Sinoatrial Node Dose Is Associated With Worse Survival in Patients Undergoing Definitive Stereotactic Body Radiation Therapy for Central Lung Cancers.

PURPOSE: Our purpose was to evaluate the clinical consequences of sinoatrial node (SAN) and atrioventricular node (AVN) irradiation in patients undergoing stereotactic body radiation therapy (SBRT) for central non-small cell lung cancer (NSCLC) tumors. METHODS AND MATERIALS: A single-institutional retrospective review of patients with primary NSCLC undergoing definitive SBRT for centrally located thoracic tumors from February 2007 to December 2021 was performed. The SAN and AVN were contoured in accordance with a published contouring atlas, and the maximum dose (Dmax) and mean dose (Dmean) for each structure were calculated. Sequential log rank testing between the 50th and 90th percentiles was used to identify potential cutoff values for the corresponding dosimetric parameters and overall survival. RESULTS: Among 93 eligible patients, the median age was 72.5 years (IQR, 66.6-78.3), and median follow-up was 32.4 months (IQR, 13.0-49.6). The median SAN Dmax and Dmean were 95 cGy (range, 9-5394) and 58 cGy (range, 7-3168), respectively. The median AVN Dmax and Dmean were 45 cGy (range, 4-2121) and 34 cGy (range, 3-1667), respectively. Candidate cutoff values for SAN Dmax and Dmean were 1309 and 836 cGy, respectively. No associations between AVN parameters and survival outcomes were identified. Upon multivariate Cox regression, the SAN Dmax cutoff (hazard ratio [HR], 2.03 [1.09-3.79]; P = .026) and SAN Dmean cutoff (HR, 2.22 [1.20-4.12]; P = .011) were significantly associated with overall survival. For noncancer-associated survival, the SAN Dmax cutoff trended toward significance (HR, 2.02 [0.89-4.57]; P = .092), and the SAN Dmean cutoff remained significantly associated (HR, 2.34 [1.05-5.18]; P = .037). CONCLUSIONS: For patients undergoing SBRT for NSCLC, SAN Dmax and Dmean were significantly associated with worse overall survival using cut-off values of 1309 and 836 cGy, respectively. Further studies examining the effect of SAN irradiation during SBRT are warranted.

Long-Term Survival and Failure Outcomes of Single-Fraction Stereotactic Body Radiation Therapy in Early Stage NSCLC.

Introduction: This study aims to report our 13-year institutional experience with single-fraction stereotactic body radiation therapy (SF-SBRT) for early stage NSCLC. Methods: A single-institutional retrospective review of patients with biopsy-proven peripheral cT1-2N0M0 NSCLC undergoing definitive SF-SBRT between September 2008 and May 2022 was performed. All patients were treated to 27 Gy with heterogeneity corrections or 30 Gy without. Primary outcomes were overall survival and progression-free survival. Secondary outcomes included local failure, nodal failure, distant failure, and second primary lung cancer. Results: Among 263 eligible patients, the median age was 76 years (interquartile range [IQR]: 70-81 y) and median follow-up time was 27.2 months (IQR: 14.25-44.9 mo). Median tumor size was 1.9 cm (IQR: 1.4-2.6 cm), and 224 (85%) tumors were T1. There were 92 patients (35%) alive at the time of analysis with a median follow-up of 34.0 months (IQR: 16.6-50.0 mo). Two- and five-year overall survival was 65% and 26%, respectively. A total of 74 patients (28%) developed disease progression. Rates of five-year local failure, nodal failure, distant failure, and second primary lung cancer were 12.7%, 14.7%, 23.5%, and 12.0%, respectively. Conclusions: Consistent with multiple prospective randomized trials, in a large real-world retrospective cohort, SF-SBRT for peripheral early stage NSCLC was an effective treatment approach.

Brachial Plexopathy After Single-Fraction Stereotactic Body Radiation Therapy in Apical Lung Tumors.

PURPOSE: The objective of this study was to evaluate the incidence of brachial plexus injury (BPI) after single-fraction stereotactic body radiation therapy (SBRT) to apical lung tumors. METHODS AND MATERIALS: A retrospective cohort analysis was performed of all patients treated with single-fraction lung SBRT at our institution from 2007 to 2022. Apical tumors were identified as those with an epicenter located above the arch of the aorta. Dosimetric analysis of dose to the brachial plexus (BP) was done using both the subclavian vessel (SCV) surrogate structure and anatomic BP. BPI was assessed per Common Terminology Criteria for Adverse Events, version 4.0, as regional paresthesia, marked discomfort and muscle weakness, and limited movement of the arm or hand. RESULTS: A total of 45 patients met inclusion criteria with median follow-up of 21 months. There were 9 patients who exceeded the BP dose constraint using the SCV or anatomic BP volume. Only 1 patient (2.2%) developed grade 2 BPI, occurring 7 months after SBRT. Dose to the anatomic BP for the affected patient was 26.39 Gy. For the entire cohort, the median SCV and anatomic maximum BP doses were 8.44 and 7.14 Gy, respectively. CONCLUSIONS: There is considerable variability in dose delivered to the BP after SBRT to apical lung tumors. BPI after single-fraction SBRT to apical tumors is rare and rates are comparable with those reported with multifraction regimens.

Right Atrial Dose Is Associated with Worse Outcome in Patients Undergoing Definitive Stereotactic Body Radiation Therapy for Central Lung Tumors.

The consequence of cardiac substructure irradiation in patients receiving stereotactic body radiation therapy (SBRT) is not well characterized. We reviewed the charts of patients with central lung tumors managed by definitive SBRT from June 2010-April 2019. All patients were treated with five fractions, typically either 5000 cGy (44.6%) or 5500 cGy (42.2%). Via a multi-patient atlas, fourteen cardiac substructures were autosegmented, manually reviewed and analyzed using dosimetric parameters. A total of 83 patients were included with a median follow up of 33.4 months. Univariate Cox regression analysis identified a D45% dose to the right atria and ventricle for further study. Sequential log-rank testing evaluating an association between non-cancer associated survival and D45% dose to the right atria or ventricle and association was employed, identifying candidate cutoff values of 890.3 cGy and 564.4 cGy, respectively. Kaplan-Meier analysis using the reported cutoff values found the D45% right atria constraint to be significantly associated with non-cancer associated (p ≤ 0.001) and overall survival (p ≤ 0.001) but not the right ventricle constraint. Within a multivariate model, the proposed right atria D45% cutoff remained significantly correlated with non-cancer associated survival (Hazard's Ratio (HR) ≤ 8.5, 95% confidence interval (CI) 1.1-64.5, p ≤ 0.04) and OS (HR ≤ 6.1, 95% CI 1.0-36.8, p ≤ 0.04). In conclusion, a dose to D45% of the right atria significantly correlated with outcome and the candidate constraint of 890 cGy stratified non-cancer associated and OS. The inclusion of these findings with previously characterized relationships between proximal airway constraints and survival enhances our understanding of why centrally located tumors are high risk and potentially identifies key constraints in organ at risk prioritization.

Exceeding Radiation Dose to Volume Parameters for the Proximal Airways with Stereotactic Body Radiation Therapy Is More Likely for Ultracentral Lung Tumors and Associated with Worse Outcome.

The preferred radiotherapeutic approach for central (CLT) and ultracentral (UCLT) lung tumors is unclear. We assessed the toxicity and outcomes of patients with CLT and UCLT who underwent definitive five-fraction stereotactic body radiation therapy (SBRT). We reviewed the charts of patients with either CLT or UCLT managed with SBRT from June 2010-April 2019. CLT were defined as gross tumor volume (GTV) within 2 cm of either the proximal bronchial tree, trachea, mediastinum, aorta, or spinal cord. UCLT were defined as GTV abutting any of these structures. Propensity score matching was performed for gender, performance status, and history of prior lung cancer. Within this cohort of 83 patients, 43 (51.8%) patients had UCLT. The median patient age was 73.1 years with a median follow up of 29.9 months. The two most common dose fractionation schemes were 5000 cGy (44.6%) and 5500 cGy (42.2%) in five fractions. Multivariate analysis revealed UCLT to be associated with worse overall survival (OS) (HR = 1.9, p = 0.02) but not time to progression (TTP). Using propensity score match pairing, UCLT correlated with reduced non-cancer associated survival (p = 0.049) and OS (p = 0.03), but not TTP. Within the matched cohort, dosimetric study found exceeding a D4cc of 18 Gy to either the proximal bronchus (HR = 3.9, p = 0.007) or trachea (HR = 4.0, p = 0.02) was correlated with worse non-cancer associated survival. In patients undergoing five fraction SBRT, UCLT location was associated with worse non-cancer associated survival and OS, which could be secondary to excessive D4cc dose to the proximal airways.

Prior Treatment for Non-small Cell Lung Cancer Is Associated With Improved Survival in Patients who Undergo Definitive Stereotactic Body Radiation Therapy for a Subsequent Lung Malignancy: A Retrospective Multivariate and Matched Pair Analysis.

BACKGROUND: Despite occurring commonly, the prognoses of second early-stage non-small cell lung cancers (NSCLC) are not well known. METHODS: The authors retrospectively reviewed the charts of inoperable patients who underwent thoracic stereotactic body radiation therapy (SBRT) from February 2007 to April 2019. Those with previous small cell lung cancers or SBRT treatments for tumors other than NSCLC were excluded. Multivariate Cox regression and a matched pair cohort analyses evaluated the prognoses of patients undergoing definitive SBRT for a new second primary. RESULTS: Of 438 patients who underwent definitive SBRT for NSCLC, 84 had previously treated NSCLC. Univariate log-rank tests identified gender, Karnofksy performance status (KPS), prior lung cancer, anticoagulation use, and history of heart disease to correlate with overall survival (OS) (P<0.05). These factors were incorporated into a multivariate Cox regression model that demonstrated female sex (P=0.004, hazard ratio [HR]=0.68), KPS (P<0.001, HR=2.0), and prior lung cancer (P=0.049, HR=0.7) to be significantly associated with OS. A similar approach found only gender (P=0.017, HR=0.64) and tumor stage (P=0.02, HR=1.7) to correlate with relapse-free survival. To support the Cox regression analysis, propensity score matching was performed using gender, age, KPS, tumor stage, history of heart disease, and anticoagulation use. Kaplan-Meier survival analysis within the matched pairs found prior lung cancer to be associated with improved OS (P=0.011), but not relapse-free survival (P=0.44). CONCLUSIONS: Compared with initial lung cancer SBRT inoperable cases, ablative radiotherapy for new primaries was associated with improved OS. Physicians should not be dissuaded from offering SBRT to such patients.

A pilot study of stereotactic body radiation therapy (SBRT) after surgery for stage III non-small cell lung cancer.

BACKGROUND: Standard therapy for stage III non-small cell lung cancer with chemotherapy and conventional radiation has suboptimal outcomes. We hypothesized that a combination of surgery followed by stereotactic body radiation therapy (SBRT) would be a safe alternative. METHODS: Patients with stage IIIA (multistation N2) or IIIB non-small cell lung cancer were enrolled from March 2013 to December 2015. The protocol included transcervical extended mediastinal lymphadenectomy (TEMLA) followed by surgical resection, 10 Gy SBRT directed to the involved mediastinum/hilar stations and/or positive surgical margins, and adjuvant systemic therapy. Patients not suitable for anatomic lung resection were treated with 30 Gy to the primary tumor. The primary efficacy end-point was the proportion of patients with grade 3 or higher adverse events (AE) or toxicities. RESULTS: Of 10 patients, 7 patients underwent neoadjuvant chemotherapy. All patients had TEMLA. Nine of 10 patients underwent surgical resection. The remaining patient had an unresectable tumor and received 30 Gy SBRT to the primary lesion. All patients had post-operative SBRT. Median follow-up was 18 months. There were no perioperative mortalities. Six patients had any grade 3 AEs with no grade 4-5 AEs. Of these, 4 were not attributable to radiation. Pulmonary-related grade 3 AEs were experienced by 2 patients. There were no failures within the 10 Gy volume. Overall survival and progression-free survival rates at 2 years were 68% (90% CI 36-86) and 40% (90% CI 16-63), respectively. CONCLUSIONS: In carefully selected patients with locally advanced non-small cell lung cancer, combining surgery with SBRT was well tolerated with no local failure. TRIAL REGISTRATION: ClinicalTrials.gov identifying number NCT01781741 . Registered February 1, 2013.

Therapeutic approaches in the management of locally advanced rectal cancer.

Combined-modality therapy, using radiotherapy and chemotherapy with surgery, has been the traditional therapeutic algorithm for locally advanced rectal cancer. Standard of care in the United States has evolved to include neoadjuvant concurrent chemotherapy and radiotherapy followed by surgical excision and adjuvant chemotherapy. This approach has led to a significant improvement in local recurrences (LR), to the point where distant sites are the more common site of failure. Further improvements in local control have failed to improve overall survival. This article reviews historical trials that shifted the treatment paradigm to the current standard of care, as well as recent research trials, which have sought to incorporate new treatment methodologies, and treatment agents to improve outcomes. Finally this article describes ongoing studies and their potential impact on the future of therapeutic management of locally-advanced rectal cancer.

Stereotactic Body Radiotherapy for the Treatment of Renal Tumors.

The purpose of this study was to evaluate the response of actively growing renal masses to stereotactic body radiation therapy (SBRT). We retrospectively reviewed our institutional review board-approved kidney database and identified 4 patients who underwent SBRT, 15 Gy dose, for their rapidly growing renal masses. Three patients had a decreased tumor size after radiation treatment by 20.8%, 38.1%, and 20%. The other patient had a size gain of 5.6%. This patient maintained a similar tumor growth rate before and after SBRT. Mean follow-up time was 13.8 months. SBRT represents an effective management option in select patients with larger rapidly growing kidney masses.

The role of active surveillance in the management of prostate cancer.

In 2010, NCCN incorporated active surveillance (AS) into the NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer, and the 2012 update serves as an excellent resource with the most current evidence regarding treatment options for men with all stages of disease. However, the lack of clinical trials that directly compare various treatment modalities or identify the best management, especially for men with low-risk prostate cancer, makes the decision-making process difficult for both patients and physicians. Although general agreement exists on definitions of candidates for AS-men with low-volume and low-grade disease thought to be at low risk for rapid progression-several key issues remain in establishing and supporting the role of AS in the management of prostate cancer, such as optimal timing and appropriate triggers for active treatment. The decision to initially pursue AS rather than active treatment after prostate cancer diagnosis is complex and involves myriad factors, including estimation of life expectancy, consideration of quality of life, and assessment of ultimate oncologic outcome.

A prospective trial of volumetric intensity-modulated arc therapy vs conventional intensity modulated radiation therapy in advanced head and neck cancer.

AIM: To prospectively compare volumetric intensity-modulated arc therapy (VMAT) and conventional intensity-modulated radiation therapy (IMRT) in coverage of planning target volumes and avoidance of multiple organs at risk (OARs) in patients undergoing definitive chemoradiotherapy for advanced (stage III or IV) squamous cell cancer of the head and neck. METHODS: Computed tomography scans of 20 patients with advanced tumors of the larynx, naso-, oro- and hypopharynx were prospectively planned using IMRT (7 field) and VMAT using two arcs. Calculated doses to planning target volume (PTV) and OAR were compared between IMRT and VMAT plans. Dose-volume histograms (DVH) were utilized to obtain calculated doses to PTV and OAR, including parotids, cochlea, spinal cord, brainstem, anterior tongue, pituitary and brachial plexus. DVH's for all structures were compared between IMRT and VMAT plans. In addition the plans were compared for dose conformity and homogeneity. The final treatment plan was chosen by the treating radiation oncologist. RESULTS: VMAT was chosen as the ultimate plan in 18 of 20 patients (90%) because the plans were thought to be otherwise clinically equivalent. The IMRT plan was chosen in 2 of 20 patients because the VMAT plan produced concentric irradiation of the cord which was not overcome even with an avoidance structure. For all patients, VMAT plans had a lower number of average monitor units on average (MU = 542.85) than IMRT plans (MU = 1612.58) (P < 0.001). Using the conformity index (CI), defined as the 95% isodose volume divided by the PTV, the IMRT plan was more conformal with a lower conformity index (CI = 1.61) than the VMAT plan (CI = 2.00) (P = 0.003). Dose homogeneity, as measured by average standard deviation of dose distribution over the PTV, was not different with VMAT (1.45 Gy) or IMRT (1.73 Gy) (P = 0.069). There were no differences in sparing organs at risk. CONCLUSION: In this prospective study, VMAT plans were chosen over IMRT 90% of the time. Compared to IMRT, VMAT plans used only one third of the MUs, had shorter treatment times, and similar sparing of OAR. Overall, VMAT provided similar dose homogeneity but less conformity in PTV irradiation compared to IMRT. This difference in conformity was not clinically significant.

Theoretical quality assessment of myocardial elastography with in vivo validation.

Myocardial elastography (ME), a radio frequency (RF)-based speckle tracking technique with one-dimensional (1-D) cross correlation and novel recorrelation methods in a 2-D search was proposed to estimate and fully image 2-D transmural deformation field and to detect abnormal cardiac function. A theoretical framework was first developed in order to evaluate the performance of 2-D myocardial elastography based on a previously developed 3-D finite-element model of the canine left ventricle. A normal (control) and an ischemic (left-circumflex, LCx) model, which more completely represented myocardial deformation than a kinematic model, were considered. A 2-D convolutional image formation model was first used to generate RF signals for quality assessment of ME in the normal and ischemic cases. A 3-D image formation model was further developed to investigate the effect of the out-of-plane motion on the 2-D, in-plane motion estimation. Both orthogonal, in-plane displacement components (i.e., lateral and axial) between consecutive RF frames were iteratively estimated. All the estimated incremental 2-D displacements from end-diastole (ED) to end-systole (ES) were then accumulated to acquire the cumulative 2-D displacements, which were further used to calculate the cumulative 2-D systolic finite strains. Furthermore, the cumulative systolic radial and circumferential strains, which were angle- and frame-rate independent, were obtained from the 2-D finite-strain components and imaged in full view to detect the ischemic region. We also explored the theoretical understanding of the limitations of our technique for the accurate depiction of disease and validated it in vivo against tagged magnetic resonance imaging (tMRI) in the case of a normal human myocardium in a 2-D short-axis (SA) echocardiographic view. The theoretical framework succeeded in demonstrating that the 2-D myocardial elastography technique was a reliable tool for the complete estimation and depiction of the in-plane myocardial deformation field as well as for accurate identification of pathological mechanical function using established finite-element, left-ventricular canine models. In a preliminary study, the 2-D myocardial elastography was shown capable of imaging myocardial deformation comparable to equivalent tMRI estimates in a clinical setting.

ECG-gated, mechanical and electromechanical wave imaging of cardiovascular tissues in vivo.

In simplistic terms, the motion of the heart can be summarized as an active contraction and passive relaxation of the myocardium. However, the local motion of cardiovascular tissues over the course of an entire cardiac cycle results from various transient events such as the valves closing/opening, sudden changes in blood pressure and electrical conduction of the myocardium. The transient motion generated by most of these events occurs within a very short time (on the order of 1 ms) and cannot be imaged correctly with conventional imaging systems, due to their limited temporal resolution. In this paper, we propose a method for imaging this rapid transient motion of tissues in cardiovascular applications. Our method is based on imaging tissues with ultrasound at high frame rates (up to 8000 fps) by synchronizing the two-dimensional (2D) image acquisition on the electrocardiogram (ECG) signals. In vivo feasibility is demonstrated in anesthetized mice. The propagation of several transient mechanical waves was imaged in different regions of the myocardium and the wave phase velocities were found to be between 0.44 m/s and 5 m/s. These waves may be generated by either a purely mechanical effects or through electromechanical coupling in the myocardium depending on the phase of the cardiac cycle, in which they occur. The abdominal aorta was also imaged using the same technique and the propagation of a mechanical pulse wave was imaged. The pulse wave velocity was measured and the Young's modulus of the vessel wall was derived based on the Moens-Korteweg equation. This method could potentially be used for mapping the stiffness of the myocardium and the artery walls and may lead to the early diagnosis of cardiovascular diseases.

Elastographic imaging of strain distribution in the anterior cruciate ligament and at the ligament-bone insertions.

The anterior cruciate ligament (ACL) functions as a mechanical stabilizer in the tibiofemoral joint, and is the most commonly injured knee ligament. To improve the clinical outcome of tendon grafts used for ACL reconstructions, our long-term goal is to promote graft-bone integration via the regeneration of the native ligament-bone interface. An understanding of strain distribution at this interface is crucial for functional scaffold design and clinical evaluation. Experimental determination, however, has been difficult due to the small length scale of the insertion sites. This study utilizes ultrasound elastography to characterize the response of the ACL and ACL-bone interface under tension. Specifically, bovine tibiofemoral joints were mounted on a material testing system and loaded in tension while radiofrequency (RF) data were acquired at 5 MHz. Axial strain elastograms between RF frames and a reference frame were generated using crosscorrelation and recorrelation techniques. Elastographic analyses revealed that when the joint was loaded in tension, complex strains with both compressive and tensile components occurred at the tibial insertion, with higher strains found at the insertion sites. In addition, the displacement was greatest at the ACL proper and decreased in value gradually from ligament to bone, likely a reflection of the matrix organization at the ligament-bone interface. Our results indicate that elastography is a novel method that can be readily used to characterize the mechanical properties of the ACL and its insertions into bone.

Imaging the mechanics and electromechanics of the heart.

The heart is a mechanical pump that is electrically driven. We have previously shown that the contractility of the cardiac muscle can reliably be used in order to assess the extent of ischemia using myocardial elastography. Myocardial elastography estimates displacement and strain during the natural contraction of the myocardium using signal processing techniques on echocardiograms in order to assess the change in mechanical properties as a result of disease. In this paper, we showed that elastographic techniques can be used to estimate and image both the mechanics and electromechanics of normal and pathological hearts in vivo. In order to image the mechanics throughout the entire cardiac cycle, the minimum frame rate was determined to be on the order of 150 fps in a long-axis view and 300 fps in a short-axis view. The incremental and cumulative displacement and strains were measured and imaged for the characterization of normal function and differentiation from infracted myocardium. In order to image the electromechanical function, the incremental displacement was imaged inconsecutive cardiac cycles during end-systole in both dogs and humans. The contraction wave velocity in normal dogs was found to be twice higher than in normal humans and twice lower than in ischemic dogs. In conclusion, we have demonstrated that elastographic techniques can be used to detect and quantify the mechanics and electromechanics of the myocardium in vivo. Ongoing investigations entail assessment of myocardial elastography in characterizing and quantifying ischemia and infarction in vivo.