Proton therapy reduces the effective dose to immune cells in breast cancer patients.

BACKGROUND: The effective dose to circulating immune cells (EDIC) is associated with survival in lung and esophageal cancer patients. This study aimed to evaluate the benefit of intensity-modulated proton therapy (IMPT) for EDIC reduction as compared to volumetric modulated arc therapy (VMAT) in patients with locally advanced breast cancer (BC). MATERIALS AND METHODS: Ten BC patients treated with locoregional VMAT after breast-conserving surgery were included. Mean dose to the heart (MHD), lungs (MLD), and liver (MlD), as well as the integral dose to the body (ITD), were retrieved, and we calculated EDIC as 0.12â€¯× MLD + 0.08â€¯× MHD + 0.15â€¯× 0.85â€¯× âˆš(n/45)â€¯× MlD + (0.45 + 0.35â€¯× 0.85â€¯× âˆš(n/45))â€¯× ITD/(62â€¯× 103), where n is the number of fractions. EDIC was compared between VMAT and IMPT plans. RESULTS: Median EDIC was reduced from 3.37 Gy (range: 2.53-5.99) with VMAT to 2.13 Gy (1.31-3.77) with IMPT (p < 0.01). For left-sided BC patients, EDIC was reduced from 3.15 Gy (2.53-3.78) with VMAT to 1.65 Gy (1.31-3.77) with IMPT (p < 0.01). For right-sided BC patients, EDIC was reduced from 5.60 Gy (5.06-5.99) with VMAT to 3.38 Gy (3.10-3.77) with IMPT (p < 0.01). Right-sided BC patients had a higher EDIC irrespective of the technique. Integral dose reduction was the main driver of EDIC reduction with IMPT and was associated with lung sparing for left-sided BC patients or liver sparing for right-sided BC patients. CONCLUSION: IMPT significantly reduced EDIC in BC patients undergoing locoregional adjuvant radiotherapy. Integral total dose reduction, associated with improved lung sparing in left-sided BC patients or liver sparing in right-sided BC patients, mainly drove EDIC reduction with IMPT. The emergence of dynamic models taking into account the circulatory kinetics of immune cells may improve the accuracy of the estimate of the dose received by the immune system compared to calculation of the EDIC, which is based solely on static dosimetric data.

Determinants of radiation dose to immune cells during breast radiotherapy.

BACKGROUND: The immune system has been identified as an organ at risk in esophageal and lung cancers. However, the dosimetric impact of radiotherapy on immune system exposure in patients treated for breast cancer has never been studied. METHODS: A monocentric retrospective dosimetric study included 163 patients treated at the Institut Curie (Paris, France) between 2010 and 2016 with locoregional helical tomotherapy after conservative surgery or total mastectomy. The effective dose to the immune system (EDIC) was calculated based on diverse dosimetric parameters. The clinical and volumetric determinants of EDIC in adjuvant radiotherapy of breast cancer were analyzed. RESULTS: The median EDIC for the population was 4.23 Gy, ranging from 1.82 to 6.19 Gy. Right-sided radiotherapy and regional lymph node irradiation were associated with significantly higher EDIC in univariate (4.38 Gy vs. 3.94 Gy, p < 0.01, and 4.27 Gy vs. 3.44 Gy, p < 0.01, respectively) and multivariate analyses (p < 0.01 and p < 0.01). Liver overexposure was the main contributor to EDIC increase in right-sided breast cancer patients (+0.38 Gy [95%CI: +0.30; +0.46]), while the integral total dose increase was the main contributor to EDIC increase in cases of regional node irradiation (+0.63 Gy [95%CI: +0.42; +0.85]). CONCLUSION: The EDIC score during adjuvant radiotherapy after breast cancer was statistically significantly higher in the case of right-sided radiotherapy and regional lymph node irradiation. Liver irradiation is the main contributor to immune system exposure in adjuvant irradiation of right-sided breast cancer. Populations in which an association between EDIC and survival would exist have yet to be identified but could potentially include patients treated for triple-negative breast cancer with a poor response to neoadjuvant chemoimmunotherapy.

Dosimetric evaluation of the benefit of deep inspiration breath hold (DIBH) for locoregional irradiation of right breast cancer with volumetric modulated arctherapy (VMAT).

INTRODUCTION: Right-lateralized cardiac substructures can be substantially exposed during right breast cancer (R-BC) radiotherapy. The cardiac benefit of deep inspiration breath hold (DIBH) is established in combination with volumetric modulated arctherapy (VMAT) for left breast cancer with regional node irradiation but is unknown for R-BC. This study evaluated the dosimetric benefit of DIBH for locoregional irradiation of R-BC with VMAT. MATERIAL AND METHODS: All patients treated for R-BC with adjuvant locoregional DIBH-VMAT in the Department of Radiation Oncology of the Institut Curie (Paris, France) until December 2022 were included, corresponding to 15 patients. FB- and DIBH-VMAT plans were compared both for a normofractionated regimen (50 Gy/25fx) used for treatment and a replanned hypofractionated regimen (40 Gy/15fx). Dose to the heart, cardiac substructures (sinoatrial node (SAN), atrio-ventricular node (AVN), right coronary artery, left anterior descending coronary artery, left ventricle), ipsilateral lung and liver were retrieved and compared. RESULTS: Mean heart dose (MHD) was 3.33 Gy with FB vs. 3.10 Gy with DIBH on normofractionated plans (p = 0.489), and 2.58 Gy with FB vs. 2.41 Gy with DIBH on hypofractionated plan (p = 0.489). The benefit of DIBH was not significant for any cardiac substructure. The most exposed cardiac substructure were the SAN (mean dose of 6.62 Gy for FB- and 5.64 Gy for DIBH-VMAT on normofractionated plans) and the RCA (mean dose of 4.21 Gy for FB- and 4.06 Gy for DIBH-VMAT on normofractionated plans). The maximum benefit was observed for the RCA with a median individual dose reduction of 0.84 Gy on normofractionated plans (p = 0.599). No significant dosimetric difference were observed for right lung. Liver mean dose was significantly lower with DIBH with median values decreasing from 2.54 Gy to 0.87 Gy (p = 0.01). CONCLUSION: Adding DIBH to efficient cardiac-sparing radiotherapy techniques, such as VMAT, is not justified in the general case for locoregional R-BC irradiation. Specific R-BC patient subpopulations who could benefit from additional DIBH combination with locoregional VMAT are yet to be identified.

Large scale experience of two ultrahypofractionated 5 fractions regimes after breast conserving surgery from a single centre.

PURPOSE: Ultra-hypofractionation breast radiotherapy is a safe alternative to moderate hypofractionation. This study reports the results of two ultrahypofractionated regimens used in clinical practice in a high-volume radiotherapy center in terms of efficacy and of tolerance. METHODS: we included all patients treated in an adjuvant setting with five fractions after breast conserving surgery (BCS), for a histologically-confirmed invasive or in situ breast carcinoma. Radiotherapy regimens after BCS were either a 5-week schedule with 5 weekly fractions of 5,7 Gy or a one-week schedule with 5 daily fractions of 5,2 Gy. Adverse events were recorded and local-relapse free survival (LRFS), locoregional-relapse free survival (LRRFS), metastasis-free survival (MFS), for breast-cancer specific survival (BCSS) and overall survival (OS) were evaluated. RESULTS: Between December 2014 and December 2022, 396 patients (400 breasts) were treated with ultrahypofractionated radiotherapy. Five-year LRFS was 98.8% (95% confidence interval: 97.1%-100%), and 5-year OS was 96.0% (95%CI: 92.6-99.5%). Age was statistically associated with OS in univariate analysis (HR: 1.16, 95%CI: 1.04-1.42, p = .01). Four patients (1.0%) experienced acute grade 3 radiation-induced adverse events, and 8 patients (2.3%) acute grade 2 toxicities. Twenty-three patients (5.8%) experienced late toxicity, all of them being graded as grade 1. The use of the 5.7 Gy-weekly-fraction regimen and the delivery of a tumor bed boost were significantly associated with acute radiodermatitis (p < .01; p = .02; respectively) and late fibrosis (p < .01; p = .049; respectively). CONCLUSIONS: ultrahypofractionated radiotherapy was associated with an excellent tumor control rate in our 'real-life' cohort with low-risk breast cancer patients. However, delivery of a tumor bed boost and using weekly 5.7-Gy fractions were associated with an increased risk of acute and late cutaneous toxicities.

A review of uncertainties in radiotherapy dose reconstruction and their impacts on dose-response relationships.

Proper understanding of the risk of radiation-induced late effects for patients receiving external photon beam radiotherapy requires the determination of reliable dose-response relationships. Although significant efforts have been devoted to improving dose estimates for the study of late effects, the most often questioned explanatory variable is still the dose. In this work, based on a literature review, we provide an in-depth description of the radiotherapy dose reconstruction process for the study of late effects. In particular, we focus on the identification of the main sources of dose uncertainty involved in this process and summarise their impacts on the dose-response relationship for radiotherapy late effects. We provide a number of recommendations for making progress in estimating the uncertainties in current studies of radiotherapy late effects and reducing these uncertainties in future studies.

Scripting a planning avoidance structure to perform simultaneous integrated boost breast on Halcyon linear accelerators.

When planning a simultaneous integrated boost in breast treatment with sliding window intensity-modulated radiotherapy, the use of an oblique anterior field can be advantageous. To limit the irradiation to the tumor bed on the oblique anterior field, we use the "fixed jaw" option during optimization in Eclipse (v15.6, Varian Medical System). However, this option is not available for Halcyon (Varian Medical System) linear accelerators because the beam-defining collimator is only composed of a dual-layer multileaf collimator (MLC) without any jaw collimator. Hence, the optimizer opens the leaves on all target volumes, and leaves facing the heart or medullary canal may be opened on the oblique anterior field. To avoid this unacceptable behavior, we created an avoidance structure using the Eclipse Scripting Application Programming Interface (ESAPI) to force the optimizer to close the leaves when facing critical organs at risk. The avoidance structure was the whole body of the patient subtracted from every beam path used: the tangential fields collimated to the breast planning target volume (PTV) and the oblique anterior field collimated to the tumor bed PTV. The ESAPI has a built-in method that returns a table of points, drawing the outline of a structure at the isocenter plane of a beam. We used this method to build the avoidance structure. We planned 6 breast cancer patients using this structure, and we were able to meet all dosimetric constraints. All MLC leaves were fully closed outside the tumor bed PTV for the oblique anterior field.

Addressing the dosimetric impact of bone cement and vertebroplasty in stereotactic body radiation therapy.

PURPOSE: Bone cement used for vertebroplasty can affect the accuracy on the dose calculation of the radiation therapy treatment. In addition the CT values of high density objects themselves can be misrepresented in kVCT images. The aim of our study is then to propose a streamlined approach for estimating the real density of cement implants used in stereotactic body radiation therapy. METHODS: Several samples of cement were manufactured and irradiated in order to investigate the impact of their composition on the radiation dose. The validity of the CT conversion method for a range of photon energies was investigated, for the studied samples and on six patients. Calculations and measurements were carried out with various overridden densities and dose prediction algorithms (AXB with dose-to-medium reporting or AAA) in order to find the effective density override. RESULTS: Relative dose differences of several percent were found between the dose measured and calculated downstream of the implant using an ion chamber and TPS or EPID dosimetry. If the correct density is assigned to the implant, calculations can provide clinically acceptable accuracy (gamma criteria of 3%/2 mm). The use of MV imaging significantly favors the attribution of a correct equivalent density to the implants compared to the use of kVCT images. CONCLUSION: The porosity and relative density of the various studied implants vary significantly. Bone cement density estimations can be characterized using MV imaging or planar in vivo dosimetry, which could help determining whether errors in dose calculations are due to incorrect densities.

Risk of Subsequent Leukemia After a Solid Tumor in Childhood: Impact of Bone Marrow Radiation Therapy and Chemotherapy.

PURPOSE: To investigate the roles of radiation therapy and chemotherapy in the occurrence of subsequent leukemia after childhood cancer. METHODS AND MATERIALS: We analyzed data from a case-control study with 35 cases and 140 controls. The active bone marrow (ABM) was segmented into 19 compartments, and the radiation dose was estimated in each. The chemotherapy drug doses were also estimated to enable adjustments. Models capable of accounting for radiation dose heterogeneity were implemented for analysis. RESULTS: Univariate analysis showed a significant trend in the increase of secondary leukemia risk with radiation dose, after accounting for dose heterogeneity (P=.046). This trend became nonsignificant after adjustment for doses of epipodophyllotoxins, alkylating agents, and platinum compounds and the first cancer on multivariate analysis (P=.388). The role of the radiation dose appeared to be dwarfed, mostly by the alkylating agents (odds ratio 6.9, 95% confidence interval 1.9-25.0). Among the patients who have received >16 Gy to the ABM, the radiogenic risk of secondary leukemia was about 4 times greater in the subgroup with no alkylating agents than in the subgroup receiving ≥10 g/m(2). CONCLUSIONS: Notwithstanding the limitations resulting from the size of our study population and the quite systematic co-treatment with chemotherapy, the use of detailed information on the radiation dose distribution to ABM enabled consideration of the role of radiation therapy in secondary leukemia induction after childhood cancer.

Retrospective reconstructions of active bone marrow dose-volume histograms.

PURPOSE: To present a method for calculating dose-volume histograms (DVH's) to the active bone marrow (ABM) of patients who had undergone radiation therapy (RT) and subsequently developed leukemia. METHODS AND MATERIALS: The study focuses on 15 patients treated between 1961 and 1996. Whole-body RT planning computed tomographic (CT) data were not available. We therefore generated representative whole-body CTs similar to patient anatomy. In addition, we developed a method enabling us to obtain information on the density distribution of ABM all over the skeleton. Dose could then be calculated in a series of points distributed all over the skeleton in such a way that their local density reflected age-specific data for ABM distribution. Dose to particular regions and dose-volume histograms of the entire ABM were estimated for all patients. RESULTS: Depending on patient age, the total number of dose calculation points generated ranged from 1,190,970 to 4,108,524. The average dose to ABM ranged from 0.3 to 16.4 Gy. Dose-volume histograms analysis showed that the median doses (D50%) ranged from 0.06 to 12.8 Gy. We also evaluated the inhomogeneity of individual patient ABM dose distribution according to clinical situation. It was evident that the coefficient of variation of the dose for the whole ABM ranged from 1.0 to 5.7, which means that the standard deviation could be more than 5 times higher than the mean. CONCLUSIONS: For patients with available long-term follow-up data, our method provides reconstruction of dose-volume data comparable to detailed dose calculations, which have become standard in modern CT-based 3-dimensional RT planning. Our strategy of using dose-volume histograms offers new perspectives to retrospective epidemiological studies.