Heart Dose Research Articles

Proton Therapy for Bilateral Breast Cancer Maximizes Normal-Tissue Sparing.

Treatment for bilateral breast cancer with radiation therapy is technically challenging. We evaluated the clinical and dosimetric outcomes of a small series of patients with synchronous bilateral breast cancer, including a photon dosimetric comparison, to identify optimal treatment planning approaches. We reviewed a registry of patients (simultaneously) diagnosed with synchronous bilateral breast cancers who underwent postoperative definitive adjuvant proton therapy at our institution between 2012 and 2021. All patients were treated with double-scattered proton or pencil-beam scanning therapies. For comparison, intensity-modulated radiation therapy photon plans optimized for organ sparing and coverage were generated after treatment. Six patients were included. The median patient age was 66 years; all were female with no history of breast cancer or radiation therapy. Two (33%) patients received breast/chest wall-only treatments, 1 (17%) required breast plus level I axillary treatment to one side and breast plus regional nodal irradiation (RNI) to the other, and 3 (50%) received bilateral breast/chest plus RNI; dosimetric results are reported for each group's median. Analysis showed clinical target coverage was comparable between proton and photon techniques (V95% of 96.4% with proton, 97.8% with photon). However, protons could deliver superior organ sparing at clinically relevant dose metrics for virtually all structures: a 6.7 Gy absolute reduction in the mean heart dose (7.5 Gy with photons to 0.7 Gy with protons), a 47% to 57% relative reduction in D0.1cm3 to coronary arteries, a 54% relative reduction in lung V20 Gy, and an absolute 7.6 Gy reduction to the brachial plexus. There was also greater esophagus and spinal cord sparing. The overall survival rate was 100% at 1.5 years of median follow-up (0.5-4.9), and all patients were free of disease. For toxicity, all patients had some form of acute side effects: 66% experienced grade 2 breast/chest pain or soreness; 100% had grade 2 radiation dermatitis or skin induration; 33% had grade 2 fatigue; and 17% had grade 2 esophagitis (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5.0; US National Cancer Institute, Bethesda, Maryland). Subacute toxicity (within 6 months) was observed for 17% of patients with delayed onset of grade 3 dermatitis in the setting of preexisting lupus, 17% with a delayed surgical wound complication, and 17% with grade 2 soft tissue fibrosis. No grade 4 or 5 events were observed. Substantial dose reductions to multiple organs at risk while maintaining target coverage make proton the preferred modality for bilateral breast cancer treatment when available.

Abstract GS4-05: Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy

Abstract Purpose/Objectives: Proton therapy is under investigation in breast cancer as a strategy to reduce heart and lung exposure, which is associated with late cardiopulmonary adverse events and secondary malignancy. To date, studies investigating postmastectomy radiotherapy (PMRT) with protons have used conventional fractionation. We hypothesized that condensing treatment to 15 fractions would be safe based on evidence that breast cancer is more sensitive to higher dose fractions than surrounding normal tissues. Materials/Methods: We conducted a randomized non-inferiority phase II trial comparing conventional and hypofractionated proton PMRT with primary endpoint of 24-month complication rate (defined as grade 3 or higher late adverse events using CTCAE, v 4.0 and/or unplanned surgical intervention in patients undergoing mastectomy with reconstruction). With a 10% non-inferiority margin the study ensured 80% power and had a one sided-type I error rate of 0.05. Cardiotoxicity was assessed with serial transthoracic conventional and 2-dimensional speckle tracking echocardiography (2D-STE). Eligibility included age ≥ 18 years with non-inflammatory breast cancer resected by mastectomy with indications for PMRT. Assignment of treatments was balanced with respect to immediate breast reconstruction (IBR). Conventional fractionation group received 50 Gy in 25 fractions of 2 Gy, and hypofractionation group received 40.05 Gy in 15 fractions of 2.67 Gy (RBE 1.1). Target volume included the chest wall and axillary, supraclavicular, and internal mammary lymph nodes. All patients were treated with multi-field optimized pencil beam scanning (intensity modulated proton therapy). Results: Between 2016 and 2018, 82 patients were enrolled and randomized (41 conventional, 41 hypofractionation). Median patient age was 52 years. 32.9% were staged T3-T4 and 79.3% node positive at diagnosis. 57 of 82 patients (69.5%) elected IBR. The median mean heart dose was 0.49 Gy and the median ipsilateral lung volume receiving 40% of prescription or greater (V40%) was 13.6%. No significant changes on conventional or 2D-STE at end-of-treatment or 3-month follow-up compared to baseline were observed. The rate of ≥ grade 2 acute dermatitis was lower with hypofractionation (44% vs 15%, p = 0.006). Other ≥ grade 2 acute adverse events including esophagitis (0 vs 5%), infection (5% vs 2.4%) and skin hyperpigmentation (7.3% vs 4.8%) were not significantly different between the two arms. With a median follow-up of 38.3 months, the 24-month complication rate was conventional 14.6% vs hypofractionation 17.1% (absolute difference 2.4%, p=0.17, 95% CI [-, 15.7%]). In patients with IBR, 6 of 28 (21.4%) conventional and 7 of 29 (24.1%) hypofractionated patients developed complications (p =0.80). There was no significant difference in 3-year disease-free survival between the conventional (89.4%; 95% CI 80.0 – 99.8%) and hypofractionated (92.4%, 95% CI 84.5 – 100.0%) arms (p = 0.91). One local recurrence occurred in the hypofractionated arm simultaneous with regional and distant relapse. The remaining 6 recurrences were isolated distant events. Conclusions: Proton PMRT provided excellent locoregional control and normal tissue sparing. There were no subclinical echocardiographic changes indicative of radiation-induced cardiac dysfunction. Hypofractionation resulted in comparable disease control, tolerability and reconstruction outcomes as conventional fractionation. Although non-inferiority of hypofractionation could not be established based on the upper bound of the 95% confidence interval for complication rate being greater than 10%, both conventional and hypofractionation may be considered appropriate regimens for ongoing phase 3 randomized trials comparing photon and proton radiotherapy. Citation Format: Robert Mutter, Sharmila Giri, Briant Fruth, Nicholas Remmes, Aman Anand, Kathryn Ruddy, Hector Villarraga, Sebastian Santos Patarroyo, Elizabeth Yan, Kenneth Merrell, Lisa McGee, Tamara Vern-Gross, Bradley Stish, Robert Gao, Judy C. Boughey, Sean Park, Kimberly Corbin, Carlos Vargas. Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-05.

Death without progression as an endpoint to describe cardiac radiation effects in locally advanced non-small cell lung cancer.

Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0-2; n=66), CCI intermediate (3-4; n=78), and CCI high (≥5; n=43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Median follow-up was 7.3years for survivors. Death occurred in 143 patients (76.5%), including death after progression in 118 (63.1%) and DWP in 25 (13.4%). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose≥10Gy vs<10Gy, DWP was higher (5-year rate, 16.9% vs 6.7%, p=0.04) and OS worse (median, 22.9 vs 34.1months, p<0.001). Ventricle (left, right, and bilateral) and pericardial but not atrial substructure dose were associated with DWP, whereas all three were inversely associated with OS. Cutpoint analysis identified right ventricle mean dose≥5.5Gy as a predictor of DWP. In the external cohort, we confirmed an association of ventricle, but not atrial, dose with DWP. Cardiovascular substructure dose showed distinct associations with DWP. Future cardiotoxicity studies in NSCLC could consider DWP as an endpoint.

Low doses to the heart in daily practice for treating left-sided breast cancer using accelerated partial-breast irradiation by multicatheter brachytherapy and deep-inspiration breath-hold using a SIB

PurposeThe aim of this study was to analyze the heart dose for left-sided breast cancer that can be achieved during daily practice in patients treated with multicatheter brachytherapy (MCBT) accelerated partial-breast irradiation (APBI) and deep-inspiration breath-hold (DIBH) whole-breast irradiation (WBI) using a simultaneous integrated tumor bed boost (SIB)—two different concepts which nonetheless share some patient overlap.Materials and methodsWe analyzed the nominal average dose (Dmean) to the heart as well as the biologically effective dose (BED) and the equivalent dose in 2‑Gy fractions (EQD2) for an α/β of 3 in 30 MCBT-APBI patients and 22 patients treated with DIBH plus SIB. For further dosimetric comparison, we contoured the breast planning target volume (PTV) in each of the brachytherapy planning CTs according to the ESTRO guidelines and computed tangential field plans. Mean dose (Dmean), EQD2 Dmean, and BED Dmean for three dosing schemes were calculated: 50 Gy/25 fractions and two hypofractionated regimens, i.e., 40.05 Gy/15 fractions and 26 Gy/5 fractions. Furthermore, we calculated tangential field plans without a boost for the 22 cases treated with SIB with the standard dosing scheme of 40.05 Gy/15 fractions.ResultsMCBT and DIBH radiation therapy both show low-dose exposure of the heart. As expected, hypofractionation leads to sparing of the heart dose. Although MCBT plans were not optimized regarding dose to the heart, Dmean differed significantly between MCBT and DIBH (1.28 Gy vs. 1.91 Gy, p < 0.001) in favor of MCBT, even if the Dmean in each group was very low. In MCBT radiation, the PTV–heart distance is significantly associated with the dose to the heart (p < 0.001), but it is not in DIBH radiotherapy using SIB.ConclusionIn daily practice, both DIBH radiation therapy as well as MCBT show a very low heart exposure and may thus reduce long term cardiac morbidity as compared to currently available long-term clinical data of patients treated with conventional tangential field plans in free breathing. Our analysis confirms particularly good cardiac sparing with MCBT-APBI, so that this technique should be offered to patients with left-sided breast cancer if the tumor-associated eligibility criteria are fulfilled.

Leveraging intelligent optimization for automated, cardiac-sparing accelerated partial breast treatment planning.

Accelerated partial breast irradiation (APBI) yields similar rates of recurrence and cosmetic outcomes as compared to whole breast radiation therapy (RT) when patients and treatment techniques are appropriately selected. APBI combined with stereotactic body radiation therapy (SBRT) is a promising technique for precisely delivering high levels of radiation while avoiding uninvolved breast tissue. Here we investigate the feasibility of automatically generating high quality APBI plans in the Ethos adaptive workspace with a specific emphasis on sparing the heart. Nine patients (10 target volumes) were utilized to iteratively tune an Ethos APBI planning template for automatic plan generation. Twenty patients previously treated on a TrueBeam Edge accelerator were then automatically replanned using this template without manual intervention or reoptimization. The unbiased validation cohort Ethos plans were benchmarked via adherence to planning objectives, a comparison of DVH and quality indices against the clinical Edge plans, and qualitative reviews by two board-certified radiation oncologists. 85% (17/20) of automated validation cohort plans met all planning objectives; three plans did not achieve the contralateral lung V1.5Gy objective, but all other objectives were achieved. Compared to the Eclipse generated plans, the proposed Ethos template generated plans with greater evaluation planning target volume (PTV_Eval) V100% coverage (p = 0.01), significantly decreased heart V1.5Gy (p< 0.001), and increased contralateral breast V5Gy, skin D0.01cc, and RTOG conformity index (p = 0.03, p = 0.03, and p = 0.01, respectively). However, only the reduction in heart dose was significant after correcting for multiple testing. Physicist-selected plans were deemed clinically acceptable without modification for 75% and 90% of plans by physicians A and B, respectively. Physicians A and B scored at least one automatically generated plan as clinically acceptable for 100% and 95% of planning intents, respectively. Standard left- and right-sided planning templates automatically generated APBI plans of comparable quality to manually generated plans treated on a stereotactic linear accelerator, with a significant reduction in heart dose compared to Eclipse generated plans. The methods presented in this work elucidate an approach for generating automated, cardiac-sparing APBI treatment plans for daily adaptive RT with high efficiency.

Correlation of Mean Heart Dose and Cardiac Biomarkers with Electrocardiographic Changes in Patients Receiving Thoracic Radiation Therapy.

Cardiotoxicity is a well-recognized, serious adverse effect of thoracic radiation therapy. This study aimed to evaluate longitudinal electrocardiogram (ECG) changes in patients receiving thoracic radiation therapy and identify correlating factors that can predict the risk of cardiotoxicity. This retrospective study included 202 patients treated with thoracic radiation therapy, and chemotherapy and targeted therapy were allowed. Mean heart dose (MHD) was evaluated on dose-volume histograms. ECG, high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal B-type natriuretic peptide (NT-proBNP) analyses were conducted before irradiation and during the follow-up period of 6-12 months (average 8 months). Chi square test and logistic regression analysis were applied to identify risk factors associated with ECG changes. At a median time of 3 months postirradiation, 46.5% of patients showed ECG changes, and 33.0% of patients achieved baseline ECG levels during the follow-up period at a median of 5 months postirradiation. Logistic regression analysis identified MHD, hs-cTnT and NT-pro BNP as significant factors associated with ECG changes (P < 0.05). Hs-cTnT and NT-proBNP were increased significantly after radiation therapy compared with baseline levels (P < 0.05), and these increases were observed as a median time of 2 months postirradiation, which was earlier than ECG changes. Higher MHD and elevated hs-cTnT and NT-proBNP levels correlated with an increased risk of ECG changes in patients receiving thoracic radiation therapy. Early identification of patients at high risk of cardiotoxicity and timely intervention might reduce the incidence of radiation-induced cardiac toxicity.

Cardiac and Pulmonary Dosimetric Parameters in Patients With Lung Cancer Undergoing Postoperative Radiation Therapy Across a Statewide Consortium

The recently published Lung Adjuvant Radiotherapy Trial (Lung ART) reported increased rates of cardiac and pulmonary toxic effects in the postoperative radiation therapy (PORT) arm. It remains unknown whether the dosimetric parameters reported in Lung ART are representative of contemporary real-world practice, which remains relevant for patients undergoing PORT for positive surgical margins. The purpose of this study was to examine heart and lung dose exposure in patients receiving PORT for non-small cell lung cancer across a statewide consortium. From 2012 to 2022, demographic and dosimetric data were prospectively collected for 377 patients at 27 academic and community centers within the Michigan Radiation Oncology Quality Consortium undergoing PORT for nonmetastatic non-small cell lung cancer. Dosimetric parameters for target coverage and organ-at-risk exposure were calculated using data from dose-volume histograms, and rates of 3-dimensional conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) utilization were assessed. Fifty-one percent of patients in this cohort had N2 disease at the time of surgery, and 25% had a positive margin. Sixty-six percent of patients were treated with IMRT compared with 32% with 3D-CRT. The planning target volume was significantly smaller in patients treated with 3D-CRT (149.2 vs 265.4 cm3; P < .0001). The median mean heart dose for all patients was 8.7 Gy (interquartile range [IQR], 3.5-15.3 Gy), the median heart volume receiving at least 5 Gy (V5) was 35.2% (IQR, 18.5%-60.2%), and the median heart volume receiving at least 35 Gy (V35) was 9% (IQR, 3.2%-17.7%). The median mean lung dose was 11.4 Gy (IQR, 8.1-14.3 Gy), and the median lung volume receiving at least 20 Gy (V20) was 19.6% (IQR, 12.7%-25.4%). These dosimetric parameters did not significantly differ by treatment modality (IMRT vs 3D-CRT) or in patients with positive versus negative surgical margins. With increased rates of IMRT use, cardiac and lung dosimetric parameters in this statewide consortium were slightly lower than those reported in Lung ART. These data provide useful benchmarks for treatment planning in patients undergoing PORT for positive surgical margins.

An integrated solution of deep reinforcement learning for automatic IMRT treatment planning in non-small-cell lung cancer.

To develop and evaluate an integrated solution for automatic intensity-modulated radiation therapy (IMRT) planning in non-small-cell lung cancer (NSCLC) cases. A novel algorithm named as multi-objectives adjustment policy network (MOAPN) was proposed and trained to learn how to adjust multiple optimization objectives in commercial Eclipse treatment planning system (TPS), based on the multi-agent deep reinforcement learning (DRL) scheme. Furthermore, a three-dimensional (3D) dose prediction module was developed to generate the patient-specific initial optimization objectives to reduce the overall exploration space during MOAPN training. 114 previously treated NSCLC cases suitable for stereotactic body radiotherapy (SBRT) were selected from the clinical database. 87 cases were used for the model training, and the remaining 27 cases for evaluating the feasibility and effectiveness of MOAPN in automatic treatment planning. For all tested cases, the average number of adjustment steps was 21 ± 5.9 (mean ± 1 standard deviation). Compared with the MOAPN initial plans, the actual dose of chest wall, spinal cord, heart, lung (affected side), esophagus and bronchus in the MOAPN final plans reduced by 14.5%, 11.6%, 4.7%, 16.7%, 1.6% and 7.7%, respectively. The dose result of OARs in the MOAPN final plans was similar to those in the clinical plans. The complete automatic treatment plan for a new case was generated based on the integrated solution, with about 5-6min. We successfully developed an integrated solution for automatic treatment planning. Using the 3D dose prediction module to obtain the patient-specific optimization objectives, MOAPN formed action-value policy can simultaneously adjust multiple objectives to obtain a high-quality plan in a shorter time. This integrated solution contributes to improving the efficiency of the overall planning workflow and reducing the variation of plan quality in different regions and treatment centers. Although improvement is warranted, this proof-of-concept study has demonstrated the feasibility of this integrated solution in automatic treatment planning based on the Eclipse TPS.

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.

Robustness of VMAT to setup errors in postmastectomy radiotherapy of left-sided breast cancer: Impact of bolus thickness.

Volumetric modulated arc therapy (VMAT) with varied bolus thicknesses has been employed in postmastectomy radiotherapy (PMRT) of breast cancer to improve superficial target coverage. However, impact of bolus thickness on plan robustness remains unclear. The study enrolled ten patients with left-sided breast cancer who received radiotherapy using VMAT with 5 mm and 10 mm bolus (VMAT-5B and VMAT-10B). Inter-fractional setup errors were simulated by introducing a 3 mm shift to isocenter of the original plans in the anterior-posterior, left-right, and inferior-superior directions. The plans (perturbed plans) were recalculated without changing other parameters. Dose volume histograms (DVH) were collected for plan evaluation. Absolute dose differences in DVH endpoints for the clinical target volume (CTV), heart, and left lung between the perturbed plans and the original ones were used for robustness analysis. VMAT-10B showed better target coverage, while VMAT-5B was superior in organs-at-risk (OARs) sparing. As expected, small setup errors of 3 mm could induce dose fluctuations in CTV and OARs. The differences in CTV were small in VMAT-5B, with a maximum difference of -1.05 Gy for the posterior shifts. For VMAT-10B, isocenter shifts in the posterior and right directions significantly decreased CTV coverage. The differences were -1.69 Gy, -1.48 Gy and -1.99 Gy, -1.69 Gy for ΔD95% and ΔD98%, respectively. Regarding the OARs, only isocenter shifts in the posterior, right, and inferior directions increased dose to the left lung and the heart. Differences in VMAT-10B were milder than those in VMAT-5B. Specifically, mean heart dose were increased by 0.42 Gy (range 0.10 ~ 0.95 Gy) and 0.20 Gy (range -0.11 ~ 0.72 Gy), and mean dose for the left lung were increased by 1.02 Gy (range 0.79 ~ 1.18 Gy) and 0.68 Gy (range 0.47 ~ 0.84 Gy) in VMAT-5B and VMAT-10B, respectively. High-dose volumes in the organs were increased by approximate 0 ~ 2 and 1 ~ 3 percentage points, respectively. Nevertheless, most of the dosimetric parameters in the perturbed plans were still clinically acceptable. VMAT-5B appears to be more robust to 3 mm setup errors than VMAT-10B. VMAT-5B also resulted in better OARs sparing with acceptable target coverage and dose homogeneity. Therefore 5 mm bolus is recommended for PMRT of left-sided breast cancer using VMAT.

Different meaning of the mean heart dose between 3D-CRT and IMRT for breast cancer radiotherapy.

Previous studies in 2D and in 3D conformal radiotherapy concludes that the maximal heart distance and the mean heart dose (MHD) are considered predictive of late cardiac toxicities. As the use of inverse-planned intensity modulated radiation therapy (IMRT) is increasing worldwide, we hypothesized that this 3D MHD might not be representative of heart exposure after IMRT for breast cancer (BC). Patients with left-sided BC and unfavorable cardiac anatomy received IMRT. Their treatment plan was compared to a virtual treatment plan for 3D conformal radiotherapy with similar target volume coverage (study A). Then, a second 3D conformal treatment plan was generated to achieve equivalent individual MHD obtained by IMRT. Then the heart and left anterior descending (LAD) coronary artery exposures were analyzed (study B). Last, the relationship between MHD and the heart volume or LAD coronary artery volume receiving at least 30Gy, 40Gy and 45Gy in function of each additional 1Gy to the MHD was assessed (study C). A significant decrease of heart and LAD coronary artery exposure to high dose was observed with the IMRT compared with the 3D conformal radiotherapy plans that both ensured adequate target coverage (study A). The results of study B and C showed that 3D MHD was not representative of similar heart substructure exposure with IMRT, especially in the case of high dose exposure. The mean heart dose is not a representative dosimetric parameter to assess heart exposure following IMRT. Equivalent MHD values following IMRT and 3DRT BC treatment do not represent the same dose distribution leading to extreme caution when using this parameter for IMRT plan validation.

The risk of valvular heart disease in the French Childhood Cancer Survivors’ Study: Contribution of dose-volume histogram parameters

Background and purposeValvular Heart Disease (VHD) is a known complication of childhood cancer after radiotherapy treatment. However, the dose-volume-effect relationships have not been fully explored. Materials and methodsWe obtained individual heart Dose Volume Histograms (DVH) for survivors of the French Childhood Cancer Survivors Study (FCCSS) who had received radiotherapy. We calculated the Mean Dose to the Heart (MHD) in Gy, as well as the heart DVH parameters (Vd Gy, which represents the percentage of heart volume receiving at least d Gy), fixing the thresholds to 0.1 Gy, 5 Gy, 20 Gy, and 40 Gy. We analyzed them furtherly in the subpopulation of the cohort that was treated with a dose lower than 5 Gy (V0.1Gy|V5Gy=0%), 20 Gy (V5Gy|V20Gy=0%), and 40 Gy (V20Gy|V40Gy=0%), respectively. We investigated their role in the occurrence of a VHD in this population-based observational cohort study using the Cox proportional hazard model, adjusting for age at cancer diagnosis and chemotherapy exposure. ResultsMedian follow-up was 30.6 years. Eighty-one patients out of the 7462 (1 %) with complete data experienced a severe VHD (grade ≥ 3). The risk of VHD increased along with the MHD, and it was associated with high doses to the heart (V40Gy < 50 %, hazard ratio (HR) = 7.96, 95 % CI: 4.26–14.88 and V20Gy|V40Gy=0% >50 %, HR = 5.03, 95 % CI: [2.35–10.76]). Doses 5–20 Gy to more than 50 % (V5Gy|V20Gy=0% >50 %) of the heart induced a marginally non-significant estimated risk. We also observed a remarkable risk increase with attained age. ConclusionsOur results provide new insight into the VHD risk that may impact current treatments and long-term follow-up of childhood cancer survivors.

Radiation dose to heart and cardiac substructures and risk of coronary artery disease in early breast cancer patients: A DBCG study based on modern radiation therapy techniques

BackgroundCoronary artery disease (CAD) has been reported as a late effect following radiation therapy (RT) of early breast cancer (BC). This study aims to report individual RT doses to the heart and cardiac substructures in patients treated with CT-based RT and to investigate if a dose–response relationship between RT dose and CAD exists using modern radiation therapy techniques. MethodsPatients registered in the Danish Breast Cancer Group database from 2005 to 2016 with CT-based RT were eligible. Among 15,765 patients, the study included 204 with CAD after irradiation (cases) and 408 matched controls. Individual planning CTs were retrieved, the heart and cardiac substructures were delineated and dose-volume parameters were extracted. ResultsThe median follow-up time was 7.3 years (IQR: 4.6–10.0). Among cases, the median mean heart dose was 1.6 Gy (IQR 0.2–6.1) and 0.8 Gy (0.1–2.9) for left-sided and right-sided patients, respectively (p < 0.001). The highest RT doses were observed in the left ventricle and left anterior descending coronary artery for left-sided RT and in the right atrium and the right coronary artery after right-sided RT. The highest left-minus-right dose-difference was located in the distal part of the left anterior descending coronary artery where also the highest left-versus-right ratio of events was observed. However, no significant difference in the distribution of CAD was observed by laterality. Furthermore, no significant differences in the dose-volume parameters were observed for cases versus controls. ConclusionsCAD tended to occur in the part of the heart with the highest left-minus- right dose difference, however, no significant risk of CAD was observed at 7 years' median follow-up.

Cardiac toxicity in patients with lung cancer receiving thoracic radiotherapy and immunotherapy.

Immune checkpoint inhibitors (ICIs) are used to treat locally-advanced and metastatic lung cancer, which can lead to severe immunogenic-related cardiotoxicities. We assessed the risk of cardiotoxicity in ICI-treated lung cancer patients with or without cardiac radiation from thoracic radiotherapy. Retrospective data was collected on Stage III-IV lung cancer patients who received ICIs between 2015 and 2018. All cardiotoxicities associated with ICI were assessed in correlation with the timing of radiotherapy (RT) in relation to ICI, and the mean RT heart dose. The rate of cardiac events in relation to RT timing and heart dose was compared using multiple logistic regression including the Framingham risk score and steroid use prior to ICI therapy. Of 194 ICI-treated patients evaluated, 55.2% (n=107/194) patients had received thoracic RT at a median dose of 60.4 Gy (range, 15-75). Cardiotoxicities such as non-ST elevated myocardial infarction and new onset supraventricular tachycardias were observed in 13 (12.2%) of those who had thoracic RT versus 9 (10.3%) who did not (p=0.87). 38 patients who received RT concurrently with ICI did not develop any cardiotoxicity whereas 14.1% (n=22/156) of those who did not receive concurrent RT developed cardiotoxicities (univariate, p=0.030; multivariate, p=0.055). There were no significant differences in the mean heart RT dose, Framingham risk score, and steroid treatment between patients that received concurrent RT with ICI versus non-concurrent RT/ICI. ICI-related cardiotoxicities were not significantly associated with patients who received concurrent thoracic radiotherapy in this retrospective review. Further validation of prospective studies is needed to confirm these results.

Dose and organ displacement comparisons with breast conservative radiotherapy using abdominal and thoracic deep-inspiration breath-holds: A comparative dosimetric study.

Deep-inspiration breath-hold (DIBH) reduces the radiation dose to the heart and lungs during breast radiotherapy in cancer. However, there is not enough discussion about suitable breathing methods for DIBH. Therefore, we investigated the radiation doses and organ and body surface displacement in abdominal DIBH (A-DIBH) and thoracic DIBH (T-DIBH). Free-breathing, A-DIBH, and T-DIBH computed tomography images of 100 patients were used. After contouring the targets, heart, and lungs, radiotherapy plans were created. We investigated the heart and lung doses, the associations between the heart and left lung displacements, and the thorax and abdominal surface displacements. No significant differences were observed in the target dose indices. However, the heart and lung doses were significantly lower in A-DIBH than in T-DIBH for all the indices; the mean heart and lung doses were 1.69 and 3.48 Gy, and 1.91 and 3.55 Gy in A-DIBH and T-DIBH, respectively. The inferior displacement of the heart and the left lung was more significant in A-DIBH. Therefore, inferior expansion of the heart and lungs may be responsible for the respective dose reductions. The abdominal surface displaced more than the thoracic surface in both A-DIBH and T-DIBH, and thoracic surface displacement was greater in T-DIBH than in A-DIBH. Moreover, A-DIBH can be identified because abdominal surface displacement was greater in A-DIBH than in T-DIBH. In conclusion, A-DIBH and T-DIBH could be distinguished by comparing the abdominal and thoracic surfaces of A-DIBH and T-DIBH, thereby ensuring the implementation of A-DIBH and reducing the heart and lung doses.

Institutional experience of using active breathing control for paediatric and teenage patients receiving thoraco-abdominal radiotherapy

IntroductionActive Breathing Control (ABC) is a motion management strategy that facilitates reproducible breath-hold for thoracic radiotherapy (RT), which may reduce radiation dose to organs at risk (OARs). Reduction of radiation-induced toxicity is of high importance in younger patients. However, there is little published literature on the feasibility of ABC in this group. The purpose of this study was to report our experience of using ABC for paediatric and teenage patients. MethodsPatients ≤18 years referred for thoracic RT using ABC at our centre from 2013–2021 were identified. Electronic records were retrospectively reviewed to obtain information on diagnosis, RT dose and technique, OAR dosimetry, tolerability of ABC, post-treatment imaging and early toxicity rates. Results12 patients completed RT and were able to comply with ABC during planning and for the duration of RT. Median age was 15.5 years (10–18 years). Diagnoses were: Hodgkin lymphoma (n = 5), mediastinal B-cell lymphoma (n = 1), Ewing sarcoma (n = 5) and rhabdomyosarcoma (n = 1). For mediastinal RT cases (n = 6), median dose delivered was 30.6Gy(19.8–40Gy), median mean heart dose was 11.4Gy(4.8–19.4Gy), median mean lung dose was 9.9Gy(5.7–14.5Gy) and mean lung V20 was 10.9%. For ipsilateral RT cases, (n = 6), median hemithorax and total doses to primary tumour were 18Gy(15–20Gy) and 52.2Gy(36–60Gy) respectively. Median mean heart dose was 19.5Gy(10.6–33.2Gy) and median mean lung dose was 17.7Gy(16.3–30.5Gy). Mean bilateral lung V20 was 39.6%. Median mean contralateral lung dose was 5.2Gy(3.5–11.6Gy) and mean contralateral lung V20 was 1.5%. At a median follow-up of 36 months, only 1 patient had symptomatic radiation pneumonitis having received further thoracic RT following relapse. ConclusionsABC is feasible and well tolerated in younger patients receiving RT. Children as young as 10 years are able to comply. Use of ABC results in OAR dosimetry which is comparable to similar data in adults and can facilitate RT for extensive thoracic sarcoma

Dosimetric Comparision of Coplanar versus Noncoplanar Volumetric Modulated Arc Therapy for Treatment of Bilateral Breast Cancers.

The purpose of this study was to compare the dosimetric parameters of volumetric modulated arc therapy (VMAT) treatment plans using coplanar and noncoplanar beams in patients with bilateral breast cancer/s (BBCs) in terms of organ at risk sparing and target volume coverage. The hypothesis was to test whether VMAT with noncoplanar beams can result in lesser dose delivery to critical organs such as heart and lung, which will result in lesser overall toxicity. Data of nine BBC cases treated at our hospital were retrieved. Computed tomography simulation data of these cases was used to generate noncoplanar VMAT plans and the parameters were compared with standard VMAT coplanar plans. Contouring was done using radiation therapy oncology group guidelines. Forty-five Gray in 25 fractions was planned followed by 10 Gy in five fractions boost in breast conservation cases. No significant difference in planning target volume (PTV) coverage was found for the right breast/chestwall (P = 0.940), left breast/chestwall (P = 0.872), and in the total PTV (P = 0.929). Noncoplanar beams resulted in better cardiac sparing in terms of Dmean heart. The difference in mean dose was >1 Gy (8.80 ± 0.28 - 7.28 ± 0.33, P < 0.001). The Dmean, V20 and V30 values for total lung slightly favor noncoplanar beams, although there was no statistically significant difference. The average monitor units (MUs) were similar for coplanar plans (1515 MU) and noncoplanar plans (1455 MU), but the overall treatment time was higher in noncoplanar plans due to more complex setup and beam arrangement. For noncoplanar VMAT plans, the mean conformity index was slightly better although the homogeneity indices were similar. VMAT plans with noncoplanar beam arrangements had significant dosimetric advantages in terms of sparing of critical organs, that is Dmean of heart doses with almost equivalent lung doses and equally good target coverage. Larger studies with clinical implications need to be considered to validate this data.

Predicted cardiac and second cancer risks for patients undergoing VMAT for mediastinal Hodgkin lymphoma

Background and purposeTo predict treatment-related cardiovascular disease (CVD) and second cancer 30-year absolute mortality risks (AMR30) for patients with mediastinal Hodgkin lymphoma in a large multicentre radiation oncology network in Ireland.Material and methodsThis study includes consecutive patients treated for mediastinal lymphoma using chemotherapy and involved site radiotherapy (RT) 2016–2019. Radiation doses to heart, left ventricle, cardiac valves, lungs, oesophagus, carotid arteries and female breasts were calculated. Individual CVD and second cancer AMR30 were predicted using Irish background population rates and dose–response relationships.ResultsForty-four patients with Hodgkin lymphoma were identified, 23 females, median age 28 years. Ninety-eight percent received anthracycline, 80% received 4–6 cycles ABVD. Volumetric modulated arc therapy (VMAT) ± deep inspiration breath hold (DIBH) was delivered, median total prescribed dose 30 Gy. Average mean heart dose 9.8 Gy (range 0.2–23.8 Gy). Excess treatment-related mean AMR30 from CVD was 2.18% (0.79, 0.90, 0.01, 0.13 and 0.35% for coronary disease, heart failure, valvular disease, stroke and other cardiac diseases), 1.07% due to chemotherapy and a further 1.11% from RT. Excess mean AMR30 for second cancers following RT were: lung cancer 2.20%, breast cancer in females 0.34%, and oesophageal cancer 0.28%.ConclusionFor patients with mediastinal lymphoma excess mortality risks from CVD and second cancers remain clinically significant despite contemporary chemotherapy and photon-RT. Efforts to reduce the toxicity of combined modality treatment, for example, using DIBH, reduced margins and advanced RT, e.g. proton beam therapy, should be continued to further reduce potentially fatal treatment effects.

Hypofractionated radiotherapy in postmastectomy locally advanced breast cancer: an interim report on acute toxicities and dosimetry.

There is a growing interest in the use of hypofractionation in the setting of post-mastectomy radiation therapy (PMRT). Here, we present an interim report on the acute toxicities and the dosimetry of a 15-day hypofractionated regimen. Patients aged 18-75 years who underwent mastectomy and had pathological stage IIB-IIIC or any clinical stage who had received neoadjuvant chemotherapy were treated with PMRT at a dose of 43.5 Gy in 15 fractions. Acute toxicities were scored using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Between September 2020 and September 2021, 92 patients were enrolled in the study. Majority experienced grade 1 dermatitis during the course of treatment. Skin toxicities peaked two weeks after PMRT in which 57 patients (62%) had grade 2 dermatitis and 6 patients (7%) had grade 3 dermatitis. Most resolved one month after treatment, with all resolving at three months. Grade 2 fatigue occurred in 4 patients (4%). There were no grade 3 fatigue or pneumonitis of any grade. The average V95% for the chest wall, axilla, and supraclavicular fossa were 91.5%, 99.3%, and 97.5%, respectively. Average ipsilateral lung V17 was 43.6%, while the mean heart dose averaged at 3.46 Gy. This interim report showed that hypofractionated PMRT is associated with a low incidence of clinically significant acute toxicities. With the use of the 3-dimensional conformal radiotherapy technique and volume-based planning, adequate target volume coverage and acceptable heart doses were achieved, although with a slightly higher ipsilateral lung dose.

Toxicities and Deaths From Intercurrent Disease Following Contemporary Postoperative Radiotherapy in Resected Non-Small-Cell Lung Cancer

IntroductionThe role of postoperative radiotherapy (PORT) in patients with resected locally advanced non-small-cell lung cancer (NSCLC) remains controversial due to the radiation techniques used in randomized trials. We conducted a retrospective cohort study evaluating contemporary PORT techniques to evaluate the safety of PORT and risk of death from intercurrent disease . Materials and MethodsWe analyzed consecutive patients with NSCLC treated in a single center that underwent PORT for pN2 disease and/or positive margin, with 3-dimensional conformal radiotherapy (3DRT), intensity modulated radiotherapy , or proton RT (PRT), between 2008 and 2019. Clinical details were collected including intercurrent deaths, defined as death without cancer recurrence. Kaplan-Meier and Cox-Proportional Hazards Models were used. ResultsOf 119 patients, 21 (17.6%) received 3DRT, 47 (39.5%) intensity modulated radiotherapy, and 51 (42.9%) PRT. Median follow-up was 40 months (range 8-136) and median RT dose was 5040cGy. Most patients (65.5%) received sequential adjuvant chemoRT; 18.5% received concurrent chemoRT. The rate of grade 3 toxicities was 9.2%. There were 13 (10.9%) deaths from intercurrent diseases, including 6 from second primary cancers and 2 from cardiopulmonary diseases. There were 2 additional deaths from cardiopulmonary disease in patients with cancer progression at time of death. Mean, V5Gy, V30Gy heart doses and mean lung doses were significantly lower with PRT. Three-year OS and disease-free-survival were 70.1% and 49.9%. ConclusionPORT using contemporary techniques was well tolerated with acceptable toxicity and low rates of intercurrent deaths. Proton therapy significantly reduced heart and lung doses, but radiotherapy modality was not associated with differences in intercurrent disease.