Plastic scintillator-based dosimeters for ultra-high dose rate (UHDR) electron radiotherapy.

This paper reports the development of dosimeters based on plastic scintillating fibers imaged by a charge-coupled device camera, and their performance evaluation through irradiations with the electron Flash research accelerator located at the Centro Pisano Flash Radiotherapy. The dosimeter prototypes were composed of a piece of plastic scintillating fiber optically coupled to a clear optical fiber which transported the scintillation signal to the readout systems (an imaging system and a photodiode). The following properties were tested: linearity, capability to reconstruct the percentage depth dose curve in solid water and to sample in time the single beam pulse. The stem effect contribution was evaluated with three methods, and a proof-of-concept one-dimensional array was developed and tested for online beam profiling. Results show linearity up to 10 Gy per pulse, and good capability to reconstruct both the timing and spatial profiles of the beam, thus suggesting that plastic scintillating fibers may be good candidates for low-energy electron Flash dosimetry.

First in vitro measurement of VHEE relative biological effectiveness (RBE) in lung and prostate cancer cells using the ARES linac at DESY.

Very high energy electrons (VHEE) are a potential candidate for radiotherapy applications. This includes tumours in inhomogeneous regions such as lung and prostate cancers, due to the insensitivity of VHEE to inhomogeneities. This study explores how electrons in the VHEE range can be used to perform successful in vitro radiobiological studies. The ARES (accelerator research experiment at SINBAD) facility at DESY, Hamburg, Germany was used to deliver 154 MeV electrons to both prostate (PC3) and lung (A549) cancer cells in suspension. Dose was delivered to samples with repeatability and uniformity, quantified with Gafchromic film. Cell survival in response to VHEE was measured using the clonogenic assay to determine the biological effectiveness of VHEE in cancer cells for the first time using this method. Equivalent experiments were performed using 300 kVp X-rays, to enable VHEE irradiated cells to be compared with conventional photons. VHEE irradiated cancer cell survival was fitted to the linear quadratic (LQ) model (R2 = 0.96-0.97). The damage from VHEE and X-ray irradiated cells at doses between 1.41 and 6.33 Gy are comparable, suggesting similar relative biological effectiveness (RBE) between the two modalities. This suggests VHEE is as damaging as photon radiotherapy and therefore could be used to successfully damage cancer cells during radiotherapy. The RBE of VHEE was quantified as the relative doses required for 50% (D0.5) and 10% (D0.1) cell survival. Using these values, VHEE RBE was measured as 0.93 (D0.5) and 0.99 (D0.1) for A549 and 0.74 (D0.5) and 0.93 (D0.1) for PC3 cell lines respectively. For the first time, this study has shown that 154 MeV electrons can be used to effectively kill lung and prostate cancer cells, suggesting that VHEE would be a viable radiotherapy modality. Several studies have shown that VHEE has characteristics that would offer significant improvements over conventional photon radiotherapy for example, electrons are relatively easy to steer and can be used to deliver dose rapidly and with high efficiency. Studies have shown improved dose distribution with VHEE in treatment plans, in comparison to VMAT, indicating that VHEE can offer improved and safer treatment plans with reduced side effects. The biological response of cancer cells to VHEE has not been sufficiently studied as of yet, however this initial study provides some initial insights into cell damage. VHEE offers significant benefits over photon radiotherapy and therefore more studies are required to fully understand the biological effectiveness of VHEE.

Technical note: A comparison of in-house 3D-printed and commercially available patient-specific skin collimators for use with electron beam therapy.

PURPOSE: Skin collimation is a useful tool in electron beam therapy (EBT) to decrease the penumbra at the field edge and minimize dose to nearby superficial organs at risk (OARs), but manually fabricating these collimation devices in the clinic to conform to the patient's anatomy can be a difficult and time intensive process. This work compares two types of patient-specific skin collimation (in-house 3D printed and vendor-provided machined brass) using clinically relevant metrics. METHODS: Attenuation measurements were performed to determine the thickness of each material needed to adequately shield both 6 and 9 MeV electron beams. Relative and absolute dose planes at various depths were measured using radiochromic film to compare the surface dose, flatness, and penumbra of the different skin collimation materials. RESULTS: Clinically acceptable thicknesses of each material were determined for both 6 and 9 MeV electron beams. Field width, flatness, and penumbra results between the two systems were very similar and significantly improved compared to measurements performed with no surface collimation. CONCLUSION: Both skin collimation methods investigated in this work generate sharp penumbras at the field edge and can minimize dose to superficial OARs compared to treatment fields with no surface collimation. The benefits of skin collimation are greatest for lower energy electron beams, and the benefits decrease as the measurement depth increases. Using bolus with skin collimation is recommended to avoid surface dose enhancement seen with collimators placed on the skin surface. Ultimately, the appropriate choice of material will depend on the desire to create these devices in-house or outsource the fabrication to a vendor.

The effect of electron backscatter and charge build up in media on beam current transformer signal for ultra-high dose rate (FLASH) electron beam monitoring.

Objective.Beam current transformers (BCT) are promising detectors for real-time beam monitoring in ultra-high dose rate (UHDR) electron radiotherapy. However, previous studies have reported a significant sensitivity of the BCT signal to changes in source-to-surface distance (SSD), field size, and phantom material which have until now been attributed to the fluctuating levels of electrons backscattered within the BCT. The purpose of this study is to evaluate this hypothesis, with the goal of understanding and mitigating the variations in BCT signal due to changes in irradiation conditions.Approach.Monte Carlo simulations and experimental measurements were conducted with a UHDR-capable intra-operative electron linear accelerator to analyze the impact of backscattered electrons on BCT signal. The potential influence of charge accumulation in media as a mechanism affecting BCT signal perturbation was further investigated by examining the effects of phantom conductivity and electrical grounding. Finally, the effectiveness of Faraday shielding to mitigate BCT signal variations is evaluated.Main Results.Monte Carlo simulations indicated that the fraction of electrons backscattered in water and on the collimator plastic at 6 and 9 MeV is lower than 1%, suggesting that backscattered electrons alone cannot account for the observed BCT signal variations. However, our experimental measurements confirmed previous findings of BCT response variation up to 15% for different field diameters. A significant impact of phantom type on BCT response was also observed, with variations in BCT signal as high as 14.1% when comparing measurements in water and solid water. The introduction of a Faraday shield to our applicators effectively mitigated the dependencies of BCT signal on SSD, field size, and phantom material.Significance.Our results indicate that variations in BCT signal as a function of SSD, field size, and phantom material are likely driven by an electric field originating in dielectric materials exposed to the UHDR electron beam. Strategies such as Faraday shielding were shown to effectively prevent these electric fields from affecting BCT signal, enabling reliable BCT-based electron UHDR beam monitoring.

Planar dose calculation of electron therapy.

Purpose.The aim of this study is to determine the planar dose distribution of irregularly-shaped electron beams at their maximum dose depth (zmax) using the modied lateral build-up ratio (LBR) and curve-fitting methods.Methods.Circular and irregular cutouts were created using Cerrobend alloy for a 14 × 14 cm2applicator. Percentage depth dose (PDD) at the standard source-surface-distance (SSD = 100 cm) and point dose at different SSD were measured for each cutout. Orthogonal profiles of the cutouts were measured atzmax. Data were collected for 6, 9, 12, and 15 MeV electron beam energies on a VERSA HDTMLINAC using the IBA Blue Phantom23D water phantom system. The planar dose distributions of the cutouts were also measured atzmaxin solid water using EDR2 films.Results.The measured PDD curves were normalized to a normalization depth (d0) of 1 mm. The lateral-buildup-ratio (LBR), lateral spread parameter (σR(z)), and effective SSD (SSDeff) for each cutout were calculated using the PDD of the open applicator as the reference field. The modified LBR method was then employed to calculate the planar dose distribution of the irregular cutouts within the field at least 5 mm from the edge. A simple curve-fitting model was developed based on the profile shapes of the circular cutouts around the field edge. This model was used to calculate the planar dose distribution of the irregular cutouts in the region from 3 mm outside to 5 mm inside the field edge. Finally, the calculated planar dose distribution was compared with the film measurement.Conclusions.The planar dose distribution of electron therapy for irregular cutouts atzmaxwas calculated using the improved LBR method and a simple curve-fitting model. The calculated profiles were within 3% of the measured values. The gamma passing rate with a 3%/3 mm and 10% dose threshold was more than 96%.

IOeRT conventional and FLASH treatment planning system implementation exploiting fast GPU Monte Carlo: The case of breast cancer.

Partial breast irradiation for the treatment of early-stage breast cancer patients can be performed by means of Intra Operative electron Radiation Therapy (IOeRT). One of the main limitations of this technique is the absence of a treatment planning system (TPS) that could greatly help in ensuring a proper coverage of the target volume during irradiation. An IOeRT TPS has been developed using a fast Monte Carlo (MC) and an ultrasound imaging system to provide the best irradiation strategy (electron beam energy, applicator position and bevel angle) and to facilitate the optimisation of dose prescription and delivery to the target volume while maximising the organs at risk sparing. The study has been performed in silico, exploiting MC simulations of a breast cancer treatment. Ultrasound-based input has been used to compute the absorbed dose maps in different irradiation strategies and a quantitative comparison between the different options was carried out using Dose Volume Histograms. The system was capable of exploring different beam energies and applicator positions in few minutes, identifying the best strategy with an overall computation time that was found to be completely compatible with clinical implementation. The systematic uncertainty related to tissue deformation during treatment delivery with respect to imaging acquisition was taken into account. The potential and feasibility of a GPU based full MC TPS implementation of IOeRT breast cancer treatments has been demonstrated in-silico. This long awaited tool will greatly improve the treatment safety and efficacy, overcoming the limits identified within the clinical trials carried out so far.

Dose and dose rate dependence of the tissue sparing effect at ultra-high dose rate studied for proton and electron beams using the zebrafish embryo model.

PURPOSE: A better characterization of the dependence of the tissue sparing effect at ultra-high dose rate (UHDR) on physical beam parameters (dose, dose rate, radiation quality) would be helpful towards a mechanistic understanding of the FLASH effect and for its broader clinical translation. To address this, a comprehensive study on the normal tissue sparing at UHDR using the zebrafish embryo (ZFE) model was conducted. METHODS: One-day-old ZFE were irradiated over a wide dose range (15-95 Gy) in three different beams (proton entrance channel, proton spread out Bragg peak and 30 MeV electrons) at UHDR and reference dose rate. After irradiation the ZFE were incubated for 4 days and then analyzed for four different biological endpoints (pericardial edema, curved spine, embryo length and eye diameter). RESULTS: Dose-effect curves were obtained and a sparing effect at UHDR was observed for all three beams. It was demonstrated that proton relative biological effectiveness and UHDR sparing are both relevant to predict the resulting dose response. Dose dependent FLASH modifying factors (FMF) for ZFE were found to be compatible with rodent data from the literature. It was found that the UHDR sparing effect saturates at doses above âˆ¼ 50 Gy with an FMF of âˆ¼ 0.7-0.8. A strong dose rate dependence of the tissue sparing effect in ZFE was observed. The magnitude of the maximum sparing effect was comparable for all studied biological endpoints. CONCLUSION: The ZFE model was shown to be a suitable pre-clinical high-throughput model for radiobiological studies on FLASH radiotherapy, providing results comparable to rodent models. This underlines the relevance of ZFE studies for FLASH radiotherapy research.

Very high-energy electron therapy as light-particle alternative to transmission proton FLASH therapy - An evaluation of dosimetric performances.

PURPOSE: Clinical translation of FLASH-radiotherapy (RT) to deep-seated tumours is still a technological challenge. One proposed solution consists of using ultra-high dose rate transmission proton (TP) beams of about 200-250 MeV to irradiate the tumour with the flat entrance of the proton depth-dose profile. This work evaluates the dosimetric performance of very high-energy electron (VHEE)-based RT (50-250 MeV) as a potential alternative to TP-based RT for the clinical transfer of the FLASH effect. METHODS: Basic physics characteristics of VHEE and TP beams were compared utilizing Monte Carlo simulations in water. A VHEE-enabled research treatment planning system was used to evaluate the plan quality achievable with VHEE beams of different energies, compared to 250 MeV TP beams for a glioblastoma, an oesophagus, and a prostate cancer case. RESULTS: Like TP, VHEE above 100 MeV can treat targets with roughly flat (within ± 20 %) depth-dose distributions. The achievable dosimetric target conformity and adjacent organs-at-risk (OAR) sparing is consequently driven for both modalities by their lateral beam penumbrae. Electron beams of 400[500] MeV match the penumbra of 200[250] MeV TP beams and penumbra is increased for lower electron energies. For the investigated patient cases, VHEE plans with energies of 150 MeV and above achieved a dosimetric plan quality comparable to that of 250 MeV TP plans. For the glioblastoma and the oesophagus case, although having a decreased conformity, even 100 MeV VHEE plans provided a similar target coverage and OAR sparing compared to TP. CONCLUSIONS: VHEE-based FLASH-RT using sufficiently high beam energies may provide a lighter-particle alternative to TP-based FLASH-RT with comparable dosimetric plan quality.

Long-Term Outcomes Using Electron IOERT APBI for Early Stage Breast Cancer: The Verona University Hospital Experience.

METHODS AND MATERIALS: From July 2006 to December 2015, 295 patients suitable for breast-conserving therapy entered a single-arm phase II study and were treated with IOERT as radical treatment. Inclusion criteria were age >50, postmenopausal status, cT1N0M0 stage, grade G1-G2, positive estrogen receptor status; unicentric and unifocal disease, histologically proven invasive ductal carcinoma no previous breast irradiation, good performance status. RESULTS: With a median follow-up of 7.1 years (95% CI, 6.5;7.4) 6 women (2.0%) experienced a true local recurrence (reappearance of the tumour in the same quadrant). Five-year overall survival and local recurrence-free survival were 96% (95% CI, 92.9;97.8) and 94.9% (95% CI, 91.6;97.0) respectively. CONCLUSION: Our trial suggests that, in highly selected early stage breast cancers, a single-dose IOERT can be safely delivered with excellent results and very low long-term recurrence rates.

Megavolt bremsstrahlung measurements from linear induction accelerators demonstrate possible use as a FLASH radiotherapy source to reduce acute toxicity.

Recent studies indicate better efficacy and healthy tissue sparing with high dose-rate FLASH radiotherapy (FLASH-RT) cancer treatment. This technique delivers a prompt high radiation dose rather than fractional doses over time. While some suggest thresholds of > 40 Gy s-1 with a maximal effect at > 100 Gy s-1, accumulated evidence shows that instantaneous dose-rate and irradiation time are critical. Mechanisms are still debated, but toxicity is minimized while inducing apoptosis in malignant tissue. Delivery technologies to date show that a capability gap exists with clinic scale, broad area, deep penetrating, high dose rate systems. Based on these trends, if FLASH-RT is adopted, it may become a dominant approach except in the least technologically advanced countries. The linear induction accelerator (LIA) developed for high instantaneous and high average dose-rate, species independent charged particle acceleration, has yet to be considered for this application. We review the status of LIA technology, explore the physics of bremsstrahlung-converter-target interactions and our work on stabilizing the electron beam. While the gradient of the LIA is low, we present our preliminary work to improve the gradient by an order of magnitude, presenting a point design for a multibeam FLASH-RT system using a single accelerator for application to conformal FLASH-RT.

PARP-Targeted Auger Therapy in p53 Mutant Colon Cancer Xenograft Mouse Models.

Despite Auger electrons being highly appealing due to their short-range and high linear energy transfer to surrounding tissues, the progress in the field has been limited due to the challenge in delivering a therapeutic dose within the close proximity of cancer cell's DNA. Here, we demonstrate that the PARP inhibitor 123I-MAPi is a viable agent for the systemic administration and treatment of p53 mutant cancers. Significantly, minimal off-site toxicity was observed in mice administered with up to 74 MBq of 127I-PARPi. Taken together, these results lay the foundation for future clinical evaluation and broader preclinical investigations. By harnessing the scaffold of the PARP inhibitor Olaparib, we were able to deliver therapeutic levels of Auger radiation to the site of human colorectal cancer xenograft tumors after systemic administration. In-depth toxicity studies analyzed blood chemistry levels and markers associated with specific organ toxicity. Finally, p53+/+ and p53-/- human colorectal cancer cell lines were evaluated for the ability of 123I-MAPi to induce tumor growth delay. Toxicity studies demonstrate that both 123I-MAPi and its stable isotopologue, 127I-PARPi, have no significant off-site toxicity when administered systemically. Analysis following 123I-MAPi treatment confirmed its ability to induce DNA damage at the site of xenograft tumors when administered systemically. Finally, we demonstrate that 123I-MAPi generates a therapeutic response in p53-/-, but not p53+/+, subcutaneous xenograft tumors in mouse models. Taken together, these results represent the first example of a PARP Auger theranostic agent capable of delivering a therapeutic dose to xenograft human colorectal cancer tumors upon systemic administration without causing significant toxicity to surrounding mouse organs. Moreover, it suggests that a PARP Auger theranostic can act as a targeted therapeutic for cancers with mutated p53 pathways. This landmark goal paves the way for clinical evaluation of 123I-MAPi for pan cancer therapeutics.

How we treat advanced stage cutaneous T-cell lymphoma - mycosis fungoides and Sézary syndrome.

T-cell lymphomas (TCLs) constitute a rare subset of non-Hodgkin lymphomas, with mycosis fungoides/Sézary syndrome (MF/SS) being the most common subtype of cutaneous TCLs (CTCLs). Considered an incurable but treatable disease, MF/SS management presents several challenges including diagnostic delays, debilitating effect on patients' quality of life, need for several lines of therapies, multidisciplinary care and cumulative drug toxicities limiting duration of use. The present review intends to provide an overview of the recent advances in our understanding of the biology of CTCL and how these are being leveraged to provide additional treatment options for management of advanced and recurrent disease. In addition, the discussion of the different modalities of treatment is summarised to further outline the importance of multidisciplinary care and early referral to CTCL centres.

Evaluation of monoxide film-based dosimeters for surface dose detection in electron therapy.

Generally, electron therapy is applied to tumors on or close to the skin surface. However, this causes a variety of skin-related side effects. To alleviate the risk of these side effects, clinical treatment uses skin dosimeters to verify the therapeutic dose. However, dosimeters suffer from poor accuracy, because their attachment sites are approximated with the help of naked eyes. Therefore, a dosimeter based on a flexible material that can adjust to the contours of the human body is required. In this study, the reproducibility, linearity, dose-rate dependence, and percentage depth ionization (PDI) of PbO and HgO film-based dosimeters are evaluated to explore their potential as large-scale flexible dosimeters. The results demonstrate that both dosimeters deliver impressive reproducibility (within 1.5%) and linearity (≥ 0.9990). The relative standard deviations of the dose-rate dependence of the PbO and HgO dosimeters were 0.94% and 1.16% at 6 MeV, respectively, and 1.08% and 1.25% at 9 MeV, respectively, with the PbO dosimeter outperforming the 1.1% of existing diodes. The PDI analysis of the PbO and HgO dosimeters returned values of 0.014 cm (-0.074 cm) and 0.051 cm (-0.016 cm), respectively at 6 MeV (9 MeV) compared to the thimble chamber and R50. Therefore, the maximum error of each dosimeter is within the allowable range of 0.1 cm. In short, the analysis reveals that the PbO dosimeter delivers a superior performance relative to its HgO counterpart and has strong potential for use as a surface dosimeter. Thus, flexible monoxide materials have the necessary qualities to be used for dosimeters that meet the requisite quality assurance standards and can satisfy a variety of radiation-related applications as flexible functional materials.

State of the art in breast intraoperative electron radiation therapy after intraoperative ultrasound introduction.

BACKGROUND: Breast intraoperative electron radiation therapy (B-IOERT) can be used in clinical practice both as elective irradiation (partial breast irradiation - APBI) in low risk breast cancer patients, and as an anticipated boost. The procedure generally includes the use of a shielding disk between the residual breast and the pectoralis fascia for the protection of the tissues underneath the target volume. The aim of the study was to evaluate the role of intraoperative ultrasound (IOUS) in improving the quality of B-IOERT. PATIENTS AND METHODS: B-IOERT was introduced in Trieste in 2012 and its technique was improved in 2014 with IOUS. Both, needle and IOUS were used to measure target thickness and the latter was used even to check the correct position of the shielding disk. The primary endpoint of the study was the evaluation of the effectiveness of IOUS in reducing the risk of a disk misalignment related to B-IOERT and the secondary endpoint was the analysis of acute and late toxicity, by comparing two groups of patients treated with IOERT as a boost, either measured with IOUS and needle (Group 1) or with needle alone (Group 2). Acute and late toxicity were evaluated by validated scoring systems. RESULTS: From the institutional patients who were treated between June 2012 and October 2019, 109 were eligible for this study (corresponding to 110 cases, as one patients underwent bilateral conservative surgery and bilateral B-IOERT). Of these, 38 were allocated to group 1 and 72 to group 2. The target thickness measured with the IOUS probe and with the needle were similar (mean difference of 0.1 mm, p = 0.38). The percentage of patients in which the shield was perfectly aligned after IOUS introduction increased from 23% to more than 70%. Moreover, patients treated after IOUS guidance had less acute toxicity (36.8% vs. 48.6%, p = 0.33) from radiation therapy, which reached no statistical significance. Late toxicity turned out to be similar regardless of the use of IOUS guidance: 39.5% vs. 37.5% (p = 0.99). CONCLUSIONS: IOUS showed to be accurate in measuring the target depth and decrease the misalignment between collimator and disk. Furthermore there was an absolute decrease in acute toxicity, even though not statistically significant, in the group of women who underwent B-IOERT with IOUS guidance.

Intraoperative electron beam radiotherapy and perioperative high-dose-rate brachytherapy in previously irradiated oligorecurrent gynecological cancer: clinical outcome analysis.

BACKGROUND: Pelvic recurrences from previously irradiated gynecological cancer lack solid evidence for recommendation on salvage. METHODS: A total of 58 patients were included in this clinical analysis. Salvage surgery was performed for locoregional relapse within previously irradiated pelvic area after initial surgery and adjuvant radiotherapy or radical external beam radiotherapy. The primary tumor diagnosis included cervical cancer (n = 47, 81%), uterine cancer (n = 4, 7%), and other types (n = 7, 12%). Thirty-three patients received adjuvant IOERT (1984-2000) at a median dose of 15 Gy (range 10-20 Gy) and 25 patients received adjuvant PHDRB (2001-2016) at a median dose of 32 Gy (range 24-40 Gy) in 6, 8, or 10 b.i.d. fractions. RESULTS: The median follow-up was 5.6 years (range 0.5-14.2 years). Twenty-nine (50.0%) patients had positive surgical margins. Grade ≥ 3 toxic events were recorded in 34 (58.6%) patients. The local control rate at 2 years was 51% and remained stable up to 14 years. Disease-free survival rates at 2, 5, and 10 years were 17.2, 15.5, and 15.5%, respectively. Overall survival rates at 2, 5, and 10 years were 58.1, 17.8, and 17.8%, respectively. CONCLUSIONS: IOERT and PHDRB account for an effective salvage in oligorecurrent gynecological tumors. Patients with previous pelvic radiation suitable for salvage surgery and at risk of inadequate margins could benefit from adjuvant reirradiation in form of IOERT or PHDRB. However, the rate of severe grade ≥ 3 toxicity associated with the entire treatment program is relevant and needs to be closely counterbalanced against the expected therapeutic gain.

IOERT versus external beam electrons for boost radiotherapy in stage I/II breast cancer: 10-year results of a phase III randomized study.

BACKGROUND: Intraoperative radiotherapy with electrons (IOERT) boost could be not inferior to external beam radiotherapy (EBRT) boost in terms of local control and tissue tolerance. The aim of the study is to present the long-term follow-up results on local control, esthetic evaluation, and toxicity of a prospective study on early-stage breast cancer patients treated with breast-conserving surgery with an IOERT boost of 10 Gy (experimental group) versus 5 × 2 Gy EBRT boost (standard arm). Both arms received whole-breast irradiation (WBI) with 50 Gy (2 Gy single dose). METHODS: A single-institution phase III randomized study to compare IOERT versus EBRT boost in early-stage breast cancer was conducted as a non-inferiority trial. Primary endpoints were the evaluation of in-breast true recurrences (IBTR) and out-field local recurrences (LR) as well as toxicity and cosmetic results. Secondary endpoints were overall survival (OS), disease-free survival (DFS), and patient's grade of satisfaction with cosmetic outcomes. RESULTS: Between 1999 and 2004, 245 patients were randomized: 133 for IOERT and 112 for EBRT. The median follow-up was 12 years (range 10-16 years). The cumulative risk of IBTR at 5-10 years was 0.8% and 4.3% after IOERT, compared to 4.2% and 5.3% after EBRT boost (p = 0.709). The cumulative risk of out-field LR at 5-10 years was 4.7% and 7.9% for IOERT versus 5.2% and 10.3% for EBRT (p = 0.762). All of the IOERT arm recurrences were observed at > 100 months' follow-up, whereas the mean time to recurrence in the EBRT group was earlier (55.2 months) (p < 0.05). No late complications associated with IOERT were observed. The overall cosmetic results were scored as good or excellent in physician and patient evaluations for both IOERT and EBRT. There were significantly better scores for IOERT at all time points in physician and patient evaluations with the greatest difference at the end of EBRT (p = 0.006 objective and p = 0.0004 subjective) and most narrow difference at 12 months after the end of EBRT (p = 0.08 objective and p = 0.04 subjective analysis). CONCLUSION: A 10-Gy IOERT boost during breast-conserving surgery provides high local control rates without significant morbidity. Although not significantly superior to external beam boosts, the median time to local recurrences after IOERT is prolonged by more than 4 years.

Intraoperative irradiation for early breast cancer (ELIOT): long-term recurrence and survival outcomes from a single-centre, randomised, phase 3 equivalence trial.

BACKGROUND: In the randomised, phase 3 equivalence trial on electron intraoperative radiotherapy (ELIOT), accelerated partial breast irradiation (APBI) with the use of intraoperative radiotherapy was associated with a higher rate of ipsilateral breast tumour recurrence (IBTR) than whole-breast irradiation (WBI) in patients with early-stage breast cancer. Here, we aimed to examine the planned long-term recurrence and survival outcomes from the ELIOT trial. METHODS: This single-centre, randomised, phase 3 equivalence trial was done at the European Institute of Oncology (Milan, Italy). Eligible women, aged 48-75 years with a clinical diagnosis of a unicentric breast carcinoma with an ultrasound diameter not exceeding 25 mm, clinically negative axillary lymph nodes, and who were suitable for breast-conserving surgery, were randomly assigned (1:1) via a web-based system, with a random permuted block design (block size of 16) and stratified by clinical tumour size, to receive post-operative WBI with conventional fractionation (50 Gy given as 25 fractions of 2 Gy, plus a 10 Gy boost), or 21 Gy intraoperative radiotherapy with electrons (ELIOT) in a single dose to the tumour bed during surgery. The trial was open label and no-one was masked to treatment group assignment. The primary endpoint was the occurrence of IBTR. The trial was designed assuming a 5-year IBTR rate of 3% in the WBI group and equivalence of the two groups, if the 5-year IBTR rate in the ELIOT group did not exceed a 2·5 times excess, corresponding to 7·5%. Overall survival was the secondary endpoint. The main analysis was done by intention to treat. The cumulative incidence of IBTR events and overall survival were assessed at 5, 10, and 15 years of follow-up. This trial is registered with ClinicalTrials.gov, NCT01849133. FINDINGS: Between Nov 20, 2000, and Dec 27, 2007, 1305 women were enrolled and randomly assigned: 654 to the WBI group and 651 to the ELIOT group. After a median follow-up of 12·4 years (IQR 9·7-14·7), 86 (7%) patients developed IBTR, with 70 (11%) cases in the ELIOT group and 16 (2%) in the WBI group, corresponding to an absolute excess of 54 IBTRs in the ELIOT group (HR 4·62, 95% CI 2·68-7·95, p<0·0001). In the ELIOT group, the 5-year IBTR rate was 4·2% (95% CI 2·8-5·9), the 10-year rate was 8·1% (6·1-10·3), and the 15-year rate was 12·6% (9·8-15·9). In the WBI group, the 5-year IBTR rate was 0·5% (95% CI 0·1-1·3), the 10-year rate was 1·1% (0·5-2·2), and the 15-year rate was 2·4% (1·4-4·0). At final follow-up on March 11, 2019, 193 (15%) women had died from any cause, with no difference between the two groups (98 deaths in the ELIOT group vs 95 in the WBI group; HR 1·03, 95% CI 0·77-1·36, p=0·85). In the ELIOT group, the overall survival rate was 96·8% (95% CI 95·1-97·9) at 5 years, 90·7% (88·2-92·7) at 10 years, and 83·4% (79·7-86·4) at 15 years; and in the WBI group, the overall survival rate was 96·8% (95·1-97·9) at 5 years, 92·7% (90·4-94·4) at 10 years, and 82·4% (78·5-85·6) at 15 years. We did not collect long-term data on adverse events. INTERPRETATION: The long-term results of this trial confirmed the higher rate of IBTR in the ELIOT group than in the WBI group, without any differences in overall survival. ELIOT should be offered to selected patients at low-risk of IBTR. FUNDING: Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, Umberto Veronesi Foundation, American Italian Cancer Foundation, The Lombardy Region, and Italian Ministry of Health.

Outcome of hypofractionated breast irradiation and intraoperative electron boost in early breast cancer: A randomized non-inferiority clinical trial.

BACKGROUND: Intraoperative electron radiotherapy (IOERT) followed by hypofractionated whole breast irradiation (HWBI) provides the shortest possible time of adjuvant breast irradiation. The efficacy of either method has been described in previous reports; however, to our knowledge, the efficacy of combined therapy has not been reported. AIM: To compare the toxicity and cosmetic outcome of IOERT as a tumor bed boost followed by HWBI with conventional whole breast irradiation (CWBI) followed by external electron tumor bed boost (EETBB) after breast conserving surgery (BCS) in patients with invasive breast cancer. METHODS: In 2019, a prospective noninferiority trial (IRCT20180919041070N2) was started. After BCS, early-stage breast cancer patients were treated by IOERT (10 Gy) and HWBI (42.56 Gy in 16 fractions) or CWBI (50 Gy in 25 fraction) and EETBB (10 Gy in 5) in a double-arm design. Acute/late toxicity and cosmetic outcome were evaluated by common toxicity criteria (CTC) after 1-year follow-up (FUP) at the level of p < .05. RESULTS: Of 60 eligible patients, 30 were allocated to each group. Regarding acute effects after a median FUP of 12 months, CTC-score of grade II-III erythema (p = .001) and desquamation (p = .005) were significantly higher in CWBI+EETBB compared to IOERT+ HWBI. However, there were no significant differences at the end of radiotherapy and after 1 month, 6 months, and 1 year. Cosmetic outcome after radiation was similar in both groups mostly rating as good/excellent after 1-year FUP. CONCLUSIONS: Boost-IOERT/HWBI regimen has comparable acute and late treatment toxicity profiles compared to the CWBI.

Palliative radiation therapy for symptomatic advance breast cancer.

In this study, we evaluated the effectiveness of palliative breast radiation therapy (RT), with single fraction RT compared with fractionated RT. Our study showed that both RT fractionation schemas provide palliation. Single fraction RT allowed for treatment with minimal interference with systemic therapy, whereas fractionated RT provided a more durable palliative response. Due to equivalent palliative response, at our institution we have increasingly been providing single fraction RT palliation during the COVID-19 pandemic.

Electron beam intraoperative radiotherapy for metastatic epidural spinal cord compression: a prospective observational study.

To assess the additional effects of intraoperative radiotherapy (IORT) with decompression surgery and adjuvant external beam radiotherapy (EBRT) for metastatic epidural spinal cord compression (MESCC). This single-arm institutional prospective observational study recruited patients between June 2017 and March 2020 and included those with symptoms of spinal cord compression owing to metastases, who were diagnosed using MRI. Patients with radiation-sensitive primary tumors and those who could not tolerate surgery were excluded. The treatment protocol comprised decompression surgery and electron beam IORT of 20 Gy in a single fraction followed by EBRT of 30 Gy in 10 fractions. The primary endpoints included the 1-year local failure rate and ambulatory functions. The study was closed in May 2019 owing to changes in treatment policies at our institution. Twenty patients were registered between June 2017 and May 2019. Although all patients completed surgery and IORT, 2 did not receive postoperative EBRT. Patients most commonly had colorectal cancer (4 patients), followed by thyroid cancer, renal cell carcinoma, lung cancer, breast cancer, sarcomas, and other cancers (3, 3, 2, 2, 2, and 4 patients, respectively). The median follow-up duration was 16 months (range 2-30 months); the 1-year local failure rate was 16%. On comparing ambulatory functions pre-treatment and at 1 year after treatment, improvement, no change, and worsening were observed in 3, 9, and 0 patients, respectively. This study's findings suggest that decompression surgery and IORT followed by EBRT are effective in achieving local control and maintaining ambulation in patients with MESCC.