[Subclinical heart injury in patients receiving hypofractionated radiotherapy after breast conserving surgery: a preliminary analysis of prospective study].

Objective: To evaluate the incidence of early cardiac injury in patients with left-sided breast cancer receiving hypofractionated radiotherapy after breast conserving surgery, and to investigate the correlation between cardiac injury and hypofractionated radiotherapy dose. Methods: We prospectively enrolled 103 breast cancer patients who received whole breast with or without regional nodal irradiation after breast conserving surgery using either deep inspiration breath-hold (DIBH) or free breathing (FB) radiotherapy technique. Cardiac examinations that included N-terminal pro-B-type natriuretic peptide (NT-proBNP), electrocardiogram, and myocardial perfusion imaging were performed routinely before and after radiotherapy. The effects of heart dose, systemic therapy and individual factors (Framingham score) on the incidence of cardiac events were analyzed. Results: The median age was 48 years. The mean dose (Dmean) of the heart, left anterior descending coronary artery (LAD), left ventricular (LV), and right ventricular (RV) were 4.0, 16.9, 6.3, and 4.4 Gy, respectively. With a median follow-up of 13.4 months, no patient had clinical cardiac abnormalities. The incidence rates of subclinical cardiac events at 1- 6- and 12-month were 23.5%, 31.6%, and 41.3%, respectively. The DIBH group had a lower mean dose, maximum dose, and V5-V40 in the heart, LAD, LV, and RV than the FB group (P<0.001). Univariate analysis showed an increased incidence of subclinical cardiac events with heart Dmean >4 Gy, LAD V40 > 20%, LV Dmean >6 Gy, RV Dmean >7 Gy, or cumulative doses of anthracycline or taxane > 300 mg/m(2) (All P<0.05). Anti-HER2 targeted therapy, endocrine therapy and Framingham score were not associated with the incidence of subclinical cardiac events (all P>0.05). Multivariate analysis demonstrated that Dmean of LV and RV were independently associated with the increased incidence of subclinical cardiac events. Conclusions: Early subclinical heart injury are found in patients with left-sided breast cancer after hypofractionated radiotherapy. The increased incidence of subclinical cardiac events after radiotherapy is positively associated with the cardiac radiation doses.

Demystifying the Results of RTOG 0617: Identification of Dose Sensitive Cardiac Subregions Associated With Overall Survival.

INTRODUCTION: The RTOG 0617 trial presented a worse survival for patients with lung cancer treated in the high-dose (74 Gy) arm. In multivariable models, radiation level and whole-heart volumetric dose parameters were associated with survival. In this work, we consider heart subregions to explain the observed survival difference between radiation levels. METHODS: Voxel-based analysis identified anatomical regions where the dose was associated with survival. Bootstrapping clinical and dosimetric variables into an elastic net model selected variables associated with survival. Multivariable Cox regression survival models assessed the significance of dose to the heart subregion, compared with whole heart v5 and v30. Finally, the trial outcome was assessed after propensity score matching of patients on lung dose, heart subregion dose, and tumor volume. RESULTS: A total of 458 patients were eligible for voxel-based analysis. A region of significance (p < 0.001) was identified in the base of the heart. Bootstrapping selected mean lung dose, radiation level, log tumor volume, and heart region dose. The multivariable Cox model exhibited dose to the heart region (p = 0.02), and tumor volume (p = 0.03) were significantly associated with survival, and radiation level was not significant (p = 0.07). The models exhibited that whole heart v5 and v30 were not associated with survival, with radiation level being significant (p < 0.05). In the matched cohort, no significant survival difference was seen between radiation levels. CONCLUSIONS: Dose to the base of the heart is associated with overall survival, partly removing the radiation level effect, and explaining that worse survival in the high-dose arm is owing, in part, to the heart subregion dose. By defining a heart avoidance region, future dose escalation trials may be feasible.

Predictors of cardiac dose sparing in deep inspiratory breath-hold technique for radiation of left breast cancer patients.

Introduction: Radiation therapy to left breast cancer patients results in significant exposure to heart resulting in long-term cardiac morbidity. This exposure can be reduced by performing deep inspiratory breath-hold (DIBH) technique, however, patient selection criteria or predictive parameters are not routinely used which can identify patients who will have significant benefit with this technique. This study intends to find and use these predictive parameters measured on free-breathing (FB) simulation scan which can help to select such patients so as to develop our institutional protocol. Methods: A total of 35 patients of left breast cancer postsurgery were recruited in the study. All patients underwent 2-3 sessions of DIBH coaching followed by planning computed tomography scan in both FB phase and DIBH phase. Various anatomical parameters such as cardiac contact distance parasagittal (CCDps), CCD axial, heart-chest distance (HCD), and D were measured on FB scan and were correlated with a mean heart dose achieved in DIBH scan. Results: Dose to normal structures, namely heart and lung, was drastically reduced for DIBH scan over FB scan. V5, V10, and V20 of heart also followed a similar reduction. The mean dose to heart in FB scan was 5.34 Gy, while in DIBH scan, it was 2.79 Gy which was statistically significant. Among all the parameters measured, CCDps and D had a statistically significant positive correlation with the mean heart dose in DIBH phase while HCD had a negative correlation which was statistically significant. Conclusion: Cardiac parameters on FB scan such as CCDps, HCD, and D predict the patients with usual cardiac risk who will benefit most with DIBH techniques setting an arbitrarily cutoff value.

Dosimetric Evaluation of Cardiac Structures on Left Breast Cancer Radiotherapy: Impact of Movement, Dose Calculation Algorithm and Treatment Technique.

Background: Breast cancer is the most frequently diagnosed and leading cause of cancer-related deaths among females. The treatment of breast cancer with radiotherapy, albeit effective, has been shown to be toxic to the heart, resulting in an elevated risk of cardiovascular disease and associated fatalities. Methods: In this study, we evaluated the impact of respiratory movement, treatment plans and dose calculation algorithm on the dose delivered to the heart and its substructures during left breast radiotherapy over a cohort of 10 patients. We did this through three image sets, four different treatment plans and the employment of three algorithms on the same treatment plan. The dose parameters were then employed to estimate the impact on the 9-year excess cumulative risk for acute cardiac events by applying the model proposed by Darby. Results: The left ventricle was the structure most irradiated. Due to the lack of four-dimensional computed tomography (4DCT), we used a set of images called phase-average CT that correspond to the average of the images from the respiratory cycle (exhale, exhale 50%, inhale, inhale 50%). When considering these images, nearly 10% of the heart received more than 5 Gy and doses were on average 27% higher when compared to free breathing images. Deep inspiration breath-hold plans reduced cardiac dose for nine out of 10 patients and reduced mean heart dose in about 50% when compared to reference plans. We also found that the implementation of deep inspiration breath-hold would reduce the relative lifetime risk of ischemic heart disease to 10%, in comparison to 21% from the reference plan. Conclusion: Our findings illustrate the importance of a more accurate determination of the dose and its consideration in cardiologists' consultation, a factor often overlooked during clinical examination. They also motivate the evaluation of the dose to the heart substructures to derive new heart dose constraints, and a more mindful and individualized clinical practice depending on the treatment employed.

Radiation therapy in the thoracic region: Radio-induced cardiovascular disease, cardiac delineation and sparing, cardiac dose constraints, and cardiac implantable electronic devices.

Radiation therapy in the thoracic region may deliver incidental ionizing radiation to the surrounding healthy structures, including the heart. Radio-induced heart toxicity has long been a concern in breast cancer and Hodgkin's lymphoma and was deemed a long-term event. However, recent data highlight the need to limit the dose to the heart in less favorable thoracic cancers too, such as lung and esophageal cancers in which incidental irradiation led to increased mortality. This article will summarize available cardiac dose constraints in various clinical settings and the types of radio-induced cardiovascular diseases encountered as well as delineation of cardiac subheadings and management of cardiac devices. Although still not completely deciphered, heart dose constraints remain intensively investigated and the mean dose to the heart is no longer the only dosimetric parameter to consider since the left anterior descending artery as well as the left ventricle should also be part of dosimetry constraints.

The relationship between cardiac dosimetry and tumour quadrant location in left sided whole breast and chest wall adjuvant radiotherapy.

BACKGROUND: Radiotherapy after breast surgery decreases locoregional recurrence and improves survival. This is not without risks from radiation exposure and could have implications in clinical practice. Our study investigates the correlation between tumour location and radiation dose to the heart. METHODS: Left-sided breast cancer patients who had radiotherapy at Aberdeen Royal Infirmary in 2010 were identified. Tumour location was established from notes and imaging. Radiotherapy planning scans were reviewed, and cardiac doses calculated. The mean cardiac dose, maximum dose and volume of the heart in the field, along with V5-V40, were determined. RESULTS: 40 patients had mastectomies and 118 breast conserving surgery. The median percentage of the heart in the field and the Interquartile Range was 0.59% (0.03-1.74) for all patients, with the highest for lower inner quadrant (LIQ) tumours 1.20% (0.29-2.40), followed by mastectomy 0.94% (0.02-1.82). The mean heart dose showed a higher median for mastectomies 1.59 Gy (1.00-1.94), followed by LIQ tumours 1.58 Gy (1.31-2.28), with an overall median of 1.42 Gy (1.13-1.95). The median percentage of the heart in the field, the mean cardiac dose and V5-V30 did not reach statistical significance, however, V40 and the maximum dose did. CONCLUSIONS: The benefits of radiotherapy after breast cancer surgery are established, but with potential harm from cardiac exposure. Our cohort showed higher radiation exposure to the heart in patients with LIQ tumours and mastectomies but reached significance only for V40 and maximum dose. This highlights tumour location as a potentially important risk factor for cardiac exposure with breast radiotherapy.

TROG 14.04: Multicentre Study of Feasibility and Impact on Anxiety of DIBH in Breast Cancer Patients.

AIMS: The aim of TROG 14.04 was to assess the feasibility of deep inspiration breath hold (DIBH) and its impact on radiation dose to the heart in patients with left-sided breast cancer undergoing radiotherapy. Secondary end points pertained to patient anxiety and cost of delivering a DIBH programme. MATERIALS AND METHODS: The study comprised two groups - left-sided breast cancer patients engaging DIBH and right-sided breast cancer patients using free breathing through radiotherapy. The primary end point was the feasibility of DIBH, defined as left-sided breast cancer patients' ability to breath hold for 15 s, decrease in heart dose in DIBH compared with the free breathing treatment plan and reproducibility of radiotherapy delivery using mid-lung distance (MLD) assessed on electronic portal imaging as the surrogate. The time required for treatment delivery, patient-reported outcomes and resource requirement were compared between the groups. RESULTS: Between February and November 2018, 32 left-sided and 30 right-sided breast cancer patients from six radiotherapy centres were enrolled. Two left-sided breast cancer patients did not undergo DIBH (one treated in free breathing as per investigator choice, one withdrawn). The mean heart dose was reduced from 2.8 Gy (free breathing) to 1.5 Gy (DIBH). Set-up reproducibility in the first week of treatment assessed by MLD was 1.88 ± 1.04 mm (average ± 1 standard deviation) for DIBH and 1.59 ± 0.93 mm for free breathing patients. Using a reproducibility cut-off for MLD of 2 mm (1 standard deviation) as per study protocol, DIBH was feasible for 67% of DIBH patients. Radiotherapy delivery using DIBH took about 2 min longer than for free breathing. Anxiety was not significantly different in DIBH patients and decreased over the course of treatment in both groups. CONCLUSION: Although DIBH was shown to require about 2 min longer per treatment slot, it has the potential to reduce heart dose in left-sided breast cancer patients by nearly a half, provided careful assessment of breath hold reproducibility is carried out.

Prone Positioning With Deep Inspiration Breath Hold for Left Breast Radiotherapy.

BACKGROUND: With advances in treatment, outcomes for early-stage breast cancer are improving. We investigated the combination of prone position and deep inspiration breath hold to decrease cardiac doses for left-sided breast radiotherapy. MATERIAL AND METHODS: Fifteen patients with left-sided breast cancer were enrolled on a single-institution prospective study. Each patient underwent 2 prone positioned computed tomography simulation scans utilizing free breathing and breath-hold. Separate treatment plans for each computed tomography simulation scan were created using tangential fields, and heart and left lung doses were compared between free breathing and breath-hold plans. The technique with the lower mean dose for the heart was used for treatment. All patients were treated with a hypofractionated regimen of 40 to 42 Gy in 15 to 16 fractions, followed by a lumpectomy cavity boost of 10 Gy in 5 fractions when indicated. Wilcoxon paired signed rank tests and paired t tests were performed for statistical analysis of dosimetric endpoints. RESULTS: The median age of our patients was 58 years (range, 40-72 years). One patient was not able to tolerate prone positioning at simulation, leaving 14 patients with evaluable paired scans. The average mean heart dose with free breathing and with breath-hold was 0.93 Gy and 0.72 Gy, respectively (P = .0063). The average max heart dose with free breathing and with breath-hold was 15.70 Gy and 7.19 Gy, respectively (P = .001). The average mean left lung dose with free breathing and with breath-hold was 0.65 Gy and 0.88 Gy, respectively (P = .011). CONCLUSIONS: Our results indicate that breath-hold using the real-time position management system may provide additional cardiac dose reduction in patients receiving prone left-breast radiotherapy treated with tangential fields.

A proof of concept treatment planning study of gated proton radiotherapy for cardiac soft tissue sarcoma.

BACKGROUND AND PURPOSE: Few studies on radiotherapy of cardiac targets exist, and none using a gating method according to cardiac movement. This study aimed to evaluate the dose-volume advantage of using cardiac-respiratory double gating (CRDG) in terms of target location with additional ECG signals in comparison to respiratory single gating (RSG) for proton radiotherapy of targets in the heart. MATERIALS AND METHODS: Cardiac motion was modeled using a cardiac-gated four-dimensional computed tomography scan obtained at the end-expiration. Plans with the prescription dose of 50 Gy (RSG and CRDG plans at diastole and systole phases) were compared in terms of clinically relevant dose-volume criteria for various target sizes and seven cardiac subsites. Potential dose sparing by utilizing CRDG over RSG was quantified in terms of surrounding organ at risk (OAR) doses while the dose coverage to the targets was fully ensured. RESULTS: The average mean dose reductions were 28 ± 10% when gated at diastole and 21 ± 12% at systole in heart and 30 ± 17% at diastole and 8 ± 9% at systole in left ventricle compared to respiratory single gating. The diastole phase was optimal for gated treatments for all target locations except right ventricle and interventricular septum. The right ventricle target was best treated at the systole phase. However, an optimal gating phase for the interventricular septum target could not be determined. CONCLUSIONS: We have studied the dose-volume benefits of CRDG for each cardiac subsite, and demonstrated that CRDG may spare organs at risk better than RSG.

Cardiac dose reduction using deep inspiratory breath hold (DIBH) in radiation treatment of left sided breast cancer patients with breast conservation surgery and modified radical mastectomy.

PURPOSE: Deep inspiration breath hold (DIBH) reduces heart and pulmonary doses during left-sided breast radiation therapy (RT); however, there is limited information whether the reduction in doses is similar in patients with modified radical MRM (MRM) and breast conservation surgery (BCS). The primary objective was to determine whether DIBH offers greater dosimetric reduction in cardiac doses in patients with MRM as compared to BCS with secondary objectives of documenting time consumed in counseling, simulation and planning such techniques. METHODS: Thirty patients with diagnosis of left sided breast cancer underwent CT simulation both free breathing (FB) and DIBH. Patients were grouped into two cohorts: MRM (n = 20) and BCS (n = 10). 3D-conformal plans were developed and FB was compared to DIBH for entire group (n = 30) and each cohort using Wilcoxon signed-rank tests for continuous variables and McNemar's test for discrete variables. The percent relative reduction conferred by DIBH in mean heart (Dmean heart) and left anterior descending artery dose (LADmean and LADmax), heart V25,V10, V2 and ipsilateral DmeanLung,V20, V12 were compared between the two cohorts using Wilcox rank-sum testing. A two-tailed p-value ≤ 0.05 was considered statistically significant. Time consumed during FB and DIBH from patient counseling to planning was documented. RESULTS: Patients undergoing BCS had comparable boost target coverage on DIBH and FB. For the overall group (n = 30), DIBH reduced Dmean heart and LAD dose, V25, V10 and V2 doses for the heart and Ipsilateral DmeanLung, V20, V12 which was statistically significant. For individual cohorts DIBH did not significantly reduce the lung (Ipsilateral DmeanLung, V20, V12) and LAD (LADmean and LADmax) doses for BCS while significant reduction in all cardiopulmonary doses was seen in MRM cohort. Despite significant reductions with DIBH in MRM, ipsilateral lung constraint of V12 < 15% was less commonly achieved in MRM (n = 11, 55%) requiring nodal radiation as compared to BCS (n = 3, 30%). Percent reduction in all cardiac and pulmonary dosimetric parameters with DIBH was similar in the MRM cohort as compared to BCS cohort. In total 73.1 ± 2.6 min was required for FB as compared to 108.1 ± 4.1 min in DIBH. CONCLUSION: DIBH led to significant reduction of cardiac doses in both MRM and BCS. Reduction of lung and LAD doses were significant in MRM cohort. All cardiac constraints were met with DIBH in both cohorts, lung constraints were less frequently met in MRM cohort requiring nodal radiation.

Cardiac Dose Control and Optimization Strategy for Left Breast Cancer Radiotherapy With Non-Uniform VMAT Technology.

Purpose: A novel in-house technology "Non-Uniform VMAT (NU-VMAT)" was developed for automated cardiac dose reduction and treatment planning optimization in the left breast radiotherapy. Methods: The NU-VMAT model based on IGM (gantry MLC Movement coefficient index) was established to optimize the volumetric modulated arc therapy (VMAT) MLC movement and modulation intensity in certain gantry angles. The ESAPI embedded in Eclipse® was employed to connect TPS and the optimization program via I/O relevant DICOM RT files. The adjuvant whole-breast radiotherapy of 14 patients with left breast cancer was replanned using our NU-VMAT technology in comparison with VMAT and IMRT technology. Dosimetric parameters including D1%, D99%, and Dmean of PTV, V5, V10, and V20 of ipisilateral lung, V5, D20, D30, and Dmean of heart, monitor units (MUs), and delivery time derived from IMRT, VMAT, and NU-VMAT plans were evaluated for plan quality and delivery efficiency. The quality assurance (QA) was conducted using both point-dose and planar-dose measurements for all treatment plans. Results: The IGM-NU-VMAT curves with plan optimization (range from 50% to 147%) were converged more significantly than IGM-VMAT curves (range from 0% to 297%). The dose distribution requirements of the target and normal tissues could be met using IMRT, VMAT, or NU-VMAT; the lowest Dmean was achieved in NU-VMAT plans (5.38 ± 0.46 Gy vs 5.63 ± 0.61 Gy in IMRT and 7.95 ± 0.52 Gy in VMAT plans). Statistically significant differences were found in terms of delivery time and MU when comparing IMRT with VMAT and NU-VMAT plans (P < .05). In comparison with IMRT plans, the MU and delivery time in NU-VMAT plans dramatically decreased by 69.8% and 28.4%, respectively. Moreover, NU-VMAT plans showed a high gamma passing rate (96.5% ± 1.11) in plane dose verification and minimal dose difference (2.4% ± 0.19) in point absolute dose verification. Conclusion: Our non-uniform VMAT facilitated the treatment strategy optimization for left breast cancer radiotherapy with dosimetric advantage in cardiac dose reduction and delivery efficiency in comparison with the conventional VMAT and IMRT.

Dose-response relationships for radiation-related heart disease: Impact of uncertainties in cardiac dose reconstruction.

BACKGROUND AND PURPOSE: Radiation-related heart disease (RRHD) can occur many decades after thoracic radiotherapy for Hodgkin lymphoma (HL) or childhood cancer (CC). To quantify the likely risk of RRHD for patients treated today, dose-response relationships derived from patients treated in previous decades are used. Publications presenting these dose-response relationships usually include estimates of uncertainties in the risks but ignore the effect of uncertainties in the reconstructed cardiac doses. MATERIALS/METHODS: We assessed the systematic and random uncertainties in the reconstructed doses for published dose-response relationships for RRHD risk in survivors of HL or CC. Using the same reconstruction methods as were used in the original publications, we reconstructed mean heart doses and, wherever possible, mean left-ventricular doses for an independent case-series of test patients. These patients had known, CT-based, cardiac doses which were compared with the reconstructed doses to estimate the magnitude of the uncertainties and their effect on the dose-response relationships. RESULTS: For all five reconstruction methods the relationship between reconstructed and CT-based doses was linear. For all but the simplest reconstruction method, the dose uncertainties were moderate, the effect of the systematic uncertainty on the dose-response relationships was less than 10%, and the effects of random uncertainty were small except at the highest doses. CONCLUSIONS: These results increase confidence in the published dose-response relationships for the risk of RRHD in HL and CC survivors. This may encourage doctors to use these dose-response relationships when estimating individualised risks for patients-an important aspect of personalising radiotherapy treatments today.

Comparison of the dose on specific 3DCT images and the accumulated dose for cardiac structures in esophageal tumors radiotherapy: whether specific 3DCT images can be used for dose assessment?

BACKGROUND: Cardiac activity could impact the accuracy of dose assessment for the heart, pericardium and left ventricular myocardium (LVM). The purpose of this study was to explore whether it is possible to perform dose assessment by contouring the cardiac structures on specific three-dimensional computed tomography (3DCT) images to reduce the impact of cardiac activity. METHODS: Electrocardiograph-gated 4DCT (ECG-gated 4DCT) images of 22 patients in breath-hold were collected. MIM Maestro 6.8.2 (MIM) was used to reconstruct specific 3DCT images to obtain the Maximal intensity projection (MIP) image, Average intensity projection (AIP) image and Minimum intensity projection (Min-IP) image. The heart, pericardium and LVM were contoured in 20 phases of 4DCT images (0, 5%... 95%) and the MIP, AIP and Min-IP images. Then, a radiotherapy plan was designed at the 0% phase of the 4DCT images, and the dose was transplanted to all phases of 4DCT to acquire the dose on all phases, the accumulated dose of all phases was calculated using MIM. The dose on MIP, AIP and Min-IP images were also obtained by deformable registration of the dose. The mean dose (Dmean), V5, V10, V20, V30 and V40 for the heart, pericardium and LVM in MIP, AIP and Min-IP images were compared with the corresponding parameters after dose accumulation. RESULTS: The mean values of the difference between the Dmean in the MIP image and the Dmean after accumulation for the heart, pericardium and LVM were all less than 1.50 Gy, and the dose difference for the pericardium and LVM was not statistically significant (p > 0.05). For dose-volume parameters, there was no statistically significant difference between V5, V10, and V20 of the heart and pericardium in MIP, AIP, and Min-IP images and those after accumulation (p > 0.05). For the LVM, only in the MIP image, the differences of V5, V10, V20, V30 and V40 were not significant compared to those after dose accumulation (p > 0.05). CONCLUSIONS: There was a smallest difference for the dosimetry parameters of cardiac structures on MIP image compared to corresponding parameters after dose accumulation. Therefore, it is recommended to use the MIP image for the delineation and dose assessment of cardiac structures in clinical practice.

Low cardiac and left anterior descending coronary artery dose achieved with left-sided multicatheter interstitial-accelerated partial breast irradiation.

PURPOSE: Studies have shown that an additional mean dose of 1 Gy to the heart can increase the relative risk of cardiac events. The purpose of this study was to quantify the dose delivered to the heart and left anterior descending artery (LAD) in a series of patients with left-sided breast cancer (BC) or ductal carcinoma in situ treated with multicatheter-accelerated partial breast irradiation (MC-APBI) at a single institution. METHODS AND MATERIALS: Patients with left-sided BC or ductal carcinoma in situ treated consecutively from 2005 to 2011 with MC-APBI were retrospectively identified. Cardiac and LAD contours were generated for each patient. Cardiac dosimetry and distance to the planning target volume were recorded. Patient health records were reviewed and cardiac events were recorded based on Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Twenty consecutive patients with left-sided BC treated with MC-APBI were retrospectively identified. Median followup was 41.4 months. Mean equivalent dose in 2 Gy fractions delivered to the heart and LAD were 1.3 (standard deviation: 0.7, range: 0.2-2.9) and 3.8 (standard deviation: 3.0, range: 0.4-11.3) Gy, respectively. There was an inverse linear relationship (R2 = 0.52) between heart-to-lumpectomy cavity distance and mean heart equivalent dose in 2 Gy fractions. One patient (5%) experienced symptomatic cardiac toxicity. CONCLUSIONS: MC-APBI consistently delivers average doses to the heart and LAD that are similar to those achieved in most series with deep inspiration breath-hold and lower than free-breathing radiotherapy techniques. Distance from the heart to the lumpectomy cavity and the availability of other heart-sparing technologies should be considered to minimize the risk of cardiac toxicity.

Left breast irradiation with tangential intensity modulated radiotherapy (t-IMRT) versus tangential volumetric modulated arc therapy (t-VMAT): trade-offs between secondary cancer induction risk and optimal target coverage.

BACKGROUND: Adjuvant radiotherapy is the standard treatment after breast-conserving surgery. According to meta-analyses, adjuvant 3d-conventional irradiation reduces the risk of local recurrence and thereby improves long-term survival by 5-10%. However, there is an unintended exposure of organs such as the heart, lungs and contralateral breast. Irradiation of the left breast has been related to long-term effects like increased rates of coronary events as well as second cancer induction. Modern radiotherapy techniques such as tangential intensity modulated radiotherapy (t-IMRT) and tangential volumetric modulated arc therapy (t-VMAT) and particularly deep inspiration breath hold (DIBH) technique have been developed in order to improve coverage of target volume and to reduce dose to normal tissue. The aim of this study was to compare t-IMRT-plans with t-VMAT-plans in DIBH position for left-sided breast irradiation in terms of normal tissue exposure, i.e. of lungs, heart, left anterior descending coronary artery (LADCA), as well as homogeneity (HI) and conformity index (CI) and excess absolute risk (EAR) for second cancer induction for organs at risk (OAR) after irradiation. METHODS: Twenty patients, diagnosed with left-sided breast cancer and treated with breast-preserving surgery, were included in this planning study. For each patient DIBH-t-IMRT plan using 5 to 7 beams and t-VMAT plan using four rotations were generated to achieve 95% dose coverage to 95% of the volume. Data were evaluated on the basis of dose-volume histograms: Cardiac dose and LADCA (mean and maximum dose, D25% and D45%), dose to ipsilateral and contralateral lung (mean, D20%, D30%), dose to contralateral breast (mean dose), total monitor units, V5% of total body and normal tissue integral dose (NTID). In addition, homogeneity index and conformity index, as well as the excess absolute risk (EAR) to estimate the risk of second malignancy were calculated. RESULTS: T-IMRT showed a significant reduction in mean cardiac dose of 26% (p = 0.002) compared to t-VMAT, as well as a significant reduction in the mean dose to LADCA of 20% (p = 0.03). Following t-IMRT, mean dose to the left lung was increased by 5% (p = 0.006), whereas no significant difference was found in the mean dose to the right lung and contralateral breast between the two procedures. Monitor units were 31% (p = 0.000004) lower for t-IMRT than for t-VMAT. T-IMRT technique significantly reduced normal tissue integral dose (NTID) by 19% (p = 0.000005) and the V5% of total body by 24% (p = 0.0007). In contrast, t-VMAT improved CI and HI by 2% (p = 0.001) and 0.4% (p = 0.00001), respectively. EAR with t-IMRT was significantly lower, especially for contralateral lung and contralateral breast (2-5/10,000 person years) but not for ipsilateral lung. CONCLUSION: Compared to t-VMAT, t-IMRT in left-sided breast irradiation significantly reduced dose to organs at risk as well as normal tissue integral dose, and V5% total body. EAR with t-IMRT was significantly lower for contralateral lung and contralateral breast. T-VMAT, however, achieved better homogeneity and conformity. This may be relevant in individual cases where sufficient coverage of medial lymphatic target volumes is warranted.

Safety of Continuing Trastuzumab Despite Mild Cardiotoxicity: A Phase I Trial.

OBJECTIVES: This study sought to evaluate the safety of continuing trastuzumab in patients with human epidermal growth factor receptor-positive breast cancer who developed mild cardiotoxicity. BACKGROUND: Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Current standard of care is discontinuation of trastuzumab, which can lead to worse cancer outcomes. It is unknown whether it is safe to continue trastuzumab despite mild cardiotoxicity. METHODS: Patients were eligible for this phase I, prospective, single-arm trial if left ventricular ejection fraction (LVEF) was between 40% and the lower limit of normal or if it fell ≥15% from baseline. Participants were treated with angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers in a cardio-oncology clinic and were followed clinically and with serial echocardiograms for 1 year. The primary outcome was cardiac dose-limiting toxicity, defined as cardiovascular death, LVEF <40% together with any heart failure symptoms, or LVEF <35%. RESULTS: All 20 participants received ACE inhibitors and/or beta-blockers. A total of 18 participants (90%) received all planned trastuzumab doses. Two (10%) participants developed cardiac dose-limiting toxicity (heart failure with LVEF <40%). Their LVEF and heart failure symptoms improved to nearly normal following permanent trastuzumab discontinuation. There were no deaths. LVEF rose progressively from a mean of 49% at enrollment to 55% at 12 months (p < 0.001). CONCLUSIONS: It may be feasible to continue trastuzumab despite mild cardiotoxicity in the setting of a cardio-oncology clinic, where ACE inhibitors and beta-blockers are administered. Approximately 10% of patients may develop moderate to severe heart failure using this approach. (Safety of Continuing Chemotherapy in Overt Left Ventricular Dysfunction Using Antibodies to Human Epidermal Growth Factor Receptor-2 [SCHOLAR]; NCT02907021).

Evolution of brachytherapy treatment planning to deterministic radiation transport for calculation of cardiac dose.

Brachytherapy was among the first methods of radiotherapy and has steadily continued to evolve. Here we present a brief review of the progression of dose calculation methods in brachytherapy to the current state-of-the art computerized methods for heterogeneity correction. We further review the origin and development of the BrachyVision (Varian Medical Systems, Inc., Palo Alto, CA) treatment planning system and evaluate dosimetric results from 12 patients implanted with the strut-assisted volumetric implant (SAVI) applicator (Cianna Medical, Aliso Viejo, CA) for accelerated partial breast irradiation (APBI). Dosimetric results from plans calculated using homogenous and heterogeneous algorithms have been compared to investigate the impact of heterogeneity corrections. Our study showed large percent difference between mean cardiac doses 11.8 ± 6.2% (p = 0.0007) calculated with and without heterogeneity corrections. Our findings are consistent with those of others, indicating an overestimation of the distal dose to organs-at-risk by traditional methods, especially at interfaces between air and tissue.

Reduction in low-dose to normal tissue with the addition of deep inspiration breath hold (DIBH) to volumetric modulated arc therapy (VMAT) in breast cancer patients with implant reconstruction receiving regional nodal irradiation.

BACKGROUND: Despite dosimetric benefits of volumetric modulated arc therapy (VMAT) in breast cancer patients with implant reconstruction receiving regional nodal irradiation (RNI), low dose to the thoracic structures remains a concern. Our goal was to report dosimetric effects of adding deep inspiration breath hold (DIBH) to VMAT in left-sided breast cancer patients with tissue expander (TE)/permanent implant (PI) reconstruction receiving RNI. METHODS: Ten consecutive breast cancer patients with unilateral or bilateral TE/PI reconstruction who were treated with a combination of VMAT and DIBH to the left reconstructed chest wall and regional nodes were prospectively identified. Free breathing (FB) and DIBH CT scans were acquired for each patient. VMAT plans for the same arc geometry were compared for FB versus DIBH. Prescription dose was 50 Gy in 25 fractions. Dosimetric differences were tested for statistical significance. RESULTS: For comparable coverage and target dose homogeneity, the mean dose to the heart reduced on average by 2.9 Gy (8.2 to 5.3 Gy), with the addition of DIBH (p < 0.05). The maximum dose to the left anterior descending (LAD) artery was reduced by 9.9 Gy (p < 0.05), which related closely to the reduction in the maximum heart dose (9.4 Gy). V05 Gy to the heart, ipsilateral lung, contralateral lung and total lung (p < 0.05) decreased on average by 29.6%, 5.8%, 15.4% and 10.8% respectively. No significant differences were seen in the ipsilateral lung V20 Gy or mean dose as well as in the mean contralateral breast/implant dose. However, V04 Gy and V03 Gy of the contralateral breast/implant were respectively reduced by 13.2% and 18.3% using DIBH (p < 0.05). CONCLUSION: Combination of VMAT and DIBH showed significant dosimetric gains for low dose to the heart, lungs and contralateral breast/implant. Not surprisingly, the mean and maximum dose to the heart and to the LAD were also reduced. DIBH should be considered with the use of VMAT in breast cancer patients with implant reconstructions receiving RNI.

Assessment of deep inspiration breath hold (DIBH) amplitude and reduction in cardiac dose in left breast cancer patients.

INTRODUCTION: The primary aim of this study was to examine the impact of deep inspiration breath-hold (DIBH) amplitude on subsequent mean heart dose and V30 during radiotherapy. The secondary aim was to investigate if patient age influenced DIBH amplitude. METHOD: A retrospective study of 30 patients with left-sided breast cancer was completed. Patients were randomly selected from the total number of patients dual scanned in free breathing (FB) and DIBH over a 2-year period. Plans were retrospectively virtually simulated and statistical analysis performed. RESULTS: All patients achieved decreased V30 and mean cardiac dose using DIBH. A positive correlation was found between DIBH amplitude and cardiac V30 dose reduction (p = 0.007, R = 0.48). Ratio of amplitude increase from FB to DIBH and cardiac V30 reduction was positively correlated and statistically significant (p = 0.04, R = 0.38); Ratio of amplitude increase of at least 15 times FB achieved 100% V30 dose reduction, however this was also achieved with ratio increase as low as 6.25 times FB. A statistically significant positive correlation was identified between DIBH amplitude and mean cardiac dose reduction (p = 0.003, R = 0.523). No correlation was found between patient age and amplitude ratio increase (p = 0.602, R = -0.099). CONCLUSION: A 100% reduction in cardiac V30 can be achieved with a DIBH amplitude increase of 15 times FB. A full reduction can also be achieved at much lower levels (6.25 times FB in current study); however there appears to be no pre-determining patient factors to identify this. DIBH amplitudes of 1 cm-4 cm reduce cardiac mean dose by at least 50%.

The benefit of deep inspiration breath hold: evaluating cardiac radiation exposure in patients after mastectomy and after breast-conserving surgery.

BACKGROUND: This study aims to evaluate the reduction of cardiac radiation dose and volume with deep inspiration breath hold (DIBH) technique compared to free breathing (FB) in patients with left-sided breast cancer. The study also aims to evaluate whether the benefits of DIBH vary in patients who had whole breast radiotherapy (RT) after breast-conserving surgery (BCS) and those who had chest wall RT post-mastectomy (M). METHODS: FB and DIBH plans were generated for 15 consecutive post-BCS patients and 17 post-M patients who underwent RT with DIBH using varian real-time position management (RPM) system. Cardiac shields were used in all post-BCS plans, provided that clinical treatment volume coverage was not compromised, while chest wall coverage took priority in post-M plans. The prescribed dose was 50 Gy in 25 fractions for the whole breast or the chest wall. Parameters of interest were cardiac V5, mean LAD dose, maximum LAD dose, and mean heart dose. The impact of DIBH was compared in post-BCS and post-M patients using paired t tests. To gauge clinically meaningful outcome, the proportion of patients with V5 < 5 % and mean cardiac dose <2 Gy were compared using McNemar's test. RESULTS: DIBH decreased V5 by an absolute 4.5 % (2.3 vs. 6.8 %; p < 0.0001) in post-M group, and by an absolute 2.4 % (1.3 vs. 3.7 %; p = 0.0028) in post-BCS group. DIBH decreased the mean heart dose by 107.0 cGy (127.4 vs. 234.4 cGy; p = 0.0002) in post-M group, and by 58.9 cGy (82.2 vs. 141.1 cGy; p = 0.0012) in post-BCS group. DIBH decreased mean LAD by 1201.6 cGy (670 vs. 1872.5 cGy; p = 0.0006) in post-M group, and by 799.0 cGy (425.3 vs. 1224.3 cGy; p = 0.0003) in post-BCS group. DIBH also decreased max LAD dose by 1244.3 cGy (2776.0 vs. 4020.3 cGy; p = 0.0014) in post-M group, and by 1856.3 cGy (1898.7 vs. 3754.9 cGy; p = 0.0005) in post-BCS group. In post-BCS group, cardiac V5 < 5 % was achieved in 10/15 (67 %) FB patients, and in 15/15 (100 %) DIBH patients (p = 0.002), and mean heart dose <2 Gy was achieved in 12/15 (80 %) FB patients and in 15/15 (100 %) DIBH patients (p < 0.001). This compares with post-M group, in which V5 < 5 % was achieved in 6/17 (35 %) FB patients and in 16/17 (94 %) DIBH patients (p = 0.05), and mean heart dose <2 Gy was achieved in 7/17 FB (41 %) an 16/17 DIBH patients (94 %) (p = 0.03). CONCLUSION: The results of this study suggest that there is considerable reduction in cardiac exposure in most patients with DIBH compared to FB, although less reduction is observed in the post-BCS patients. The use of cardiac shields and collimators/gantry adjustments, more readily applicable for post-BCS cases, may limit the additional benefits of DIBH. In an environment where DIBH availability is limited, the result of this study supports the preferential use of DIBH in post-M patients over post-BCS patients.