Low-dose Volume Research Articles

Ofatumumab in the treatment of multiple sclerosis - A summary of preclinical and clinical data

B-cell targeted therapies are highly effective in multiple sclerosis (MS). Most of these therapies are administered intravenously at long intervals. Ofatumumab, an anti-CD20 antibody that is administered subcutaneously at low doses on a monthly basis due to its high affinity to the target structure, became available for the treatment of MS in 2021. An overview of practice-relevant immunological and clinical data on ofatumumab is provided. The high affinity of ofatumumab to the target structure allows low dose and low volume administration, with the release and absorption profile after subcutaneous application allowing for high concentrations in the lymph nodes and gradual depletion of B-cells. Rapid onset of action is achieved as well as B-cell repletion within a few months in case of discontinuation of therapy. Long-term data show stable IgG levels over up to four years and high efficacy with respect to relapse rate, progression, and cognition. According to current study data, the effect compared to teriflunomide is greater the earlier therapy is initiated. Ofatumumab has a specific B-cell depletion pattern. CD20 expressing B-cell progenitor cells in the bone marrow are preserved and therefore also the inducibility and differentiation of plasma cells. The formation of a humoral immunological memory is therefore possible. Four-year study data showed no abnormalities in the rate of severe infections or malignancies. Ofatumumab is an innovative B-cell targeted therapy. It is highly effective with a good safety and tolerability profile, well controllable and maintains immunocompetence against pathogens.

Clinical Implementation and Dosimetric Evaluation of a Robust Proton Lattice Planning Strategy Using Primary and Robust Complementary Beams

Pencil-beam scanning proton therapy has been considered a potential modality for the 3D form of spatially fractionated radiation therapy called lattice therapy. However, few practical solutions have been introduced in the clinic. Existing limitations include degradation in plan quality and robustness when using single-field versus multifield lattice plans, respectively. We propose a practical and robust proton lattice (RPL) planning method using multifield and evaluate its dosimetric characteristics compared to clinically acceptable photon lattice plans. Seven cases previously treated with photon lattice therapy were used to evaluate a novel RPL planning technique using 2-orthogonal beams: a primary beam (PB) and a robust complementary beam (RCB) that deliver 67% and 33%, respectively, of the prescribed dose to vertices inside the gross target volume (GTV). Only RCB is robustly optimized for setup and range uncertainties. The number and volume of vertices, peak-to-valley dose ratios (PVDRs), and volume of low dose to GTV of proton and photon plans were compared. The RPL technique was then used in the treatment of 2 patients and their dosimetric parameters were reported. The RPL strategy was able to achieve the clinical planning goals. Compared to previously treated photon plans, the average number of vertices increased by 30%, the average vertex volume by 49% (18.2 ± 25.9 cc vs 12.2 ± 14.5 cc, P = .21), and higher PVDR (10.5 ± 4.8 vs 2.5 ± 0.9, P < .005) was achieved. In addition, RPL plans show more conformal dose with less low dose to GTV (V30%, 60.9% ± 7.2% vs 81.6% ± 13.9% and V10%, 88.3% ± 4.5% vs 98.6% ± 3.6% [P < .01]). The RPL plan for 2 treated patients showed PVDRs of 4.61 and 14.85 with vertices-to-GTV ratios of 1.52% and 1.30%, respectively. A novel RPL planning strategy using a pair of orthogonal beams was developed and successfully translated to the clinic. The proposed method can generate better quality plans, a higher number of vertices, and higher PVDRs than currently used photon lattice plans.

Robust optimization of the Gross Tumor Volume compared to conventional Planning Target Volume-based planning in photon Stereotactic Body Radiation Therapy of lung tumors.

Robust optimization has been suggested as an approach to reduce the irradiated volume in lung Stereotactic Body Radiation Therapy (SBRT). We performed a retrospective planning study to investigate the potential benefits over Planning Target Volume (PTV)-based planning. Thirty-nine patients had additional plans using robust optimization with 5-mm isocenter shifts of the Gross Tumor Volume (GTV) created in addition to the PTV-based plan used for treatment. The optimization included the mid-position phase and the extreme breathing phases of the 4D-CT planning scan. The plans were compared for tumor coverage, isodose volumes, and doses to Organs At Risk (OAR). Additionally, we evaluated both plans with respect to observed tumor motion using the peak tumor motion seen on the planning scan and cone-beam CTs. Statistically significant reductions in irradiated isodose volumes and doses to OAR were achieved with robust optimization, while preserving tumor dose. The reductions were largest for the low-dose volumes and reductions up to 188 ccm was observed. The robust evaluation based on observed peak tumor motion showed comparable target doses between the two planning methods. Accumulated mean GTV-dose was increased by a median of 4.46 Gy and a non-significant increase of 100 Monitor Units (MU) was seen in the robust optimized plans. The robust plans required more time to prepare, and while it might not be a feasible planning strategy for all lung SBRT patients, we suggest it might be useful for selected patients.

A framework for the biophysical screening of antibody mutations targeting solvent-accessible hydrophobic and electrostatic patches for enhanced viscosity profiles

The formulation of high-concentration monoclonal antibody (mAb) solutions in low dose volumes for autoinjector devices poses challenges in manufacturability and patient administration due to elevated solution viscosity. Often many therapeutically potent mAbs are discovered, but their commercial development is stalled by unfavourable developability challenges. In this work, we present a systematic experimental framework for the computational screening of molecular descriptors to guide the design of 24 mutants with modified viscosity profiles accompanied by experimental evaluation. Our experimental observations using a model anti-IL8 mAb and eight engineered mutant variants reveal that viscosity reduction is influenced by the location of hydrophobic interactions, while targeting positively charged patches significantly increases viscosity in comparison to wild-type anti-IL-8 mAb. We conclude that most predicted in silico physicochemical properties exhibit poor correlation with measured experimental parameters for antibodies with suboptimal developability characteristics, emphasizing the need for comprehensive case-by-case evaluation of mAbs. This framework combining molecular design and triage via computational predictions with experimental evaluation aids the agile and rational design of mAbs with tailored solution viscosities, ensuring improved manufacturability and patient convenience in self-administration scenarios.

Interpretable deep learning insights: Unveiling the role of 1 Gy volume on lymphopenia after radiotherapy in breast cancer

BackgroundLymphopenia is known for its significance on poor survivals in breast cancer patients. Considering full dosimetric data, this study aimed to develop and validate predictive models for lymphopenia after radiotherapy (RT) in breast cancer. Material and methodsPatients with breast cancer treated with adjuvant RT were eligible in this multicenter study. The study endpoint was lympopenia, defined as the reduction in absolute lymphocytes and graded lymphopenia after RT. The dose-volume histogram (DVH) data of related critical structures and clinical factors were taken into account for the development of dense neural network (DNN) predictive models. The developed DNN models were validated using external patient cohorts. ResultsA total of 918 consecutive patients with invasive breast cancer enrolled. The training, testing, and external validating datasets consisted of 589, 203, and 126 patients, respectively. Treatment volumes at nearly all dose levels of the DVH were significant predictors for lymphopenia following RT, including volumes at very low-dose 1 Gy (V1) of organs at risk (OARs) including lung, heart and body, especially ipsilateral-lung V1. A final DNN model, combining full DVH dosimetric parameters of OARs and three key clinical factors, achieved a predictive accuracy of 75 % or higher. ConclusionThis study demonstrated and externally validated the significance of full dosimetric data, particularly the volume of low dose at as low as 1 Gy of critical structures on lymphopenia after radiation in patients with breast cancer. The significance of V1 deserves special attention, as modern VMAT RT technology often has a relatively high value of this parameter. Further study is warranted for RT plan optimization.

Minimizing normal tissue low dose bath for left breast Volumetric Modulated Arc Therapy (VMAT) using jaw offset.

With proper beam setup and optimization constraints in the treatment planning system, volumetric modulated arc therapy (VMAT) can improve target dose coverage and conformity while reducing doses to adjacent structures for whole breast radiation therapy. However, the low-dose bath effect on critical structures, especially the heart and the ipsilateral lung, remains a concern. In this study, we present a VMAT technique with the jaw offset VMAT (JO-VMAT) to reduce the leakage and scatter doses to critical structures for whole breast radiation therapy. The data of 10 left breast cancer patients were retrospectively used for this study. CT images were acquired on a CT scanner (GE, Discovery) with the deep-inspiration breath hold (DIBH) technique. The planning target volumes (PTVs) and the normal structures (the lungs, the heart, and the contralateral breast) were contoured on the DIBH scan. A 3D field-in-field plan (3D-FiF), a tangential VMAT (tVMAT) plan, and a JO-VMAT plan were created with the Eclipse treatment planning system. An arc treatment field with the x-jaw closed across the central axis creates a donut-shaped high-dose distribution and a cylinder-shaped low-dose volume along the central axis of gantry rotation. Applying this setup with proper multi-leaf collimator (MLC) modulation, the optimized plan potentially can provide sufficient target coverage and reduce unnecessary irradiation to critical structures. The JO-VMAT plans involve 5-6 tangential arcs (3 clockwise arcs and 2-3 counterclockwise arcs) with jaw offsets. The plans were optimized with objective functions specified to achieve PTV dose coverage and homogeneity; For organs at risk (OARs), objective functions were specified individually for each patient to accomplish the best achievable treatment plan. For tVMAT plans, optimization constraints were kept the same except that the jaw offset was removed from the initial beam setup. The dose volume histogram (DVH) parameters were generated for dosimetric evaluation of PTV and OARs. The D95% to the PTV was greater than the prescription dose of 42.56Gy for all the plans. With both VMAT techniques, the PTV conformity index (CI) was statistically improved from 0.62 (3D-FiF) to 0.83 for tVMAT and 0.84 for JO-VMAT plans. The difference in the homogeneity index (HI) was not significant. The Dmax to the heart was reduced from 12.15Gy for 3D-FiF to 8.26Gy for tVMAT and 7.20Gy for JO-VMAT plans. However, a low-dose bath effect was observed with tVMAT plans to all the critical structures including the lungs, the heart, and the contralateral breast. With JO-VMAT, the V5Gy and V2Gy of the heart were reduced by 32.7% and 15.4% compared to 3D-FiF plans. Significantly, the ipsilateral lung showed a reduction in mean dose (4.65-3.44Gy) and low dose parameters (23.4% reduction for V5Gy and 10.7% reduction for V2Gy) for JO-VMAT plans compared to the 3D-FiF plans. The V2Gy dose to the contralateral lung and breast was minimal with JO-VMAT techniques. A JO-VMAT technique was evaluated in this study and compared with 3D-FiF and tVMAT techniques. Our results showed that the JO-VMAT technique can achieve clinically comparable coverage and homogeneity and significantly improve dose conformity within PTV. Additionally, JO-VMAT eliminated the low-dose bath effect at all OARs evaluation metrics including the ipsilateral/contralateral lung, the heart, and the contralateral breast compared to 3D-FiF and tVMAT. This technique is feasible for the whole breast radiation therapy of left breast cancers.

Salvage Ablative Radiotherapy for Isolated Local Recurrence of Pancreatic Adenocarcinoma following Definitive Surgery.

Introduction: The rate of isolated locoregional recurrence after surgery for pancreatic adenocarcinoma (PDAC) approaches 25%. Ablative radiation therapy (A-RT) has improved outcomes for locally advanced disease in the primary setting. We sought to evaluate the outcomes of salvage A-RT for isolated locoregional recurrence and examine the relationship between subsequent patterns of failure, radiation dose, and treatment volume. Methods: We conducted a retrospective analysis of all consecutive participants who underwent A-RT for an isolated locoregional recurrence of PDAC after prior surgery at our institution between 2016 and 2021. Treatment consisted of ablative dose (BED10 98-100 Gy) to the gross disease with an additional prophylactic low dose (BED10 < 50 Gy), with the elective volume covering a 1.5 cm isotropic expansion around the gross disease and the circumference of the involved vessels. Local and locoregional failure (LF and LRF, respectively) estimated by the cumulative incidence function with competing risks, distant metastasis-free and overall survival (DMFS and OS, respectively) estimated by the Kaplan-Meier method, and toxicities scored by CTCAE v5.0 are reported. Location of recurrence was mapped to the dose region on the initial radiation plan. Results: Among 65 participants (of whom two had two A-RT courses), the median age was 67 (range 37-87) years, 36 (55%) were male, and 53 (82%) had undergone pancreaticoduodenectomy with a median disease-free interval to locoregional recurrence of 16 (range, 6-71) months. Twenty-seven participants (42%) received chemotherapy prior to A-RT. With a median follow-up of 35 months (95%CI, 26-56 months) from diagnosis of recurrence, 24-month OS and DMFS were 57% (95%CI, 46-72%) and 22% (95%CI, 14-37%), respectively, while 24-month cumulative incidence of in-field LF and total LRF were 28% (95%CI, 17-40%) and 36% (95%CI 24-48%), respectively. First failure after A-RT was distant in 35 patients (53.8%), locoregional in 12 patients (18.5%), and synchronous distant and locoregional in 10 patients (15.4%). Most locoregional failures occurred in elective low-dose volumes. Acute and chronic grade 3-4 toxicities were noted in 1 (1.5%) and 5 patients (7.5%), respectively. Conclusions: Salvage A-RT achieves favorable OS and local control outcomes in participants with an isolated locoregional recurrence of PDAC after surgical resection. Consideration should be given to extending high-dose fields to include adjacent segments of at-risk vessels beyond direct contact with the gross disease.

Utilizing collimated aperture with proton pencil beam scanning (PBS) for stereotactic radiotherapy.

Proton stereotactic radiosurgery (PSRS) has emerged as an innovative proton therapy modality aimed at achieving precise dose delivery with minimal impact on healthy tissues. This study explores the dosimetric outcomes of PSRS in comparison to traditional intensity-modulated proton therapy (IMPT) by focusing on cases with small target volumes. A custom-made aperture system designed for proton therapy, specifically tailored to small target volumes, was developed and implemented for this investigation. A prerequisite mechanical validation through an isocentricity test precedes dosimetric assessments, ensuring the seamless integration of mechanical and dosimetry analyses. Five patients were enrolled in the study, including two with choroid melanoma and three with arteriovenous malformations (AVM). Two treatment plans were meticulously executed for each patient, one utilizing a collimated aperture and the other without. Both plans were subjected to robust optimization, maintaining identical beam arrangements and consistent optimization parameters to account for setup errors of 2mm and range uncertainties of 3.5%. Plan evaluation metrics encompassing the Heterogeneity Index (HI), Paddick Conformity Index (CIPaddick), Gradient Index (GI), and the R50% index to evaluate alterations in low-dose volume distribution. The comparative analysis between PSRS and traditional PBS treatment revealed no significant differences in plan outcomes, with both modalities demonstrating comparable target coverage. However, collimated apertures resulted in discernible improvements in dose conformity, dose fall-off, and reduced low-dose volume. This study underscores the advantageous impact of the aperture system on proton therapy, particularly in cases involving small target volumes.

Assessment of minimum target dose as a predictor of local failure after spine SBRT

ObjectivesMetastasis-directed stereotactic body radiation therapy (SBRT) has demonstrated robust clinical benefits in carefully selected patients, improving local control and even overall survival (OS). We assess a large database to determine clinical and dosimetric predictors of local failure after spine SBRT. MethodsSpine SBRT treatments with imaging follow-up were identified. Patients were treated with a simultaneous integrated boost technique using 1 or 3 fractions, delivering 20–24 Gy in 1 fraction to the gross tumor volume (GTV) and 16 Gy to the low dose volume (or 27–36 Gy and 21–24 Gy for 3 fraction treatments). Exclusions included: lack of imaging follow-up, proton therapy, and benign primary histologies. Results522 eligible spine SBRT treatments (68 % single fraction) were identified in 377 unique patients. Patients had a median OS of 43.7 months (95 % confidence interval: 34.3–54.4). The cumulative incidence of local failure was 10.5 % (7.4–13.4) at 1 year and 16.3 % (12.6–19.9) at 2 years. Local control was maximized at 15.3 Gy minimum dose for single-fraction treatment (HR = 0.31, 95 % CI: 0.17 – 0.56, p < 0.0001) and confirmed via multivariable analyses. Cumulative incidence of local failure was 6.1 % (2.6–9.4) vs. 14.2 % (8.3–19.8) at 1 year using this cut-off, with comparable findings for minimum 14 Gy. Additionally, epidural and soft tissue involvement were predictive of local failure (HR = 1.77 and 2.30). ConclusionsSpine SBRT offers favorable local control; however, minimum dose to the GTV has a strong association with local control. Achieving GTV minimum dose of 14–15.3 Gy with single fraction SBRT is recommended whenever possible.

Comparison of photon energies and field techniques for ovarian dose reduction in volumetric modulated arc therapy

For fertility preservation in young female patients undergoing pelvic radiotherapy for cervical cancer, lateral ovarian transposition (LOT) is a procedure that moves the ovaries away from the radiation field. However, it is still challenging to fully protect the ovaries from radiation damage in volumetric modulated arc therapy (VMAT). In this study, we optimized VMAT techniques and simulated the effect of the LOT position on the ovarian dose. Ten cervical cancer patients who received pelvic radiotherapy after LOT were retrospectively analyzed. A restricted arc plus split field technique, which incorporated beam avoidance sectors, split field, fixed jaw, and orthogonal collimator orientation with 10 MV energy (rasf-10MV-VMAT), was designed to minimize the dose to the ovaries. This technique was compared with dual-arc conventional VMAT (dac-6MV-VMAT) and restricted arc and field VMAT (raf-6MV-VMAT) techniques with 6 MV energy. Ovarian dose, target coverage, and organs at risk (OAR) sparing were compared. The location of the ovaries in the anterior-posterior and superior-inferior directions was changed to simulate the effect of the LOT position on the ovarian dose. Compared to dac-6MV-VMAT and raf-6MV-VMAT, rasf-10MV-VMAT decreased the ovarian dose significantly more, especially for a low-dose volume. Both ovaries, received a 44.0–52.1 % lower volume of >3 Gy dose, and (0.5–1.9 Gy) lower maximum and mean doses with rasf-10MV-VMAT (p < 0.05). Rasf-10MV-VMAT also improved target conformity and coverage more than raf-6MV-VMAT (p < 0.05) and reduced the bladder mean dose more than dac-6MV-VMAT (p < 0.05). The ovarian dose decreased with the distance from the target contour, and placing the ovaries near the mid-frontal plane or as high as possible after the LOT lowered ovarian exposure. This technique, using 10 MV photon energy combined with field technique optimization, reduced the ovarian dose, particularly by decreasing the low-dose exposure of ovarian tissue and improving the target conformity simultaneously. The ovarian dose could be minimized by a proper LOT position. This optimized technique could enhance ovarian protection and fertility preservation for young female survivors of cervical cancer.

Effect of Jaw Tracking During Volumetric Modulated Arc Therapy for Facial Non-melanoma Skin Cancer.

This study aimed to analyze the dosimetric effects of jaw tracking during Volumetric Modulated Arc Therapy (VMAT) planning for facial non-melanoma skin cancer (NMSC). This study included 50 patients with facial NMSC who underwent VMAT planning with or without jaw tracking. The target volume (TV) included the primary skin lesion with a 1-cm margin around the surface and a depth of 4 mm. A total of 55 Gy in 20 fractions was prescribed, and the plans were considered acceptable if the TV was covered by 95-105% of the isodose curve. A dosimetric comparison was performed for the volumes of the low-dose regions, which were defined as <50% of the prescription dose (V10-50%). Target coverage was evaluated using the homogeneity index (HI) and conformity index (CI). The patients' mean TV was 5.137 cc (range=1.03-15.89 cc). Jaw tracking resulted in mean volume reduction rates of 3.9%, 6.6% 10.6% and 13.8% for V40%, V30%, V20%, and V10%, respectively (all p<0.001). The volume change in V50% between the two groups was 2.7% (p=0.006). No significant differences were observed in HI (p=0.449) or CI (p=0.127). The application of jaw tracking during VMAT for facial NMSC is associated with a significant reduction in the volume of low dose delivered in the radiation field (V10-50%), while maintaining target coverage. Future analyses should assess whether this volume difference affects treatment-related cosmetic outcomes.

Interpretable Deep Learning Identified the Significance of 1 Gy Volume on Lymphopenia after Radiotherapy in Breast Cancer

Lymphopenia is common after radiotherapy (RT) and is known for its significance on poor survival outcomes in patients with breast cancer. Previous work has demonstrated the significance of point dosimetric factors like the volume receiving 5 Gy. Considering the full dosimetric data together, this study aimed to develop and validate predictive models for lymphopenia after RT in breast cancer. Patients with breast cancer treated with radiation therapy in adjuvant setting and with complete dosimetric data were eligible. Combining dose-volume histogram (DVH) dosimetric and clinical factors, dense neural network (DNN) models were developed to predict both the reduction in lymphocyte counts and the graded lymphopenia in breast cancer patients after adjuvant RT. A Shapley additive explanation was applied to explain each feature's directional contributions. The generalization of DNN models was validated in both internal and independent external validation cohorts. P<0.05 was considered to be significant. A total of 928 consecutive patients with invasive breast cancer were eligible for this study. Treatment volumes of nearly all irradiation dose levels of DVH were significant predictors for lymphopenia after RT, including volumes at very low-dose 1 Gy (V1) of all structures considered including the lung, heart and body. DNN models using full DVH dosimetric and clinical factors were built and a simplified model was further established and validated in both internal and external validation cohorts. This simplified DNN AI model, combining full DVH dosimetric parameters of all OARs and five key clinical factors including baseline lymphocyte counts, tumor stage, RT technique, RT fields and RT fractionation, showed a predictive accuracy of 77% and above. This study demonstrated and externally validated the significance of an AI model of combining clinical and full dosimetric data, especially the volume of low dose at as low as 1 Gy of all critical structures on lymphopenia after RT in patients with breast cancer. The significance of V1 deserves special attention, as modern arc RT technology often has relatively high value of this parameter. Further study warranted for breast cancer RT plan optimization.

Assessment of Minimum Dose as a Strong Predictor of Local Failure after Spine SBRT

Stereotactic body radiation therapy (SBRT) has demonstrated robust clinical benefits in carefully selected patients, improving local control and even overall survival (OS). Even so, a wide range of dose-fractionation schemes are used in clinical practice. We seek to assess a large database to determine clinical and dosimetric predictors of local failure after spine SBRT. From a large institutional database, spine SBRT treatments with subsequent imaging follow-up to assess local control were identified. Patients were treated with a simultaneous integrated boost technique using 1 or 3 fractions, generally delivering 20-24 Gy in 1 fraction to the high dose volume and 16 Gy to the low dose volume (or 30-36 Gy and 24 Gy for 3 fraction treatments). Exclusions included: lack of imaging follow-up, proton therapy, and benign primary histologies. Statistical analyses included Cox proportional hazards analyses and the robust log-rank statistic for cut-point analysis. The cumulative incidence of local failure with death as a competing risk was considered as the primary endpoint. A total of 522 eligible spine SBRT treatments (68% single fraction) were identified in 377 unique patients. Patients had a median OS of 43.7 months (95% confidence interval: 34.3-54.4). The cumulative incidence of local failure was 19.3% (15.3-23.2) at 1 year and 25.6% (21.1-29.9) at 2 years. Univariate analysis identified that the minimum dose (normalized for the prescription dose) was a strong predictor of local failure (p = 0.0093). Among patients treated with a single fraction, statistical significance was maintained (p = 0.024). No other dosimetric factors were predictive of local failure. In a cut point analysis, the log-rank statistic was maximized at 15.8 Gy minimum dose for single-fraction treatment (HR = 0.51, 95% CI: 0.34 - 0.75, p = 0.0009). Cumulative incidence of local failure was 15.1% (9.8-20.2) vs. 24.7% (17.2-31.5) at 1 year using this cut-off. Comparable local control was demonstrated with a minimum dose of 14 Gy (HR = 0.57, 95%: 0.37 - 0.87, p = 0.009), with reduced local control with lower minimum doses. Among a range of clinical factors assessed, only epidural and soft tissue involvement were predictive of local failure (HR = 1.80 and 1.98, respectively). Multivariable analyses incorporating soft tissue involvement, epidural extension, and multilevel disease confirmed the 15.8 Gy cutoff for single fraction cases (HR = 0.58, 95% CI: 0.38-0.88, p = 0.011). Spine SBRT offers favorable local control using a range of dose-fractionation schemes; however, minimum dose has a strong association with local control, unlike any other dosimetric factors tested. Furthermore, statistical significance was maintained even when considering epidural extension and potential limitations from dose to the spinal cord. Our data suggests that the minimum dose should be prioritized during treatment planning, ideally to at least 14 - 15.8 Gy for single fraction.

Comparison of helical and TomoDirect techniques with simultaneous integrated boost in early breast cancer patients.

The aim of the study was to perform dosimetric comparisons of helical (H) and TomoDirect (TD) plans for whole-breast irradiation (WBI) with simultaneous integrated boost (SIB) in early-stage breast cancer patients undergoing breast conserving surgery. Fifty patients, 25 with left-side and 25 with right-side tumors, were determined for a treatment planning system for a total dose of 50.4Gy in 1.8Gy per fraction to WBI, with a SIB of 2.3Gy per fraction delivered to the tumor bed. The planning target volume (PTV) doses and the conformity (CI) and homogeneity indices (HI) for PTVbreast and PTVboost, as well as organ-at-risk (OAR) doses and treatment times, were compared between the H and TD plans. All plans met the PTV coverage criteria for the H plan, except for mean V107 of PTVbreast for TD plan. The H plan yielded better homogeneity and conformity of dose distribution compared to the TD plan. The ipsilateral mean lung doses were not significantly different between the two plans. The TD plans is advantageous for mean doses to the heart, contralateral breast and lung, spinal cord, and esophagus than the H plans. In both the H and TD plans, the right-sided breast patients had lower heart dose parameters than the left-sided breast patients. The TD plan is superior to the H plan in sparing the contralateral breast and lung by decreasing low-dose volumes. While the OAR dose advantages of TD are appealing, shorter treatment times or improved dose homogeneity and conformity for target volume may be advantageous for H plan.

Dosimetric comparison of irradiated small bowel volume with intensity modulated radiotherapy and volumetric modulated arc therapy in adjuvant pelvic radiation therapy for endometrial carcinoma

Newer treatment techniques help in reducing dose to small bowel (SB) which is an organ at risk (OAR) for pelvic radiotherapy (RT). However, instead of SB, bowel bag is contoured routinely and constraints are given. In this retrospective case series, we compared the dose received by SB while using intensity modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) techniques in patients receiving adjuvant pelvic RT for endometrial carcinoma. 10 patients with stage II EC who received VMAT were included in this single institution study. SB was contoured retrospectively in the planning computed tomography scan of these patients. An IMRT plan was also generated with a similar planning target volume coverage and organ at risk (OAR) constraints of the previously approved VMAT plan. Volume receiving 10 Gy, 20 Gy, 30 Gy, 40 Gy and 45 Gy of SB was analysed and a dosimetric comparison was made among the two plans. Anaylysis of variance (ANOVA) and unpaired t tests were used for dosimetric comparison. Mean SB volume receiving 10 Gy (V10 Gy) was 85.3% and 83.7% with IMRT and VMAT respectively. Mean SB volume receiving 45 Gy (V45 Gy) was 4.1% and 5% with IMRT and VMAT respectively. No statistically significant difference was noted in the low dose or high dose irradiated volume of SB using both techniques; however, the volume of SB getting irradiated in the absence of optimisation was found to be high in both the groups which can translate in to acute and late bowel toxicity. Further prospective studies have to be conducted to know the clinical significance of this dose-volume relationship to SB.

Bone marrow sparing in prostate cancer patients treated with Post-operative pelvic nodal radiotherapy – A proton versus photon comparison

PurposeExtending salvage radiotherapy to treat the pelvic lymph nodes (PLNRT) improves oncologic outcomes in prostate cancer (PCa). However, a larger treatment volume increases the extent of bone marrow (BM) exposure, which is associated with hematologic toxicity (HT). Given the potential long-term impact of BM dose in PCa, clinical studies on BM sparing (BMS) are warranted. Herein, we dosimetrically compared photon and proton plans for BMS. Materials and MethodsTreatment plans of 20 post-operative PCa patients treated with volumetric-modulated arc photon therapy (VMAT) PLNRT were retrospectively identified. Contours were added for the whole pelvis BM (WPBM) and BM sub-volumes: lumbar-sacral (LSBM), iliac (ILBM), and lower pelvis (LPBM). Three additional plans were created: VMAT_BMS, intensity-modulated proton therapy (IMPT), and IMPT_BMS. Normal tissue complication probabilities (NTCP) for grade >3 hematologic toxicity (HT3+) were calculated for the WPBM volumes. ResultsCompared to the original VMAT plan, mean doses to all BM sub-volumes were statistically significantly lower for VMAT_BMS, IMPT, and IMPT_BMS resulting in average NTCP percentages of 20.5 ± 5.9, 10.7 ± 4.2, 6.1 ± 2.0, and 2.5 ± 0.6, respectively. IMPT_BMS had significantly lower low dose metrics (V300cGy-V2000cGy) for WPBM and sub-volumes except for LPBM V2000cGy compared to VMAT_BMS and ILBM V20Gy compared to IMPT. In most cases, V4000cGy and V5000cGy within ILBM and LSBM were significantly higher for IMPT plans compared to VMAT plans. ConclusionsBMS plans are achievable with VMAT and IMPT without compromising target coverage or OARs constraints. IMPT plans were overall better at reducing mean and NTCP for HT3+ as well as low dose volumes to BM. However, IMPT had larger high dose volumes within LSBM and ILBM. Further studies are warranted to evaluate the clinical implications of these findings.

Dosimetric comparison of three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, and volumetric-modulated arc therapy for free-breathing whole-breast irradiation: A planning study.

Currently, recommended heart dose constraints are difficult to meet in whole-breast irradiation (WBI) for left-sided breast cancer patients, who cannot be treated with the deep inspiration breath hold. We performed a radiotherapy planning study to establish if the use of intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) allows for better sparing of the heart and its subvolumes than the three-dimensional conformal radiation therapy (3D-CRT), and how these attempts affect the dose delivered to the other organs. A total of 17 left-sided and 10 right-sided consecutive patients treated with free-breathing WBI were retrospectively included. The 3D-CRT, IMRT, and VMAT plans were generated. Several dose-volume parameters and plan quality indices were compared, separately for the left- and right-sided plans. All the techniques fulfilled the planning objectives. In the left-sided plans, there was no heart or left ventricle dose reduction with IMRT, nor with VMAT; the maximum dose in the left anterior descending coronary artery was reduced with VMAT (P = 0.005); V5 for the contralateral breast, contralateral lung, and total-body increased markedly in VMAT, and for the ipsilateral lung (V5IL) also in IMRT, compared with 3D-CRT (P < 0.001). In the right-sided plans, the V5 values, except for V5IL, did not differ between the three techniques. IMRT and VMAT had a limited heart-sparing benefit in the left-sided free-breathing WBI, at the cost of increased low-dose volumes, measured by V5. The low-dose volumes are not increased by IMRT or VMAT in the right-sided WBI, where heart sparing is not a problem, but the attempts to reduce cardiac doses in the left-sided WBI increase them.

Cross-irradiation in multiple isocenter frameless treatment for limited number of multiple brain metastases with volumetric modulated arc therapy

PurposeTo evaluate cross-irradiation among targets in multiple isocenter (multiISO) plans with simultaneous optimization for multiple brain metastases in frameless stereotactic radiotherapy. MethodsThree spherical targets separated by 3 cm were drawn on a brain CT image set. Volumetric modulated arc therapy (VMAT) plans consisting of single or two-arc beams were created using the multiISO method, in which partial arcs and selective couch angles were included to avoid cross-irradiation among the targets. Plans were evaluated using conformity index, dose volumes, and beam weight from cross-irradiation. Single isocenter (singleISO) plans were also produced and compared. The entire simulation was repeated for targets separated by 5 cm. A single patient case with two targets was also simulated for application. ResultsFor target distance of 3 cm, both the multiISO and singleISO plans with two beams were equivalent and favored based on the conformity index and dose volumes. The cross-irradiation was considerable and was not reduced effectively by partial arc or selective couch angles. With a 5- cm target distance, multiISO two-arc plans made of full or partial arc and selective couch angles were equivalent and adequate for treatment. The cross-irradiation was small and made negligible by partial arc or selective couch angles. The two-arc singleISO plan was acceptable but slightly inferior with respect to conformity index and low-dose volumes. ConclusionsMultiISO radiation treatment for multiple brain metastases was prone to cross-irradiation among targets, which led to target undercoverage from potential rotational error, though it was less than with the singleISO method. For the multiISO VMAT plan to be robust to rotational error, the plan should be designed with beams minimizing cross irradiation by incorporating a partial arc or selective couch angle to avoid irradiating neighboring targets, which is more effective for targets with greater separation.

A Dosimetric Comparison of Volumetric Modulated Arc Therapy and Intensity Modulated Radiotherapy in Patients Treated with Post-Mastectomy Radiotherapy.

Radiotherapy continues to play an important role in the management of breast cancer. This study compared the dosimetric differences between the techniques of intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) in breast cancer patients who had radiotherapy after mastectomy. Forty post-mastectomy patients (19 right-sided breast and 21 left-sided breast) treated with the IMRT technique using 7-9 fields who were re-planned with VMAT using 2 coplanar arc on the Varian Vital beam linear accelerator between January, 2020 and August, 2021 were included in this study. The patients received 42 Gy in 15 fractions to the chest wall, lymph nodes and supraclavicular nodes. The dosimetric parameter for planning target volume (PTV), organs at risk (OAR) and the integral dose to the body were analysed. Student's t-test for two independent means was used to analyse the dosimetric differences between the plans. Clinical goals were achieved for both techniques. In terms of PTV coverage at 95% (IMRT: 712.17±233) vs (VMAT: 694.9±214) and the homogeneity index (IMRT: 0.075±0.04) vs (VMAT: 0.104±0.03), IMRT resulted in better dose coverage and homogeneity than VMAT. However, with the conformity index, no significant difference was seen. As regards the OARs, the mean doses, V5, V10, V20, V30, and V40 for the Ipsilateral-lung were lower in IMRT plans than in VMAT plans with a non-significant variation (p-values = 0.141, 0.416, 0.954, 0.443, and 1 respectively). Regarding the mean dose to the heart, low-dose volumes V5, V10, and high-dose volume V30 were significantly reduced in IMRT compared to VMAT. When comparing the dose to the contralateral breast, IMRT achieved a significantly lower mean dose than VMAT (2.9 vs 3.62, p = 0.0148). For MU, VMAT showed lower MU compared to IMRT with a non-significant difference. With IMRT, better PTV coverage, homogeneity and OAR sparing were observed. Additionally, VMAT resulted in a lower delivery time than IMRT. Overall, both techniques offered dosimetric qualities that were clinically acceptable.

Radiation pneumonitis in relation to pulmonary function, dosimetric factors, TGFβ1 expression, and quality of life in breast cancer patients receiving post-operative radiotherapy: a prospective 6-month follow-up study.

To investigate development of radiation pneumonitis (RP) in relation to pulmonary function, dosimetric factors, and transforming growth factor beta-1 (TGFβ1) expression in irradiated breast cancer patients. A total of 49 breast cancer patients who received post-operative radiotherapy (RT) were evaluated in terms of pulmonary function tests (PFTs), quality of life (QoL), development of RP, dosimetric factors, cytokine levels, and lung high-resolution computed tomography (HRCT) before and after RT. ROC analysis was performed for performance of dosimetric factors in predicting RP, while frequencies of single nucleotide polymorphisms (SNPs) genotyped for TGFβ1 (rs11466345 and rs1800470) were also evaluated. All cases with RP (10.2%) recovered clinically at the end of third post-RT month. PFT and HRCT parameters were similar before and after RT overall, as well as by RP and the radiation field subgroups. ROC analysis revealed the significant role of the ipsilateral V5 (cutoff value of 45.9%, p = 0.039), V10 (29.4%, p = 0.015), V20 (23%, p = 0.017), and MLD (1200cGy, p = 0.030) in predicting RP. Higher post-RT TGFβ1 levels (p = 0.037) were noted overall and in patients with RP. Patient and control groups were similar in terms of frequencies of SNPs genotyped for TGFβ1 (rs11466345 and rs1800470). EORTC QLQ-C30 and QLQ-BR-23 scores were similar in patients with vs. without RP. Our findings revealed significant role of dosimetric factors including MLD, V20 as well as the low dose-volume metrics in predicting the risk of RP among breast cancer patients who received post-operative RT. Implementation of RT, extent of radiation field or the presence of RP had no significant impact on PFTs.