Heart Dose Research Articles

Factors Associated With Cardiac Radiation Dose Reduction After Hypofractionated Radiation Therapy for Localized, Left-Sided Breast Cancer in a Large Statewide Quality Consortium

Limiting cardiac radiation dose is important for minimizing long-term cardiac toxicity in patients with left-sided early-stage breast cancer. Prospectively collected dosimetric data were analyzed for patients undergoing moderately hypofractionated radiation therapy to the left breast within the Michigan Radiation Oncology Quality Consortium from 2016 to 2022. The mean heart dose (MHD) goal was progressively tightened from ≤2 Gy in 2016 to MHD ≤ 1.2 Gy in 2018. In 2021, a planning target volume (PTV) coverage goal was added, and the goal MHD was reduced to ≤1 Gy. Multivariate logistic regression models were developed to assess for covariates associated with meeting the MHD goals in 2016 to 2020 and the combined MHD/PTV coverage goal in 2021 to 2022. In total, 4165 patients were analyzed with a median age of 64 years. Overall average cardiac metric compliance was 91.7%. Utilization of motion management increased from 41.8% in 2016 to 2020 to 46.5% in 2021 to 2022. Similarly, use of prone positioning increased from 12.2% to 22.2% in these periods. On multivariate analysis in the 2016 to 2020 cohort, treatment with motion management (odds ratio [OR], 5.20; 95% CI, 3.59-7.54; P < .0001) or prone positioning (OR, 3.21; 95% CI, 1.85-5.57; P < .0001) was associated with meeting the MHD goal, while receipt of boost (OR, 0.25; 95% CI, 0.17-0.39; P < .0001) and omission of hormone therapy (OR, 0.65; 95% CI, 0.49-0.88; P=.0047) were associated with not meeting the MHD goal. From 2021 to 2022, treatment with motion management (OR, 1.89; 95% CI, 1.12-3.21; P=.018) or prone positioning (OR, 3.71; 95% CI, 1.73-7.95; P=.0008) was associated with meeting the combined MHD/PTV goal, while larger breast volume (≥1440 cc; OR, 0.34; 95% CI, 0.13-0.91; P=.031) was associated with not meeting the combined goal. In our statewide consortium, high rates of compliance with aggressive targets for limiting cardiac dose were achievable without sacrificing target coverage.

Evaluation of the accuracy of heart dose prediction by machine learning for selecting patients not requiring deep inspiration breath‑hold radiotherapy after breast cancer surgery.

Increased heart dose during postoperative radiotherapy (RT) for left-sided breast cancer (BC) can cause cardiac injury, which can decrease patient survival. The deep inspiration breath-hold technique (DIBH) is becoming increasingly common for reducing the mean heart dose (MHD) in patients with left-sided BC. However, treatment planning and DIBH for RT are laborious, time-consuming and costly for patients and RT staff. In addition, the proportion of patients with left BC with low MHD is considerably higher among Asian women, mainly due to their smaller breast volume compared with that in Western countries. The present study aimed to determine the optimal machine learning (ML) model for predicting the MHD after RT to pre-select patients with low MHD who will not require DIBH prior to RT planning. In total, 562 patients with BC who received postoperative RT were randomly divided into the trainval (n=449) and external (n=113) test datasets for ML using Python (version 3.8). Imbalanced data were corrected using synthetic minority oversampling with Gaussian noise. Specifically, right-left, tumor site, chest wall thickness, irradiation method, body mass index and separation were the six explanatory variables used for ML, with four supervised ML algorithms used. Using the optimal value of hyperparameter tuning with root mean squared error (RMSE) as an indicator for the internal test data, the model yielding the best F2 score evaluation was selected for final validation using the external test data. The predictive ability of MHD for true MHD after RT was the highest among all algorithms for the deep neural network, with a RMSE of 77.4, F2 score of 0.80 and area under the curve-receiver operating characteristic of 0.88, for a cut-off value of 300 cGy. The present study suggested that ML can be used to pre-select female Asian patients with low MHD who do not require DIBH for the postoperative RT of BC.

Comparison of photon intensity modulated, hybrid and volumetric modulated arc radiation treatment techniques in locally advanced non-small cell lung cancer

Background and purposeThere is no consensus on the best photon radiation technique for non-small cell lung cancer (NSCLC). This study quantified the differences between commonly used treatment techniques in NSCLC to find the optimal technique. Materials and methodsTreatment plans were retrospectively generated according to clinical guidelines for 26 stage III NSCLC patients using intensity modulated radiation therapy (IMRT), hybrid, and volumetric modulated arc therapy (VMATC, and VMATV5 optimized for lower lung and heart dose). Plans were evaluated for target coverage, organs at risk dose (including heart substructures) and normal tissue complication probabilities (NTCP). ResultsThe comparison showed significant and largest median differences (>1 Gy or >5%) in favor of IMRT for the mediastinal envelope and heart (maximum dose), in favor of the hybrid technique for the lungs (V5Gy of the total lungs and V5Gy of the contralateral lung) and in favor of VMATC for the heart (Dmean), most of the substructures of the heart, and the spinal cord (maximum dose). The VMATV5 technique had significantly lower heart dose compared to the hybrid technique and significantly lower lung dose compared to the VMATC, combining both advantages in one technique. The mean ΔNTCP did not exceed the 2 percent point (pp) for grade 5 (mortality), and 10 pp for grade ≥2 toxicities (radiation pneumonitis and acute esophageal toxicity), but ΔNTCP was mostly in favor of VMATC/V5 for individual patients. ConclusionThis planning study showed that VMATV5 was preferred as it achieved low lung and heart doses, as well as low NTCPs, simultaneously.

The Impact of Deep Inspiration Breath Hold (DIBH) Implementation on the Hybrid Technique in Left-Sided Whole Breast Irradiation: A Dosimetric Characteristic Study of 3D-CRT Hybrid VMAT in DIBH and Free Breathing Conditions, and VMAT in Free Breathing Conditions.

To investigate the impact of DIBH for heart sparing effect on left sided breast postoperative whole breast irradiation by comparing the dosimetric characteristics of 3D-CRT hybrid VMAT and pure VMAT treatment planning under DIBH condition. The primary CT data sets from previously treated left sided early breast cancer were used for pure volumetric arc therapy (VMAT) technique re-planning for the dosimetric characteristics comparison. A treatment plan of 3D-CRT hybrid VMAT technique was re-planned on the free breath (FB) condition for the investigation of the dosimetric characteristics comparison on DIBH condition. The prescribed dose for all the treatment plans was 42.5Gy in 16 fractions. All plans were optimized to cover 100% of the PTV by 95% of prescribed dose. The dosimetric differences among the 3 treatment plans for the 20 patients were analyzed using Wilcoxon signed-rank test, with p value<0.05 considered statistically significant. 3D-CRT hybrid VMAT using DIBH technique yielded the best results on the conformity index (CI) and homogeneity index (HI). By comparing this 3D-CRT hybrid VMAT technique using FB and DIBH technique, the mean heart dose (MHD) was reduced from 5.38Gy to 1.65Gy, respectively (p =0.001) and the left anterior descending coronary artery (LAD)0.03cc dose was reduced from 27.87Gy to 9.41Gy, respectively (p =0.001). 3D-CRT hybrid VMAT using DIBH technique significantly reduced the V5, V20 and D mean of the ipsilateral lung and D mean of the contralateral lung. The D5 of right breast was significantly reduced by 3D-CRT hybrid VMAT compared with VMAT using DIBH technique. The incorporation of DIBH into 3D-CRT hybrid VMAT technique provides the best benefits for the heart and the OAR with respect to the radiation dose-sparing effect without compromising the target conformity and homogeneity in the treatment planning.

Cardiac Sparing with Volumetric Modulated Arc Therapy Enabled Total Body Irradiation (CS VMAT-TBI).

Volumetric modulated arc therapy (VMAT) enabled total body irradiation (TBI) has replaced conventional TBI in our institution given the improved treatment accuracy, patient comfort, and dose modulation ability. The risk of cardiovascular disease is several folds higher among transplant patients who receive TBI, likely related to dose to the heart. We hypothesize that a cardiac-sparing (CS) VMAT-TBI technique is feasible and can meaningfully reduce dose to the heart while still adequately covering nearby lymphatic tissue. VMAT-TBI is delivered via multi-isocentric external beams in a frame-based setup. Heart is contoured as per published guidelines. A lymph node contour, which includes tonsils, neck nodal stations, mediastinal, abdominal, retroperitoneal, and pelvic nodes is created. Coverage of the lymph node contour is prioritized over organ-sparing during inverse optimization; with a goal of V90% greater than 99.5% and mean dose less than 800 cGy for the lymph nodes and heart, respectively. An IRB-approved retrospective review was performed with mean heart dose collected for all patients treated with CS VMAT-TBI and compared to a representative cohort of five patients treated with VMAT-TBI without cardiac sparing. Thirty-one patients were treated with CS VMAT-TBI between 2020-2022 with a median follow up time of 11.5 months. Mean heart dose was 796 ± 71 cGy in the CS VMAT-TBI compared to 1247 ± 29 cGy in the VMAT-TBI group without cardiac sparing (p < 0.001). Of those treated with CS VMAT-TBI, three patients relapsed; one relapse occurred in bone marrow only, one relapse occurred in bone marrow and cervical, thoracic, and intra-abdominal lymphoid tissues, and one patient was simulated but never received induction therapy due to overt progression. 100-day relapse-free survival and overall survival were 82.5% and 86.2%, respectively. Median survival time has not been met. Cardiac sparing is feasible in VMAT-TBI and is associated with significant decrease in mean heart dose of ∼450 cGy. This is estimated to confer a 33.3% decreased absolute risk for lifetime major coronary events compared to patients treated with VMAT-TBI without cardiac sparing. Although limited by short follow-up time, there does not appear to be a significant risk for early relapse despite de-escalating cardiac tissue, likely due to prioritizing coverage of lymph nodes. Prospective clinical studies are needed to further validate cardiac and other organ at risk sparing VMAT-TBI techniques.

Heart Dose Uncertainty Caused by Heartbeat during Adjuvant Breast Radiotherapy

Adjuvant radiotherapy is a crucial treatment option for breast cancer. Owing to the long survival after treatment, heart toxicity has become a critical issue in those who receive radiotherapy. The heart dose is calculated using the computed tomography (CT) images acquired during simulation. The heart volume is quite different between the systolic and diastolic phases. This study used four-dimensional (4D) CT to capture the heart image and determine the ranges of the heart dose in different phases of the heart. Patients with left-sided breast cancer who underwent breast conservative surgery followed by adjuvant radiotherapy to the entire breast between January 2016 and December 2021 were identified. The three-dimensional (3D) CT and 4DCT datasets of the patients were acquired to evaluate the variation in the heart dose. The heart volume in each respiratory phase was depicted in a box plot along with the dice similarity coefficient (DCS). A total of 32 patients met the inclusion criteria. The DCS of the heart in each respiration phase was within the range of 0.91 to 0.95. Variations in the heart volume and morphology were not evident. However, these variations were not influenced by the respiratory cycle. The median relative variations in the 4DCT volume, mean dose, V20 (≥20 Gy), and V40 (40 Gy) were 6%, 14%, 19%, and 32%, respectively. All parameters showed significant variation between the maximum values in 4DCT and planning 3DCT. When parameters in planning 3DCT were compared to minimum values in 4DCT, the heart volume and V20 still showed significant differences, whereas the mean dose (p = .052) and V40 (p = .151) did not. We found that the median variation in the heart volume during the respiratory cycle was 6%, which led to a 14% variation in the mean heart dose, 19% in V20, and 32% in V40. Dose variation should not be ignored. A more precise method for estimating the heart dose during treatment should be investigated.

Long Term Evaluation of Cardiac Events and Outcomes Following Breast Cancer Irradiation

Although whole heart dose has been associated with cardiac toxicity in patients receiving radiation therapy for breast cancer, data detailing the clinical significance of cardiac substructures, particularly the left anterior descending artery (LAD), are limited. We investigated whether dose to the LAD correlates with adverse cardiac events and death. We identified 190 female patients treated from 2002 to 2019 who received breast or chest wall irradiation, with or without regional nodal irradiation. Ninety-three patients were treated on their right side, 95 on their left, and two were bilateral. Medical records were queried in healthcare software to identify cardiac events after radiation therapy. Mean and maximum LAD and heart doses, as well as V15LAD, were calculated. Univariate and multivariate Cox regression analyses were performed to determine their association with cardiac toxicity as well as death. Cumulative incidence curves for death and cardiac toxicity were also calculated for the patient population. Median follow-up time was 68 months. Thirty patients experienced a cardiac event (15.7%), with three of these being grade 3 or higher. On univariate analyses, left side (hazard ratio 8, P<0.001), increased Mean LAD Dose per cGy (1.001, P = 0.01), Mean Heart Dose (1.16, P = 0.01), and anatomic stage (3.5, P = 0.003) were statistically significant predictors of death but not of adverse cardiac events. Statistically significant predictors of adverse cardiac events were the receipt of chemotherapy (2.68, p = 0.046) which remained significant even after adjusting for radiation parameters. There was no association with hormonal therapy use. Cumulative incidence curves predicted a 14.11% probability of a cardiac event 5 years after treatment and a 25.7% probability at 10 years after treatment. They also predicted a 9.43% probability of death at both 5- and 10-years post-treatment. On this long-term analysis, doses to the heart seemed to negatively impact survival, but did not have a clear association between cardiac events. In contrast, utilizing cytotoxic systemic therapy seemed have an association, even when adjusted for on multivariable models for cardiac events.

Assessment of Cardiac Radiation Dose in the Co-60 Prone Based Stereotactic Partial Breast Irradiation (CP-sPBI) Using the Distance from the Heart to the Planning Treatment Volume as a Surrogate Marker

Irradiation of the breast has shown to provide sharp dose gradients using Co-60 prone based stereotactic partial breast irradiation (CP-sPBI), a contemporary device for stereotactic radiotherapy for breast cancer (BC) for accelerated partial breast irradiation (APBI). In addition, the precise setup of CP-sPBI permits a small planning treatment volume (PTV) margin of 3 mm creating a greater distance from PTV to organs at risk. However, to date the factors that influence dose gradients and subsequent cardiac doses of ionizing radiation using CP-sPBI have not been well-studied. Here we evaluate distance of the heart to the lumpectomy PTV cavity and how this effects cardiac dose. A retrospective database of 113 consecutive patients treated by CP-sPBI for APBI from March 2019 to February 2023 who were treated with 30 Gy in 5 fractions were queried for analysis. The minimum distance from the heart to the PTV (hP) was measured in either the axial or sagittal view. A group of 28 patient cases were randomly selected to achieve an even distribution of 28 cases with hP < 2.75 cm and hP ≥ 2.75 cm to compare cardiac toxicities based on hP. Descriptive analyses were performed to evaluate various cardiac dosimetric parameters based on laterality of BC and hP, using the student's t test. The mean (range) hP was 4.58 cm (0.80-12.23) for all cases. The subgroup analyses of 28 patient cases with cardiac parameters showed the heart mean (range) dose of 1.20 Gy (0.01-2.11). The mean and max heart dose to the left-sided BC were similar to those to the right-sided BC (mean dose: 1.20 vs. 1.19 Gy; P = 0.97 and max dose: 10.47 vs. 5.66 Gy; P = 0.06). An inverse correlation between hP and mean heart dose was shown with the correlation coefficient of -0.81. Using a cutoff of 2.75 cm hP, the differences between hP < 2.75 and hP ≥ 2.75 cm for all cardiac dosimetric evaluations were all statistically significant, including mean (1.67 vs. 0.79 Gy; p<0.01) and maximal heart dose (14.48 vs. 4.11 Gy; p<0.01) CONCLUSION: CP-sPBI treatment delivery system was able to achieve acceptable clinically relevant heart dosimetric parameters when delivering 5 fraction APBI with a mean heart dose of 1.20 Gy for all locations of PTV cavity volume in the breast. Due to CP-sPBIs excellent dose fall-off characteristics, APBI using CP-SPBI showed clinically acceptable cardiac dosimetric parameters, particularly for PTVs located > 2.75 cm from the heart.

Factors Associated with Cardiac Radiation Dose Reduction Following Hypofractionated Radiation Therapy for Localized, Left-Sided Breast Cancer in a Large Statewide Quality Consortium

Limiting radiation dose to the heart is important for minimizing the risk of long-term cardiac toxicity in patients with left-sided early-stage breast cancer. Prospectively collected dosimetric data were analyzed for patients undergoing hypofractionated radiation therapy to the left breast for localized node-negative breast cancer within the Michigan Radiation Oncology Quality Consortium (MROQC) from 2016-2022. Goals for limiting cardiac dose were adjusted over time. From 2016-2020, the cardiac quality metric focused on total mean heart dose (MHD) from the composite whole breast and boost plans, tightening from a goal of MHD ≤2 Gy to MHD ≤1.2 Gy by 2020. In 2021-2022, the cardiac metric transitioned to a combined goal of MHD ≤1.0 Gy from the whole breast plan and ≥95% lumpectomy cavity planning target volume (PTV) receiving 95% of the prescription dose. Separate multivariate logistic regression models were developed to assess for covariates associated with meeting the MHD goal in 2016-2020 and combined MHD/PTV coverage goal in 2021-2022. In total, 4,165 patients were analyzed with a median age of 64 years. Most patients (86%) had either Tis or T1 disease, and 66% received hormone therapy. Baseline demographic and disease characteristics did not change substantially between treatment periods. Use of breath-hold or motion gating increased from 42% in 2016-2020 to 46% in 2021-2022. Similarly, use of prone positioning increased from 12% to 20%. From 2016-2020, 90.9% of plans achieved the MHD goal, compared to 93.6% of plans achieving the composite MHD/PTV goal from 2021-2022. On multivariate analysis in the 2016-2020 cohort, treatment with motion management (OR 5.20, 95% CI [3.59-7.54], p<0.0001) or prone positioning (OR 3.21, 95% CI [1.85-5.57], p < 0.0001) were associated with meeting the MHD goal, while receipt of boost (OR 0.25, 95% CI [0.17-0.39], p<0.0001) and omission of hormone therapy (OR 0.65, 95% CI [0.49-0.88], p = 0.0047), were associated with not meeting the MHD goal. During the era including composite heart dose and PTV coverage goals (2021-2022), treatment with motion management (OR 1.89, 95% CI [1.12-3.21], p = 0.018) or prone positioning (OR 3.71, 95% CI [1.73-7.95], p = 0.0008) were associated with meeting the combined goal, while larger breast volume (≥1440 cc, OR 0.34, 95% CI [0.13 - 0.91], p = 0.031) and treatment at an academic center (OR 0.36, 95% CI [0.22-0.67], p = 0.0009) were associated with not meeting the combined goal. In our statewide consortium, rates of compliance with aggressive targets for limiting cardiac dose remain high, despite tightening of these goals to include lower mean heart doses and inclusion of a concurrent PTV coverage goal. Treatment using motion management or prone positioning is associated with achieving the cardiac dose goals.

Predicted Cardiac Toxicity in Daily Cone-Beam CT-Based Online Adaptive Stereotactic Partial Breast Irradiation with Decreased PTV Margins

Partial breast irradiation (PBI) targets a smaller volume over less time compared to whole breast radiation, but the organ-at-risk (OAR) sparing allowed by its large (up to 1 cm) PTV can be improved. The heart is sensitive to low doses with conventional fractionation and NTCP models have been created for heart substructures. We hypothesized that daily online adaptive stereotactic PBI (A-SPBI) IMRT with 3-mm PTV improves dosimetry and predicted cardiac toxicity risk. Patients treated with daily CBCT-based online A-SPBI IMRT were excluded if the minimum heart dose was <1 Gy. IMRT radiation plans with 3-mm PTV margins were recreated with 1-cm margins per the Florence APBI IMRT trial planning guideline. Dose statistics were converted to the equivalent doses in 2-Gy fractions (EQD2) using α/β = 3 for use in NTCP models and for comparison using paired t tests, with differences considered significant if p≤0.05. The table details heart, left anterior descending artery (LAD), and left (LV) and right ventricle (RV) EQD2 statistics for 4 left-sided and 4 right-sided 3-mm PTV plans and their 1-cm PTV replans. For 2 patients with non-zero LV V5, 9-year excess cumulative risk of acute coronary event was <0.001% for both margin sizes. No plan reached thresholds for increased risk of non-cardiac death, major adverse cardiac event, or >10% decrease in LV ejection fraction. Given the established relationship between low MHD and cardiac events, the significant decrease in MHD revealed in comparisons of 3-mm and 1-cm PTV A-SPBI plans of our first 8 patients is promising; we expect the forthcoming larger sample size to show significant differences in substructure doses. NTCP models created for non-IMRT breast plans and targets with higher heart exposure did not predict clinically-relevant differences in cardiac risk. NTCP model development for the low heart dose achieved with A-SPBI would define expected benefit in these patients; in their absence, daily adaptation should be considered in patients with unfavorable anatomy or cardiac risk factors.

Left Anterior Descending Coronary Artery-Optimized Knowledge-Based Radiotherapy Planning in Patients with Locally Advanced Non-Small Cell Lung Cancer

The left anterior descending (LAD) coronary artery volume receiving 15 Gy (V15 Gy) has been associated with major adverse cardiac events and mortality in patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with radiotherapy (RT). However, coronary arteries are not routinely contoured as standard-of-care and there is limited data describing coronary-sparing planning techniques. Our objective was to evaluate whether LAD-sparing could be improved compared to real-world plans using a commercial knowledge-based planning (KBP) software without clinically unacceptable tradeoffs to other critical organs at risk (OAR). Retrospective replanning analysis was conducted on 31 RT plans developed for patients with LA-NSCLC. Each case was manually replanned with volumetric modulated arc radiotherapy (VMAT) optimized for LAD V15 Gy sparing with a prescription dose of 60 Gy. The resulting plans were used to create an LAD-optimized KBP model. The model included both KBP-generated objectives and additional point objectives to meet LAD (V15 Gy < 10%), lung (V5 Gy < 60%, V20 < 30%, mean < 17 Gy), heart (mean < 20 Gy), spinal cord (D0.03cc < 45 Gy), esophagus (V60 Gy < 17%, mean < 34 Gy), and planning target volume (PTV; D95% = 100%). The LAD-optimized model was deployed to replan 33 additional VMAT plans for LA-NSCLC with prescription dose 60 Gy, delivered between 2018 and 2022. Dose constraints or objectives were only unmet with KBP when not met in the original plan. Descriptive statistics were used to compare dosimetric parameters between original and LAD-optimized KBP plans. For the 33 plans identified for LAD-optimized KBP replanning, the original plans had a mean LAD V15 Gy of 17.9% (standard error [SE], 3.9%), while the LAD-optimized KBP plans had a significantly lower mean LAD V15 Gy of 5.9% (SE, 1.9%; p = 0.031). There was no significant difference in mean heart dose between the original and LAD-optimized KBP plans (8.4 Gy [SE 6.6 Gy] vs. 7.3 Gy [SE 5.8 Gy]; p = 0.48). Of these 33 KBP plans, 42% (n = 14) had mean reductions in LAD V15 Gy from 40.5% (SE 4.3%) to 10.5% (SE 3.5%; p = 0.0002), with 9/14 now able to meet < 10%, without affecting other critical OAR objectives (p > 0.5 for lungs, esophagus, spinal cord). 45% (n = 15) originally had an LAD V15 Gy < 1%, which were unchanged using KBP (p > 0.3). Four plans (12%) had higher LAD V15 Gy in the KBP vs. original plan (2/4 still meeting < 10%), due to the model prioritizing other OARs to a greater degree. Improvements in LAD-sparing was achievable in more than 40% of plans without apparent clinically significant tradeoffs in other critical OARs and without corresponding change in MHD. This result underscores the importance of standard implementation of LAD contouring and dose constraints, particularly given the discordance between whole heart and LAD dose exposure.

Impact of Lymphopenia on Treatment Outcomes in Unresectable Non-Small Cell Lung Cancer

The purpose of this study was to investigate associations between lymphopenia and radiotherapy (RT) parameters. Moreover, to investigate the prognostic role of lymphopenia, and treatment and patient-related factors. Definitive chemoradiation (CRT) with consolidative durvalumab offers the best chance for cure in patients with unresectable, locally advanced non-small cell lung cancer. However, treatment-related lymphopenia (TRL) may negatively impact outcomes. Fifty-four patients treated with CRT and durvalumab from 2017 to 2021 at a single academic center were prospectively included. Absolute lymphocyte counts (ALC), absolute neutrophil counts (ANC), and neutrophil-to lymphocyte ratio (NLR) were analyzed before (TLR1), and after CRT (TRL2), before durvalumab initiation (TRL3), and 3 months after CRT (TRL4). Patients were prospectively enrolled in the study. Categorical variables were analyzed using Pearson's chi-squared or Fisher's Exact tests. Nonparametric continuous variables were analyzed using Wilcoxon Rank-Sum test. Association of continuous clinical and dosimetric variables with hematologic toxicity was performed with Spearman's correlation. Kaplan-Meier analysis and the log-rank test were used to assess the probability of PFS and OS Cox proportional hazard models were used to estimate the effect of covariates on disease control rate. Variables that were strongly associated in univariate Cox regression analyses were entered into a multivariable Cox model. All statistical tests were two-sided, and statistical significance was set at p < 0.05. All analyses were performed using STATA version 15.1. The median follow-up was 28.4 months (m). N2-3 disease showed worse TRL2 compared to N0-1 (p = 0.013). Table 1 shows RT parameters related to TLR2. Median time to durvalumab initiation after CRT was 47 days. Patients who started durvalumab later than 42 days had a greater decrease in lymphocytes at the end of CRT compared to those who started earlier. (70.1 vs 58.8%, p = 0.025). Median overall survival (OS) and progression-free survival (PFS) were 39.4 and 22.4m, respectively. Disease control rate (DCR) with durvalumab consolidation was 70.8%. Patients with NLR >4 prior to durvalumab initiation achieved a lower DCR compared to those with a NLR ≤4 (85.7 vs 14.3%, p = 0.005). CRT-related immunosuppression is associated with delayed durvalumab initiation and worse DCR. Larger PTV and higher lung and heart doses are associated with TRL. Median real-world OS and PFS are similar to those in the PACIFIC trial.

Association of Cardiac Dose with Cardiac Events and Survival for Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC) Treated with Concurrent Chemoradiotherapy (cCRT) in the Era of Immune Checkpoint Inhibitor (ICI) Consolidation

To assess the association of cardiac dose with post-cCRT cardiac events and survival among patients (pts) with LA-NSCLC after adoption of ICI consolidation, modern radiotherapy (RT) techniques, and data-driven cardiac constraints. This single-institution, multi-site retrospective study included 335 pts with LA-NSCLC treated with definitive cCRT (60-70 Gy) from October 2017 to December 2021. Pts were evaluated for ICI consolidation. Cardiac dose constraints included heart volume receiving ≥50 Gy (V50) <25% and mean heart dose (MHD) <20 Gy. Heart, left anterior descending artery (LAD), and left ventricle were autocontoured, manually reviewed, and edited. 21 dosimetric parameters (mean dose, max dose, and min dose to the hottest x% volume [Dx%(Gy); x from 5-95 in 5% intervals]) for each were extracted, as well as LAD V15. Baseline cardiovascular disease (bCVD) was defined as heart failure (HF), coronary artery disease, peripheral vascular disease, or cerebrovascular disease. Primary endpoint was post-cCRT major adverse cardiac events (MACE), defined as acute coronary syndrome, HF hospitalization/urgent visit, coronary revascularization, or cardiac death. Secondary endpoints were grade ≥3 cardiac events (CTCAE v5.0), overall survival (OS), cancer specific mortality (CSM), and other cause mortality (OCM). Competing risk regression was used for MACE and grade ≥3 cardiac events, and Cox regression for OS, CSM, and OCM. Median age was 68 years, 139 (41%) had bCVD, and 225 (67%) received consolidation ICI. Proton therapy was used in 117 (35%), intensity-modulated RT in 199 (59%), and 3D conformal RT in 19 (6%). Median MHD was 8.7 Gy (IQR 4.6-14.4) and median LAD V15 1.4% (IQR 0-22). Median follow-up was 39.5 months. 35 MACE events occurred; 1- and 2-year cumulative incidence (CI) were 4.2% and 9.5%. No cardiac dosimetric parameter associated with MACE after adjusting for bCVD and age (e.g., MHD sHR 0.98/Gy, 95% CI 0.93-1.03, p = 0.43) or within the following 3 subgroups: no bCVD, photon therapy, and ICI consolidation. 87 grade ≥3 cardiac events occurred; 1- and 2- year CI were 12.6% and 20.4%. Heart dose was not associated with grade ≥3 cardiac events after adjusting for bCVD, ECOG, and BMI (e.g., MHD sHR 1.00/Gy, 95% CI 0.97-1.03, p = 0.85) or within the 3 aforesaid subgroups. 183 OS events occurred, including 125 CSM and 58 OCM events. Multiple cardiac dosimetric parameters associated with worse OS on multivariable analysis (e.g., LAD V15 HR 1.01/%, 95% CI 1.00-1.02, p = 0.003), driven by associations with CSM (LAD V15 HR 1.02/%, p<0.001) but not OCM (LAD V15 HR 1.00/%, p = 0.73). Median OS was worse for LAD V15 ≥10% (22.2 vs 35.1 months, p = 0.004). Among pts with LA-NSCLC treated with cCRT after adoption of ICI consolidation, modern RT techniques, and cardiac constraints, post-cCRT cardiac events were common but showed no association with cardiac dose. Cardiac dose associated with OS, driven by an association with CSM and not OCM, which may not reflect cardiac toxicity.

Intensity-Modulated Proton Therapy (IMPT) Offered Advantageous Dosimetry Compared to Volumetric Arc Therapy (VMAT) or Helical Tomotherapy (HT) in Patients with Synchronous Bilateral Breast Cancer

Radiotherapy of synchronous bilateral breast cancer poses some technical challenges with regards to dose coverage and sparing of organs at risk (OAR). In this study, we aimed to evaluate dosimetric characteristics of 3 different techniques, IMPT vs photon (VMAT and HT). We hypothesized that IMPT would result in lower doses to organs at risk, as compared to the other 2 techniques. A total of 10 patients with synchronous bilateral breast cancer who were treated with VMAT at our institution were retrospectively analyzed. Clinical target volume (CTV) included chest wall and regional nodes (supraclavicular fossa and internal mammary chain) and prescription dose was 40.05 Gy in 15 daily fractions. HT and IMPT plans were generated for each patient. Dose-volume statistics, including planning target volume (PTV) coverage and dose to OAR: lungs, heart, thyroid, spinal cord, brachial plexus and esophagus, were compared between modalities using a paired T-test. Mean age of patients was 61 years (43-84). Majority of the patients (80%) were ER+ PR+ and HER2-. 40% of patients underwent breast reconstruction following surgery. All 3 techniques provided adequate target volume distribution and OAR sparing. Compared to VMAT and HT plans, IMPT had better heart and lung sparing effects, resulting in lower mean and V25 Gy heart dose; mean, V20 Gy and V5 Gy lung dose (p<0.0001). There was no significant difference in VMAT and HT plans for mean heart and lung dose. VMAT plans showed significantly lower V25 Gy heart dose on average (p = 0.04). V5 Gy lung dose was slightly lower in HT compared to VMAT plans, approaching statistical significance (p = 0.08). PTV coverage was adequate for all 3 techniques. All techniques fulfilled cord, esophagus, thyroid and brachial plexus constraints. IMPT plans showed significantly better OAR sparing compared to photon techniques. All 3 techniques met OAR constraints, and resulted in adequate target volume coverage. As IMPT is significantly more costly than VMAT or HT techniques, appropriate patient selection is important to deliver treatment in the most resource-effective manner for patients who would derive the most benefit, for example those with young age or existing heart or lung comorbidities.

Evaluation of Observer Variation as Natural Experiment to Detect Sensitive Heart Subregions

There is growing evidence associating dose to the base of the heart to reduced survival of lung cancer patients (McWilliam EJC 2017). However, randomized evidence on the benefits of sparing the base of the heart is missing. In this study we investigate variability in the shape between patients of heart contours used in planning as a natural experiment to evaluate selective heart sparing. The core assumption is that regions that are not included in the heart delineation will not be spared. Data was collected for 1705 lung cancer patients treated in one center between 2010 and 2016 with IMRT/VMAT (55-66Gy in 20-33#) or SABR (54-60Gy in 3-8#), planned using manual heart contours, called delineation 1. Consistent reference heart contours were obtained using a commercial autocontouring software, called delineation 2. Heart shapes were mapped to spherical coordinates (φ, Φ, r) and the difference in radius Δr = r1 - r2 for each set of angles φ, Φ was calculated for all patients. A large Δr means that the manual delineation use for planning is relatively large in the direction. Cox-regression was performed for each set of angles using Δr, r2 and its interaction using overall survival as endpoint. Permutation testing is used to avoid multiple testing issues. The aim is to locate a region of the heart where bigger delineations lead to better sparing and hence better survival. On average the heart base in our manual contours extends 34 mm more superior than automatic contours, because our protocol stipulates the inclusion of the full pericardial sac. Δr was not correlated with any clinical variables and is therefore a good candidate as instrumental variable in causal inference. Univariable Cox regression of Δr showed a uniform worsening of survival with larger manual delineations, likely due to reduced overall sparing given the use of volumetric dose constraints. After including the interaction with r2, no significant heart regions were found. However, analysis using the overall volume of the manual and auto-delineated heart did show a small but significant interaction effect where larger manual delineations improved outcome for smaller hearts. Our interpretation is that delineation variability relative to autocontouring (e.g., 1.9 mm SD at right atrium, up to 15 mm SD at apex) is not big enough to impact significantly on the heart dose and therewith survival because volumetric costs functions are used. In the future we will extend this analysis to include planned dose. Variability in contouring in our cohort is not large enough to be used as a natural experiment to test the impact of selective heart sparing. However, larger volume delineations of small hearts are associated with reduced mortality, suggesting the importance of sparing the base of the heart where most contouring variability occurs.

Simulation CT Features and Radiation Cardiotoxicity in Non-Small Cell Lung Cancer

Radiation cardiotoxicity is a significant clinical dilemma in non-small cell lung cancer (NSCLC) radiation therapy (RT). Baseline cardiovascular (CV) status may influence the risk of cardiotoxicity, and may be ascertainable from the appearance of the heart on simulation computed tomography (CT). We examined the association of CT features with incidental heart dose and risk of cardiac events in NSCLC. Patients treated with curative-intent RT between 2015 and 2020 at a regional center were identified. Clinical notes were interrogated for baseline patient and CV health details, and follow-up CV events. Cardiac events were verified by a cardiologist. A deep learning-based auto-segmentation tool was applied, allowing extraction of a pre-specified list of volume parameters in a programming environment. CAC was graded as none, mild, moderate and severe in patients with a non-contrast scan. The craniocaudal relationship of the PTV and heart (Feng atlas) were annotated. A total of 478 patients were included, with a median age of 70 and Charlson Index of 5. The median mean heart dose was 6.3 Gy (IQR 2.7-11.4). The median lung V20 was 20.0% (IQR 14.8-27.1). Cardiovascular risk factors were common, with most patients having 2 (39%) or 3 (31%). A history of previous cardiac events was common, including myocardial infarction (14%), arrhythmia (11%) or heart failure (9%). A total of 6.9% and 7.1% patients developed a new atrial arrhythmia (AA) or heart failure (HF) after completing RT. The volume metrics with the highest AUC for AA and HF events were the left atrium (LA) (AUC 0.67, p = 0.0002) and left ventricle:right ventricle (LV:RV) ratio (AUC 0.66, p = 0.0021). Kaplan-Meier analysis for cardiac events dichotomizing at the optimal cut-point for maximum sensitivity and specificity demonstrated significantly different rates for both AA (LA 109cc, HR 3.35, 95% CI 1.64-6.83, p = 0.0009) and HF (LV:RV ratio 1.61, HR 2.37, 95% CI 1.19-4.74, p = 0.0143). Only 2 patients with non-contrast scans developed a myocardial infarction, both had mild CAC. The incidence of pooled cardiac events was not significantly different between patients with no (n = 2/21, 9.5%), mild (n = 10/38, 26.3%), moderate (n = 8/53, 15.1%) and severe (n = 7/24, 29.2%) CAC (p = 0.3916). Where the inferior border of the PTV was above the superior border of the heart, mean heart dose was significantly lower than compared with overlap of levels (1.9 Gy v 9.7 Gy, p<0.0001), and this was true for 3DCRT (n = 139, p<0.001), IMRT (n = 94, p<0.001) and VMAT (n = 145, p<0.001) patients. LA volume and LV:RV volume ratio are predictive for the development of AA and HF respectively. CAC grade did not differentiate patients by risk of cardiac events. Where the craniocaudal level of the PTV doesn't overlap with the level of the heart, the cardiac dose is likely to be very low. Several simulation CT features are associated with cardiac events following treatment for NSCLC and prospective evidence of cardiac risk could enable medical optimization prior to RT.

The Effect of Deep Inspiration Breath-Hold Technique on Right Coronary Artery, Heart, and Liver Doses in Right Breast Cancer Radiotherapy

The deep inspiration breath-hold (DIBH) approach has been thoroughly researched with the aim of reducing radiation exposures to normal tissues in breast cancer patients. Although heart and lung toxicity are widely addressed in many literature, radiation-associated liver toxicity and dose constraints for the right coronary artery (RCA) are not well studied in relation to breast radiotherapy. Additionally, very few studies have investigated the relationship between doses to cardiac substructures. This study aimed to determine the effect of the DIBH technique on the right coronary artery (RCA) region, cardiac substructures, and liver dose in right breast cancer irradiation. Between January 2022 and December 2022, thirty-five right breast cancer patients who previously received breast-surgery underwent computed tomography (CT) simulation with both free-breathing (FB) and DIBH techniques. Patients were contoured by a radiation oncologist on the scans using the Treatment Planning System. For cardiac substructures, reference atlas contours were used for accurate delineation and to reduce inter-observer variation. Each patient underwent two treatment plans for both the DIBH and FB datasets. The plan comprised the FB and DIBH techniques, and the doses to the cardiac substructures, ipsilateral lung, RCA region, and liver were compared using a two-tailed paired t-test. Radiotherapy was delivered with a Linac with the prescription dose of 50 Gy in 25 fractions. For both FB and DIBH irradiation groups, the mean radiation doses to the ipsilateral lung, heart, and RCA region in patients with FB and DIBH techniques were; 14.67 Gy, 2.33 Gy, 4.88 Gy and 12.05 Gy, 1.34 Gy and 3.29 Gy respectively. The mean radiation doses to the cardiac substructures; for the left ventricle, right ventricle, left atrium, and right atrium for the FB were 1.08 Gy, 1.79 Gy, 4.11 Gy, and for DIBH, 0.49 Gy, 1.49 Gy, 0.95 Gy, and 2.61 Gy, respectively. For the DIBH group, the liver maximum dose (p<0.01), right lung mean dose (p = 0.001), heart maximum dose (p = 0.009), RCA mean dose (p = 0.020), RCA maximum dose (p = 0.008), RCA V5 dose (p = 0.035), right atrium maximum dose (p = 0.009) and right ventricle mean dose (p = 0.040) were significantly lower than in patients treated in the non-gated group. DIBH resulted in considerable displacement of the liver away from the high-dose target region, such that the volume of liver in the high-dose region was reduced. Additionally, the use of the DIBH technique in right breast cancer irradiation effectively reduces the radiation doses to the cardiac substructures, such as the left ventricle, right ventricle, left atrium, right atrium, RCA region, and lungs. DIBH could lead to substantial sparing of these structures with the right breast cancer radiotherapy. Future prospective studies are required to determine whether improvements to dose-distribution will translate into improved toxicity outcomes.

Phase I-II Study of Prone Hypofractionated Accelerated Breast and Nodal Intensity Modulated Radiation Therapy

In patients (pts) with breast cancer, prone radiation therapy (RT) has been shown to reduce heart and lung dose which may decrease late toxicity. Routinely used for whole breast irradiation, its use to treat regional lymph nodes (LNs) is not widespread. In this phase I-II study, pts treated with partial mastectomy or mastectomy with 1-5 pathologically involved LNs underwent whole breast or post-mastectomy RT plus regional nodal irradiation using IMRT to the supraclavicular and level III axillary LNs. Pts who underwent sentinel LN biopsy (SLNB) alone (no axillary dissection) had the level I and II axillary LNs included in the RT field. 40.5Gy in 15 daily 2.7Gy fractions with daily concomitant 0.5Gy tumor bed boost was prescribed. Normal tissue dose constraints included heart V5Gy<5%, ipsilateral lung V10Gy<20%, contralateral lung V5Gy<15%, ipsilateral brachial plexus (BP) maximal dose (Dmax)<43Gy, spinal cord Dmax≤37.5Gy, spinal cord + 0.5cm Dmax<41Gy, thyroid contralateral lobe Dmax<16Gy, esophagus V30Gy<50% and Dmax≤40.5Gy. The primary endpoints were dosimetric feasibility and incidence of >grade 2 acute toxicity according to CTCAE, v3.0. The secondary endpoint was late toxicity. Exploratory outcomes were local recurrence, disease free survival (DFS), and overall survival (OS). Between January 2011 to December 2016, 97 pts with stage IB-IIA breast cancer were enrolled. 66 pts underwent partial mastectomy and 31 pts underwent mastectomy. 16 pts had SLNB alone. 33% (95% CI: 23.8%, 43.3%) met all protocol dose constraints. Heart, contralateral lung, spinal cord and esophagus V30Gy constraints were met by all pts. The ipsilateral lung constraint was met in 95% (95% CI: 88.6%, 98.4%) of plans with a mean V10Gy of 9.44% (SD: 6.08). The BP Dmax constraint was exceeded in 31.6% (95% CI: 22.4%, 41.9%) of plans with a mean increase of 2.86 Gy (SD: 7.92 Gy) over target. The esophageal Dmax<40.5Gy constraint was exceeded in 6 plans with an increase in 0.74 Gy (SD: 0.46 Gy) over target. There were no grade 3 acute toxicities meeting the primary toxicity endpoint. Common acute low-grade toxicities by pt included fatigue (grade 1: 54 [56%]; grade 2: 2 [2%]), esophagitis (grade 1: 8 [8%]; grade 2: 2 [2%]), dermatitis (grade 1: 81 [84%]; grade 2: 6 [6%]). At median and maximum follow up of 8.02 (IQR: 3.31) and 13.3 years, respectively, there were 2 local recurrences (2.1%). DFS and OS were 86.6% (95% CI: 78.2%, 92.7%) and 90.7% (95% CI: 83.1%, 95.7%), respectively. The incidence of pts with maximum grade 1, 2 and 3 late toxicities were 39 (40%), 14 (14%), and 2 (2%), respectively. The maximum grade late toxicities included 1 grade 3 retraction and 2 grade 3 asymmetries. There was no brachial plexopathy or pneumonitis. Patients treated with prone hypofractionated hybrid breast/chest wall tangents and IMRT to the regional LNs demonstrate excellent dosimetry to the heart, lungs and spinal cord, minimal acute and late toxicity and excellent clinical outcomes. PMID: 26723552.

Cardiopulmonary Protection for Bilateral Breast Irradiation: A Dosimetric Comparison between Proton and Photon Plans

Recent advances in cancer treatment improve cancer survivorship. Cardiovascular disease has become the leading cause of non-cancer death in breast cancer survivors. Therefore, risk of cardiopulmonary toxicities during multimodality treatment should be assessed carefully. It remains to be defined the best scenario for proton therapy to confer meaningful cardiovascular protection in the setting of breast irradiation. We hypothesized proton therapy plan provides optimal cardiopulmonary protection during bilateral breast irradiation. The study aimed to compare cardiopulmonary dosimetric parameters of proton and photon radiotherapy plans. We conducted a retrospective study and patients with bilateral breast cancer indicated for radiotherapy between January 01, 2010 and December 31, 2020 were included. All patients received whole breast or chest wall irradiation with or without regional nodal irradiation. The dose scheme was 50-50.4 Gy in 25-28 fractions. Boost was allowed if patients receiving breast conserving surgery or known risk factors. The dosimetric parameters included planning target volume, mean dose to the heart, the volume of whole lung receiving 5 Gy, 10 Gy, and 20 Gy. For photon therapy, volumetric modulated arc therapy using double partial arc plans was generated with Pinnacle 9.8, Elekta Synergy and tomotherapy helical plan was generated with Tomo Hi-Art planning system. For proton therapy, treatment planning was generated with Ray station 9A. All data was managed using SAS v.9.4 software. Analysis of variance (α = 0.05) was used to compute the dosimetry of different treatment modalities. The statistical significance was considered with a p-value <0.05. Thirty-one patients with bilateral breast cancer were included, including 12 bilateral breast irradiation patients and 6 bilateral chest wall irradiation patients. The mean dose of heart was 53.0±43.3 cGy in proton therapy while 736.6±225.1 cGy and 869.67±241.0 cGy in Tomotherapy and volumetric modulated arc therapy respectively. The volume of whole lung receiving 5 Gy was 15.4±7.91% in proton therapy while 46.1±10.8% and 46.3±2.5% in Tomotherapy and volumetric modulated arc therapy respectively. The volume of whole lung receiving 20 Gy was 7.7±4.3% in proton therapy while 15.4±5.6% and 19±3.5% in Tomotherapy and volumetric modulated arc therapy respectively. The effects of cardiopulmonary protection were more significant for chest wall irradiation over breast irradiation. Proton radiotherapy provided significant dose reduction for bilateral breast irradiation. The benefit is more significant is patients receiving bilateral chest wall irradiation. Further clinical validations will be warranted to confirm the clinical relevance of the finding.

Study on the Dynamic Changes of Myocardial Injury Markers in Radiotherapy for Esophageal Carcinoma and Its Correlation with Cardiac Dosimetry

It was hypothesized that radiotherapy for esophageal cancer could cause radiation-induced heart damage. To investigate the dynamic changes of myocardial enzyme, high-sensitive troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide precursors (PRO-BNP) and left ventricular ejection fraction (LVEF) during radiotherapy and six months after radiotherapy for middle and lower thoracic squamous cell carcinoma, and to analyze the correlation between these indicators and dose-volume histogram (DVH) parameters of the heart. A total of 35 patients with thoracic esophageal squamous cell carcinoma who underwent radical concurrent chemoradiotherapy were enrolled in the study. Radiation therapy was performed for up to 6 weeks. All patients received Intensity modulated radiation therapy (IMRT). Total radiation dose was from 50.4Gy to 60 Gy in each patient with a dose of 1.8-2.0 Gy per fraction. Blood samples to determine creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB), lactic dehydrogenase (LDH), alpha-hydroxybutyric dehydrogenase (α-HBDH), hs-TnT, PRO-BNP and LVEF were measured before radiotherapy, during (10th -20th fraction), at the end of radiotherapy, 1, 3, 6 months after radiotherapy. The dynamic changes of the above indexes were analyzed. The correlation between the above indexes and the mean heart dose (Dmean), V5-V60 (dose-volume histograms data were recorded in discrete 5Gy dose levels) of the heart in the course of radiotherapy was also analyzed. The Serum hs-TNT and LVEF show an upward trend during radiotherapy, at the end of radiotherapy and 6 months after radiotherapy for esophageal cancer. The hs-TnT of patients before, during, at the end of radiotherapy and 1, 3, and 6 months after radiotherapy were 7.2pg/ml, 9.1pg/ml, 9.1pg/ml, 9.0pg/ml, 9.4pg/ml, and 8.1pg/ml, respectively (p<0.05). The LVEF were 63.7%, 62.4%, 62.0%, 62.5%, 62.2%, 61.9% respectively (p<0.05). The pro-BNP showed an upward trend during radiotherapy and gradually returned to normal after radiotherapy. The CK and CK-MB showed a downward trend during radiotherapy and 1 month after radiotherapy, and gradually returned to normal 3 months after radiotherapy. Compared with the low dose group (the average dose of heart < 2000cGy), the high dose group (≥2000cGy) had a greater increase in hs-TNT, pro-BNP and LVEF, and a slower recovery time. There was no correlation between the changes of myocardial enzyme, hs-TnT, PRO-BNP, LVEF and the heart mean dose, V5-V60 during radiotherapy (p>0.05). Cardiac injury induced by concurrent chemoradiotherapy for middle and lower thoracic esophageal cancer can lead to the increase of serum hs-TNT and pro-BNP and the increase of LVEF in the early stage of treatment, and this phenomenon is more obvious in the high-dose group. The hs-TnT and PRO-BNP are sensitive parameters to reflect the heart damage in esophageal cancer radiotherapy, which may provide reference for the heart protection during radiotherapy.