure, and the inclusion in the optimization cost function of parameters directly associated with Flash (e.g., beam current, spot delivery sequence, and scanning speed), are needed to generate treatment plans that are taking full advantage of the potential benefits of the Flasheffect.

Quantifying the DNA-damaging Effects of FLASH Irradiation With Plasmid DNA

To investigate a plasmid DNA nicking assay approach for isolating and quantifying the DNA-damaging effects of ultrahigh-dose-rate (ie, FLASH) irradiation relative to conventional dose-rate irradiation. We constructed and irradiated phantoms containing plasmid DNA to nominal doses of 20 Gy and 30 Gy using 16 MeV electrons at conventional (0.167 Gy/s) and FLASH (46.6 Gy/s and 93.2 Gy/s) dose rates. We delivered conventional dose rates using a standard clinical Varian iX linear accelerator and FLASH dose rates (FDRs) using a modified Varian 21EX C-series linear accelerator. We ran the irradiated DNA and controls (0 Gy) through an agarose gel electrophoresis procedure that sorted and localized the DNA into bands associated with single strand breaks (SSBs), double strand breaks (DSBs), and undamaged DNA. We quantitatively analyzed the gel images to compute the relative yields of SSBs and DSBs and applied a mathematical model of plasmid DNA damage as a function of dose to compute the relative biological effectiveness (RBE) of SSB and DSB (RBESSB and RBEDSB) damage for a given endpoint and FDR. Both RBESSB and RBEDSB were less than unity with the FDR irradiations, indicating FLASH sparing. With regard to the more deleterious DNA DSB damage, the DSB RBEs of FLASH beams at dose rates of 46.6 Gy/s and 93.2 Gy/s relative to the conventional 16 MeV beam dose rate were 0.54 ± 0.15 and 0.55 ± 0.17, respectively. This study demonstrated the feasibility of using a DNA-based phantom to isolate and assess the FLASH sparing effect on DNA. We also found that FLASH irradiation causes less damage to DNA compared with a conventional dose rate. This result supports the notion that the protective effect of FLASH irradiation occurs at least partially via fundamental biochemical processes.