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With the promising results of immunotherapy (IT) in patients with stage III melanoma, the role of adjuvant radiotherapy (RT) after resection and complete lymph-node dissection (CLND) must be reassessed. We evaluate outcomes and safety of adjuvant RT and IT versus IT only in patients with resected stage III melanoma (AJCC 8th edition). This retrospective and single institution study included all consecutive patients treated for a stage III melanoma with CLND and adjuvant IT (anti-PD1) from January 2019 to December 2022. The radiotherapy associated with immunotherapy (RT+IT) group was defined by completion of IT and adjuvant RT in the lymph-node dissection area. The primary endpoint was disease-free survival (DFS). The secondaries endpoints were locoregional (lymph-node field) progression (LRR), incidence of adverse events ≥ grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) and DFS in patients with high risk of locoregional recurrence. Thirty-three patients were included and all received adjuvant IT (pembrolizumab or nivolumab). Among them, twelve received adjuvant lymph-node field radiotherapy. The median duration of follow-up was 17 months (8-45). Patients in RT+IT group had a significantly higher disease stage and more frequent extracapsular extension. At 12 months, the disease-free survival was 66.7% (95% IC: 42.5-82.5) for the IT group and 83.3% (95% IC: 48.2-95.6) for the RT+IT group (p = 0.131). After multivariate analysis, compared to patients with IT treatment, the hazard ratio (HR) was 0.216 ([0.0481, 0.965], p<0.05) for patients treated with RT+IT. The locoregional progression rates were respectively 24% and 8% in patients for which treatment was IT and RT+IT (p = 0.379). After surgery, 21% of patients presented with ≥ grade 3 adverse events. After adjuvant treatment, 6% of patients developed ≥ grade 3 immunotherapy-related events and none developed ≥ grade 3 radiation-related adverse events. In patients with resected stage III melanoma (AJCC 8th edition), adjuvant lymph-node field radiotherapy combined with immunotherapy seems to be associated with longer disease-free survival, with acceptable tolerance. However, these results need to be confirmed by long-term and prospective studies. [ABSTRACT FROM AUTHOR]

Purpose: With the promising results of immunotherapy in patients with stage III melanoma, the role of adjuvant radiotherapy after resection and complete lymph-node dissection must be reassessed. We evaluate the outcomes and safety of adjuvant radiotherapy and immunotherapy compared to immunotherapy only in patients with resected stage III melanoma., Patients and Methods: This retrospective and single institution study included patients treated for a stage III melanoma with complete lymph-node dissection and adjuvant immunotherapy from January 2019 to December 2022. The radiotherapy associated with immunotherapy group was defined by completion of immunotherapy and adjuvant radiotherapy in the lymph-node dissection area. The primary endpoint was disease-free survival. The secondary endpoints were locoregional progression, incidence of adverse events grade 3 or above and disease-free survival rate in patients with high risk of locoregional recurrence., Results: Thirty-three patients were included. Among them, twelve received adjuvant lymph-node field radiotherapy. The median duration of follow-up was 17months (range: 8-45months). Patients receiving radiotherapy and immunotherapy had a significantly higher disease stage and more frequent extracapsular extension. At 12months, the disease-free survival rate was 66.7 % for the patients receiving immunotherapy alone (95 % CI: 42.5-82.5 %) and 83.3 % for those receiving radiotherapy and immunotherapy (95 % CI: 48.2-95.6 %; P=0.131). The locoregional progression rate was 24 % in patients receiving immunotherapy and 8 % in patients receiving immunotherapy and radiotherapy (P=0.379). After adjuvant treatment, 6 % of patients developed grade 3 or above immunotherapy-related events and none developed grade 3 or above radiation-related adverse events., Conclusion: In patients with stage III melanoma, adjuvant lymph-node field radiotherapy combined with immunotherapy seems to be associated with longer disease-free survival, with acceptable tolerance. However, these results need to be confirmed by long-term and prospective studies., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Radiotherapy is a major therapeutic strategy for cancer treatment. Despite many technology advances in the last two decades, local control remains often suboptimal, especially in locally advanced tumours, which are often hypoxic, and radioresistant. In addition, irradiation of surrounding tissues and organs at risk usually precludes further dose escalation to minimize acute and late toxicities. Radiosensitizing agents such as chemotherapies targeting the DNA repair, or targeted monoclonal antibodies (cetuximab) have been shown to improve local control in many tumour types. More recently, radioenhancers have emerged as a new way to overcome the limitations of radiation. Here, we review the state of the art in this field and will focus on the past and ongoing clinical trials with the nanoparticles NBTXR3 and AGuIX®., (Copyright © 2024. Published by Elsevier Masson SAS.)

Purpose: Novel radiation therapy approaches have increased the therapeutic efficacy for malignant brain tumors over the past decades, but the balance between therapeutic gain and radiotoxicity remains a medical hardship. Synchrotron microbeam radiation therapy, an innovative technique, deposes extremely high (peak) doses in micron-wide, parallel microbeam paths, whereas the diffusing interbeam (valley) doses lie in the range of conventional radiation therapy doses. In this study, we evaluated normal tissue toxicity of whole-brain microbeam irradiation (MBI) versus that of a conventional hospital broad beam (hBB)., Methods and Materials: Normal Fischer rats (n = 6-7/group) were irradiated with one of the two modalities, exposing the entire brain to MBI valley/peak doses of 0/0, 5/200, 10/400, 13/520, 17/680, or 25/1000 Gy or to hBB doses of 7, 10, 13, 17, or 25 Gy. Two additional groups of rats received an MBI valley dose of 10 Gy coupled with an hBB dose of 7 or 15 Gy (groups MBI17* and MBI25*). Behavioral parameters were evaluated for 10 months after irradiation combined with veterinary observations., Results: MBI peak doses of ≥680 Gy caused acute toxicity and death. Animals exposed to hBB or MBI dose-dependently gained less weight than controls; rats in the hBB25 and MBI25* groups died within 6 months after irradiation. Increasing doses of MBI caused hyperactivity but no other detectable behavioral alterations in our tests. Importantly, no health concerns were seen up to an MBI valley dose of 17 Gy., Conclusions: While acute toxicity of microbeam exposures depends on very high peak doses, late toxicity mainly relates to delivery of high MBI valley doses. MBI seems to have a low impact on normal rat behavior, but further tests are warranted to fully explore this hypothesis. However, high peak and valley doses are well tolerated from a veterinary point of view. This normal tissue tolerance to whole-brain, high-dose MBI reveals a promising avenue for microbeam radiation therapy, that is, therapeutic applications of microbeams that are poised for translation to a clinical environment., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Synchrotron Microbeam Radiation Therapy (MRT) has repeatedly proven its superiority compared with conventional radiotherapy for glioma control in preclinical research. The clinical transfer phase of MRT has recently gained momentum; seven dogs with suspected glioma were treated under clinical conditions to determine the feasibility and safety of MRT. We administered a single fraction of 3D-conformal, image-guided MRT. Ultra-high-dose rate synchrotron X-ray microbeams (50 µm-wide, 400 µm-spaced) were delivered through five conformal irradiation ports. The PTV received ~25 Gy peak dose (within microbeams) per port, corresponding to a minimal cumulated valley dose (diffusing between microbeams) of 2.8 Gy. The dogs underwent clinical and MRI follow-up, and owner evaluations. One dog was lost to follow-up. Clinical exams of the remaining six dogs during the first 3 months did not indicate radiotoxicity induced by MRT. Quality of life improved from 7.3/10 [±0.7] to 8.9/10 [±0.3]. Tumor-induced seizure activity decreased significantly. A significant tumor volume reduction of 69% [±6%] was reached 3 months after MRT. Our study is the first neuro-oncologic veterinary trial of 3D-conformal Synchrotron MRT and reveals that MRT does not induce acute to subacute radiotoxicity in normal brain tissues. MRT improves quality of life and leads to remarkable tumor volume reduction despite low valley dose delivery. This trial is an essential step towards the forthcoming clinical application of MRT against deep-seated human brain tumors.

AGuIX, a novel gadolinium-based nanoparticle, has been deployed in a pioneering double-blinded Phase II clinical trial aiming to assess its efficacy in enhancing radiotherapy for tumor treatment. This paper moves towards this goal by analyzing AGuIX uptake patterns in 23 patients. A phantom was designed to establish the relationship between AGuIX concentration and longitudinal ( T 1 ) relaxation. A 3T MRI and MP2RAGE sequence were used to generate patient T 1 maps. AGuIX uptake in tumors was determined based on longitudinal relaxivity. AGuIX (or placebo) was administered to 23 patients intravenously at 100 mg/kg 1-5 hours pre-imaging. Each of 129 brain metastases across 23 patients were captured in T 1 maps and examined for AGuIX uptake and distribution. Inferred AGuIX recipients had average tumor uptakes between 0.012 and 0.17 mg/ml, with a mean of 0.055 mg/ml. Suspected placebo recipients appeared to have no appreciable uptake. Tumors presented with varying spatial AGuIX uptake distributions, suspected to be related to differences in accumulation time and patient-specific bioaccumulation factors. This research demonstrates AGuIX's ability to accumulate in brain metastases, with quantifiable uptake via T 1 mapping. Future analyses will extend these methods to complete clinical trial data (~ 134 patients) to evaluate the potential relationship between nanoparticle uptake and possible tumor response following radiotherapy.Clinical Trial Registration Number: NCT04899908.Clinical Trial Registration Date: 25/05/2021., (© 2024. The Author(s).)

Background and Purpose: Microbeam Radiation Therapy (MRT) aims to deliver higher doses to the target while minimizing radiation damage to healthy tissues using synchrotron x-ray microbeams. Translational MRT research has now started, driven by promising results from preclinical studies. This study aimed to propose a first dose-outcome model by analyzing micrometric dose distributions obtained with high-resolution 3D dose calculations, accounting for the inherent physical dose distribution complexity in MRT. The feasibility of integrating penMRT, our full Monte Carlo multiscale dose calculation algorithm based on PENELOPE into translational research on veterinary patients was also investigated., Material and Methods: Micrometric dose distributions were calculated in tumor-bearing rats and for a veterinary patient with penMRT, for conformal multi-directional MRT treatment plans. Absorbed dose maps were obtained with 0.005 × 0.005 × 1 mm 3 voxel sizes. High-resolution dose-volume histograms were extracted and analyzed against radiobiology studies., Results: The complexity of the MRT dose distribution was properly rendered at a micrometer scale on 3D dose maps, with well separated dose regions observed on the differential dose-volume histograms. The median survival time of glioma-bearing rats varied linearly with the volume fraction of the planning target volume that received doses higher than 50 Gy (R 2  = 0.98). The feasibility of using penMRT for treatment planning in large volumes has been shown on a veterinary patient., Conclusions: This study demonstrated the significant added value of penMRT for planning and prescribing MRT treatments. It also shed light on the correlation between the high-resolution 3D dose distributions and the treatment outcome., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Microbeam radiation therapy (MRT) is a radiotherapy technique combining spatial fractionation of the dose distribution on a micrometric scale, X-rays in the 50-500 keV range and dose rates up to 16 × 10 3  Gy s -1 . Nowadays, in vivo dosimetry remains a challenge due to the ultra-high radiation fluxes involved and the need for high-spatial-resolution detectors. The aim here was to develop a striped diamond portal detector enabling online microbeam monitoring during synchrotron MRT treatments. The detector, a 550 µm bulk monocrystalline diamond, is an eight-strip device, of height 3 mm, width 178 µm and with 60 µm spaced strips, surrounded by a guard ring. An eight-channel ASIC circuit for charge integration and digitization has been designed and tested. Characterization tests were performed at the ID17 biomedical beamline of the European Synchrotron Radiation Facility (ESRF). The detector measured direct and attenuated microbeams as well as interbeam fluxes with a precision level of 1%. Tests on phantoms (RW3 and anthropomorphic head phantoms) were performed and compared with simulations. Synchrotron radiation measurements were performed on an RW3 phantom for strips facing a microbeam and for strips facing an interbeam area. A 2% difference between experiments and simulations was found. In more complex geometries, a preliminary study showed that the absolute differences between simulated and recorded transmitted beams were within 2%. Obtained results showed the feasibility of performing MRT portal monitoring using a microstriped diamond detector. Online dosimetric measurements are currently ongoing during clinical veterinary trials at ESRF, and the next 153-strip detector prototype, covering the entire irradiation field, is being finalized at our institution., (open access.)

Background: The measurement of the concentration of theranostic agents in vivo is essential for the assessment of their therapeutic efficacy and their safety regarding healthy tissue. To this end, there is a need for quantitative T 1 measurements that can be obtained as part of a standard clinical imaging protocol applied to tumor patients., Purpose: To generate T 1 maps from MR images obtained with the magnetization-prepared rapid gradient echo (MPRAGE) sequence. To evaluate the feasibility of the proposed approach on phantoms, animal and patients with brain metastases., Study Type: Pilot., Phantom/animal Model/population: Solutions containing contrast agents (chelated Gd 3+ and iron nanoparticles), male rat of Wistar strain, three patients with brain metastases., Field Strength/sequence: A 3-T and 7-T, saturation recovery (SR), and MPRAGE sequences., Assessment: The MPRAGE T 1 measurement was compared to the reference SR method on phantoms and rat brain at 7-T. The robustness of the in vivo method was evaluated by studying the impact of misestimates of tissue proton density. Concentrations of Gd-based theranostic agents were measured at 3-T in gray matter and metastases in patients recruited in NanoRad clinical trial., Statistical Tests: A linear model was used to characterize the relation between T 1 measurements from the MPRAGE and the SR acquisitions obtained in vitro at 7-T., Results: The slope of the linear model was 0.966 (R 2  = 0.9934). MPRAGE-based T 1 values measured in the rat brain were 1723 msec in the thalamus. MPRAGE-based T 1 values measured in patients in white matter and gray matter amounted to 747 msec and 1690 msec. Mean concentration values of Gd 3+ in metastases were 61.47 μmol., Data Conclusion: The T 1 values obtained in vitro and in vivo support the validity of the proposed approach. The concentrations of Gd-based theranostic agents may be assessed in patients with metastases within a standard clinical imaging protocol using the MPRAGE sequence., Evidence Level: 2., Technical Efficacy: Stage 1., (© 2022 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Radiation therapy (RT), a novel approach to boost the anticancer immune response, has been progressively evaluated in the neoadjuvant setting in breast cancer (BC)., Purpose: We aimed to evaluate immunity-related indicators of response to neoadjuvant chemoradiation therapy (NACRT) in BC for better treatment personalization., Patients and Methods: We analyzed data of the first 42 patients included in the randomized phase 2 Neo-APBI-01 trial comparing standard neoadjuvant chemotherapy (NACT) and NACRT regimen in locally advanced triple-negative (TN) and luminal B (LB) subtype BC. Clinicopathological parameters, blood counts and the derived parameters, total tumor-infiltrating lymphocytes (TILs) and their subpopulation, as well as TP53 mutation status, were assessed as predictors of response., Results: Twenty-one patients were equally assigned to each group. The pathologic complete response (pCR) was 33% and 38% in the NACT and NACRT groups, respectively, with a dose-response effect. Only one LB tumor reached pCR after NACRT. Numerous parameters associated with response were identified, which differed according to the assigned treatment. In the NACRT group, baseline hemoglobin of ≥13 g/dL and body mass index of <26 were strongly associated with pCR. Higher baseline neutrophils-to-lymphocytes ratio, total TILs, and T-effector cell counts were favorable for pCR., Conclusion: This preliminary analysis identified LB and low-TIL tumors as poor responders to the NACRT protocol, which delivered RT after several cycles of chemotherapy. These findings will allow for amending the selection of patients for the trial and help better design future trials of NACRT in BC.

Background: Prostate cancer (PCa) is the most frequently diagnosed cancer in men in Europe. The impact of PCa natural history and therapeutic management on the outcomes of castration-resistant prostate cancer patients with metastasis (mCRPC) remains unclear., Objective: The objective of this study was to describe retrospectively patterns of clinical progression through diagnosis sequences before the mCRPC stage and to assess how these sequences impacted patients' disease progression and overall survival at mCRPC stage., Patients and Methods: Patients with mCRPC were identified from the Prostate Cancer Registry (PCR), an observational study in a real-world setting in 16 countries between 2013 and 2016. Patients were grouped in diagnosis sequences before mCRPC and defined by date of PCa diagnosis, first metastasis, and castration resistance. Distribution of time-to-event variables were estimated using Kaplan-Meier product-limit survival curves for overall survival (OS) and progression-free survival (PFS). Non-adjusted Cox models were conducted for efficacy endpoints (OS, PFS) to estimate hazard ratios between diagnosis sequences., Results: At the end of study, 2859 mCRPC patients were included in this analysis. Among mCRPC four diagnosis sequences were identified: 35% developed metastases (mHSPC) before becoming castration resistant (sequence 1, metachronous mHSPC), 10% developed castration resistance (nmCRPC) before metastases (sequence 2), 27% developed metastases and castration resistance within 4 months (sequence 3) and 28% of patients were de novo mHSPC (sequence 4). Median OS was 17.7 months (interquartile range (IQR): 8.8-29.9) and PFS was 6.4 months (IQR: 3.2-12.0). The univariate analyses showed no correlation between mCRPC patients' OS or PFS and the diagnosis sequence., Conclusion: This large European study describe four different patterns of prostate cancer progression to mCRPC stage. Our results indicate that patient survival becomes comparable after progression to mCRPC, regardless of the diagnosis sequence., Trial Registration: ClinicalTrials.gov identifier NCT02236637; registered September 2014., (© 2022. The Author(s).)

Background: Imaging, in radiotherapy, has become a routine tool for repositioning of the target volume at each session. The repositioning precision, currently infracentimetric, evolves along with the irradiation techniques. This retrospective study aimed to identify practices and doses resulting from the use of high energy planar imaging (portal imaging) in daily practice., Methods: A retrospective survey of portal images (PIs) was carried out over 10 years for 2,403 patients and for three linacs (1 Elekta SLi, 2 Varian Clinac) for postoperative mammary irradiations. Images were taken using a standardized number of monitor units (MU) for all patients. Due to the variable sensitivities of the detectors and the possibility of adjustment of the detector-patient distance, the number of MU were 3; 2 and 1 respectively, for Elekta SLi ® , Clinac 600 ® and Clinac 2100 ® . Then, a representative cumulated dose was calculated in simplified reference conditions (5 cm depth, beam of 10 cm × 10 cm, 6 MV), considering the total number of images taken during the whole treatment course. The consistency between the representative doses and the actual absorbed doses received by the patients was verified by simulating a series of typical cases with the treatment plan dose calculation system., Results: The delivered doses differ significantly between the three linacs. The mean representative dose values by complete treatment were 0.695; 0.241 and 0.216 Gy, respectively, for SLi, Clinac 600 and Clinac 2100. However, 15 patients were exposed to a dose >2 Gy with a maximum dose of 5.05 Gy. The simulated doses were very similar to the representative doses., Conclusions: A significant dose delivery was highlighted by this study. These representative doses are presently communicated weekly to the radiation oncologist for the radiation protection of their patients. Moreover, they should be taken into account in a possible study of long-term stochastic risks., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-19-1031). Dr. AC serves as an unpaid editorial board member of Quantitative Imaging in Medicine and Surgery. The other authors have no conflicts of interest to declare., (2021 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background and Purpose: Brain metastasis impacts greatly on patients' quality of life and survival. The phase I NANO-RAD trial assessed the safety and maximum tolerated dose of systemic administration of a novel gadolinium-based nanoparticle, AGuIX, in combination with whole brain radiotherapy in patients with multiple brain metastases not suitable for stereotactic radiotherapy., Materials and Methods: Patients with measurable brain metastases received escalating doses of AGuIX nanoparticles (15, 30, 50, 75, or 100 mg/kg intravenously) on the day of initiation of WBRT (30 Gy in 10 fractions) in 5 cohorts of 3 patients each. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events v4.03., Results: Fifteen patients with 354 metastases were included. No dose-limiting toxic effects were observed up to AGuIX 100 mg/kg. Plasma elimination half-life of AGuIX was similar for all groups (mean 1.3 h; range 0.8-3 h). Efficient targeting of metastases (T 1 MRI enhancement, tumor selectivity) and persistence of AGuIX contrast enhancement were observed in metastases from patients with primary melanoma, lung, breast, and colon cancers. The concentration of AGuIX in metastases after administration was proportional to the injected dose. Thirteen of 14 evaluable patients had a clinical benefit, with either stabilization or reduction of tumor volume. MRI analysis showed significant correlation between contrast enhancement and tumor response, thus supporting a radiosensitizing effect., Conclusion: Combining AGuIX with radiotherapy for patients with brain metastases is safe and feasible. AGuIX specifically targets brain metastases and is retained within tumors for up to 1 week; ongoing phase II studies will more definitively assess efficacy., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: The Briganti nomogram can be used with a threshold of 5% to decide when to offer lymph node dissection during radical prostatectomy. The objective of the study was to assess the accuracy of the Briganti nomogram on intermediate-risk prostate cancer patients managed in a single academic department., Methods: We retrospectively reviewed the files of all patients managed by radical prostatectomy (RP) and bilateral pelvic lymph node dissection (BPLND) in our center between 2005 and 2017. The overall accuracy of the model in predicting metastatic lymph node disease was quantified by the construction of a receiver-operator characteristic (ROC) curve. A calibration plot was drawn to represent the relationship between the predicted and observed frequencies., Results: We included 285 patients, among whom 175 (61.4%) were classified as intermediate risk as defined by D'Amico. The median follow-up was 60 (34-93) months. Twenty-seven patients (9.5%) were diagnosed with lymph node metastases. The median number of lymph nodes removed was 10 (7-14). The mean Briganti score was 19.3% in patients with lymph node involvement (LNI) and 6.3% in patients without LNI. Focusing on intermediate-risk patients, 91(52%) and 84 (48%) had a Briganti score < 5% and ≥ 5%, respectively, among whom 6 (6.6%) and 7(8.3%) had lymph node metastases. The accuracy of the score was low for intermediate risk patients with an area under the curve (AUC) of 53.1% (95% CI 0.45-0.61)., Conclusion: The Briganti nomogram in our retrospective cohort showed low accuracy for the prediction of lymph node involvement in an intermediate-risk prostate cancer population.