Clinical Factors That Affect Fiducial Tracking in Robotic SABR for Lung Tumors.

Purpose: SABR is a treatment option for patients with lung tumors that employs fiducials to track tumors during the breathing cycle. Currently, there is a paucity of data on how relative fiducial location and patient clinical characteristics affect fiducial tracking and clinical outcomes. This study aimed to identify factors that reduce the number of fiducials tracked with respiratory motion management during SABR. Methods and Materials: An institutional review board-approved retrospective review was performed of patients receiving robotic SABR for lung tumors at our institution from 2016 to 2019. Clinical data including demographics, medical history, treatment data, and follow-up were collected. Fiducial geometries were obtained with Velocity contouring software and MATLAB. Mann-Whitney U, χ2, and t tests were completed using MedCalc. Results: A total of 73 patients with 77 treatments were identified. The χ2 analysis revealed that chronic obstructive pulmonary disease was associated with having 3 or more fiducials tracked (P = .034). Tumors in lower lobes were associated with higher rates of uncertainty errors (P = .015). The number of fiducials tracked had no effect on local tumor control or overall survival, with a median of 36 months of follow-up. A total of 28 treatments had fiducial centroid data available for geometric analysis. The most common tracking errors were rigid body error (RBE; 57%) and spacing errors (36.4%). Spacing errors had a shorter average minimum interfiducial distance than nonspacing errors (1.0 cm vs 1.7 cm, respectively; P = .017). RBE treatments had a longer average maximum distance than non-RBE treatments (4.0 cm vs 3.0 cm; P = .022). Conclusions: Greater motion in lower lobes can contribute to certain tracking errors that prevent more fiducials from being tracked. Maintaining interfiducial distance between experimentally determined guidelines may limit spacing errors and RBEs, the 2 most common tracking errors. An increased number of patients in a data set may result in stronger correlations between patient and tumor factors and outcomes.

Survival Is Worse in Patients Completing Immunotherapy Prior to SBRT/SRS Compared to Those Receiving It Concurrently or After.

Purpose/Objectives: The abscopal effect could theoretically be potentiated when combined with immunomodulating drugs through increased antigen production. The optimal dosing and schedule of radiotherapy with immunotherapy are unknown, although they are actively investigated in laboratory and clinical models. Clinical data in patients treated for metastatic disease with both modalities may guide future studies. Materials and Methods: This is a single-institution retrospective review of all patients treated with stereotactic body radiotherapy (SBRT)/stereotactic radiosurgery (SRS) and immunomodulating therapy within 6 months before or after SBRT/SRS for metastatic cancer. Clinical and tumor characteristics were recorded, as well as SBRT/SRS details, immunotherapy details, and survival. Log-rank tests on Kaplan-Meier curves for overall survival (OS) that were calculated from the end of SBRT/SRS were used in univariate analysis and Cox proportional hazards regression for multivariate analysis. Results: A total of 125 patients were identified who met the inclusion criteria; 70 received SBRT, and 57 received SRS. Eighty-three patients were treated for non-small cell lung cancer, 7 patients for small cell lung cancer, and 35 patients for other cancers, with the most common one being melanoma. Fifty-three percent of patients received nivolumab, 29% pembrolizumab, 13% atezolizumab, 5% other. Twenty percent received immunotherapy before SBRT/SRS, 39% during SBRT/SRS, 41% after. Eighty-six patients had died by the time of the analysis; the median OS for the whole cohort was 9.7 months. Patients who had completed immunotherapy prior to SBRT/SRS had worse OS than those who received concurrent therapy or immunotherapy after SBRT/SRS, with a difference in median OS of 3.6 months vs. 13.0 months (p = 0.010) that was retained on multivariate analysis (p = 0.011). There was no significant difference in OS between patients receiving SRS vs. SBRT (p = 0.20), sex (p = 0.53), age >62 years (p = 0.76), or lung primary vs. others (p = 0.73) on univariate or multivariate analysis. When comparing before/concurrent to after/concurrent administration, there is a difference in survival with after/concurrent survival of 8.181 months and before survival of 13.010 months, but this was not significant (p = 0.25). Conclusions: OS appears to be worse in patients who complete immunotherapy prior to SBRT/SRS compared to those receiving it concurrently or after. The design of this retrospective review may be prone to lead time bias, although the difference in median survival is longer than the 6-month window before SBRT/SRS and could only account for part of this difference. Further analysis into causes of death and toxicity and prospective studies are needed to confirm the results of this analysis.

Circulating cytokine levels in prostate cancer patients undergoing radiation therapy: influence of neoadjuvant total androgen suppression.

BACKGROUND: The purpose of this study was to investigate the immunological impact of combining neoadjuvant total androgen suppression (TAS) with radiotherapy (xRT) in the treatment of prostate cancer by monitoring blood cytokine levels. PATIENTS AND METHODS: Participants were stage I-II prostate cancer patients receiving xRT alone (n=18) or TAS+xRT (n=19) under the procedures outlined in RTOG protocols #94-08 and #94-13. Peripheral blood samples were collected immediately prior to TAS (xRT+TAS group), immediately prior to xRT, 24 hours after initiation of xRT, and weekly during xRT. Samples were monitored for the immunoregulatory cytokines interleukin (IL)-1beta, IL-6 and transforming growth factor (TGF)beta using ELISA procedures. RESULTS: Following initiation of xRT, both patient groups demonstrated an immediate elevation of the proinflammatory cytokines IL-1beta and IL-6 in their plasma. These cytokine levels appeared to peak after 1-2 weeks of xRT before returning toward pre xRT levels. In contrast, the profibrotic cytokine TGFbeta appeared to decrease immediately following initiation of xRT, but, subsequently, underwent two distinct waves of elevation, occurring at 1-2 weeks and 5-6 weeks into the xRT. Surprisingly, while the temporal pattern of plasma cytokine response was similar in both treatment groups, the magnitude of cytokine expression was noticeably different, appearing to be significantly affected by the addition of TAS. Indeed, administration of neoadjuvant TAS appeared to bring about a marked elevation of IL-1beta and IL-6 and a significant reduction in TGFbeta when compared to patients receiving xRT alone. CONCLUSION: The precise mechanisms underlying this TAS-related increase of the proinflammatory cytokines IL-1beta and IL-6 and decrease of the profibrotic cytokine TGFbeta remain unclear. However, previous reports have documented that androgens tend to be immunosuppressive in nature. It is conceivable, therefore, that administration of TAS shifts the ratio of proinflammatory and profibrotic cytokines toward a more immunostimulatory state.

Longitudinal monitoring for the emergence of epidermal growth factor C797S resistance mutations in non-small cell lung cancer using blood-based droplet digital PCR.

Validation of assays for the C797S mutation as a biomarker for osimertinib resistance is promising in guiding treatment decision-making for multidrug resistant non-small cell lung cancer. A newly developed droplet digital PCR (ddPCR) assay was used to retrospectively evaluate the emergence of the C797S mutation in six remnant plasma samples in this case report. It was found that the detected emergence of C797S clearly correlated with clinical signs of treatment resistance. Had these data been available to aid treatment selection in real time, there would have been hope for recaptured disease response and control instead of treatment cessation. The results of this study show that highly sensitive ddPCR methods can be used for the monitoring of emergent epidermal growth factor somatic variant mutations in circulation.

Improved respiratory motion tracking through a novel fiducial marker placement guidance system during electromagnetic navigational bronchoscopy (ENB).

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is a treatment option for patients with early stage non-small cell lung cancer (NSCLC) and recurrent or oligometastatic disease who are not surgical candidates. Due to the continuous motion of tumors within the lungs, implementing a strategy to track the target lesion is crucial. One method is to place fiducial markers which the robotic SABR system is able to track during treatment. However, placing these markers in a manner that maximizes tracking efficacy can be challenging. Using a novel fiducial placement guidance system (FPGS) during fiducial deployment may offer a way to improve the quantity of fiducials tracked by the robotic SABR system. METHOD: This was an institutional, retrospective review identifying all patients who received robotic SABR for lung tumors from May 2015 until January 2017. The FPGS was instituted in May 2016. The median number of fiducials tracked and the rate of complication was compared between patients whose fiducials were placed using FPGS versus those that were not. RESULTS: A total of 128 patients with 147 treated lung lesions were identified. Of the lesions that utilized FPGS (n = 44), 28 had 2 tracked fiducials (63.6%), 14 had 3 (31.8%) and 2 had 4 (4.6%). Of the lesions treated without FPGS (n = 103), 5 had 1 tracked fiducial (4.9%), 91 had 2 (88.4%), 6 had 3 (5.8%), and 2 had 4 (1.9%). A significant improvement in the median number of fiducials tracked per fraction was observed for the lesions with fiducials placed using FPGS on Wilcoxon rank sum test (p < 0.001). The rate of complication was low and not statistically different between cohorts (p = 0.44). CONCLUSIONS: The FPGS can be used during the deployment of fiducial markers and may increase the number of fiducials tracked. TRIAL REGISTRATION: An exemption for this retrospective review was granted by the East Carolina University IRB under UMCIRB 15-001726.

Response criteria in solid tumors (PERCIST/RECIST) and SUVmax in early-stage non-small cell lung cancer patients treated with stereotactic body radiotherapy.

BACKGROUND: The purpose of this study was to evaluate the prognostic impact of Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) and of pre- and post-treatment maximum Standard Uptake Value (SUVmax) in regards to survival and tumor control for patients treated for early-stage non-small cell lung cancer (ES-NSCLC) with stereotactic body radiotherapy (SBRT). METHODS: This is a retrospective review of patients with ES-NSCLC treated at our institution using SBRT. Lobar, locoregional, and distant failures were evaluated based on PERCIST/RECIST and clinical course. Univariate analysis of the Kaplan-Meier curves for overall survival (OS), progression free survival (PFS), lobar control (LC), locoregional control (LRC), and distant control (DC) was conducted using the log-rank test. Pre- and post-treatment SUVmax were evaluated using cutoffs of < 5 and ≥ 5, < 4 and ≥ 4, and < 3 and ≥ 3. ∆SUVmax was also evaluated at various cutoffs. Cox regression analysis was conducted to evaluate survival outcomes based on age, gender, pre-treatment gross tumor volume (GTV), longest tumor dimension on imaging, and Charlson Comorbidity Index (CCI). RESULTS: This study included 95 patients (53 female, 42 male), median age 75. Lung SBRT was delivered in 3-5 fractions to a total of 48-60 Gy, with a BEDα/ß = 10Gy of at least 100 Gy. Median OS and PFS from the end of SBRT was 15.4 and 11.9 months, respectively. On univariate analysis, PERCIST/RECIST response correlated with PFS (p = 0.039), LC (p = 0.007), and LRC (p = 0.015) but not OS (p = 0.21) or DC (p = 0.94). Pre-treatment SUVmax and post-treatment SUVmax with cutoff values of < 5 and ≥ 5, < 4 and ≥ 4, and < 3 and ≥ 3 did not predict for OS, PFS, LC, LRC, or DC. ∆SUVmax did not predict for OS, PFS, LC, LRC, or DC. On multivariate analysis, pre-treatment GTV ≥ 30 cm3 was significantly associated with worse survival outcomes when accounting for other confounding variables. CONCLUSIONS: PERCIST/RECIST response is associated with improved LC and PFS in patients treated for ES-NSCLC with SBRT. In contrast, pre- and post-treatment SUVmax is not predictive of disease control or survival.

A Single-Institution Analysis of 126 Patients Treated with Stereotactic Radiosurgery for Brain Metastases.

BACKGROUND: The objective of this study was to report our institutional experience with Gamma Knife® Radiosurgery (GKRS) in the treatment of patients with brain metastases. METHODS: Retrospectively collected demographic and clinical data on 126 patients with intracranial metastases were reviewed. The patients in our study underwent GKRS at Vidant Medical Center between 2009 and 2014. Kaplan-Meier curves were used to compare survival based on clinical characteristics for univariate analysis, and a Cox proportional hazards model was used for multivariate analysis. RESULTS: The median age of the patient population was 62 years. Medicare patients constituted 51% of our patient cohort and Medicaid patients 15%. The most common tumor histologies were non-small cell lung cancer (50%), breast cancer (12.7%), and melanoma (11.9%). The median overall survival time for all patients was 5.8 months. Patients with breast cancer had the longest median survival time of 9.15 months, while patients with melanoma had the shortest median survival time of 2.86 months. On univariate analysis, the following factors were predictors for improved overall survival, ECOG score 0 or 1 vs. 2 or greater (17.0 vs. 1.8 months, p < 0.001), controlled extracranial disease vs. progressive extracranial disease (17.4 vs. 4.6 months, p = 0.0001), recursive partitioning analysis Stage I vs. II-III (18.2 vs. 6.2 months, p < 0.007), multiple GKRS treatments (p = 0.002), prior brain metastasectomy (p = 0.012), and prior chemotherapy (p = 0.021). Age, ethnicity, gender, previous external beam radiation therapy, number of brain metastases, and hemorrhagic vs. non-hemorrhagic tumors were not predictors of longer median survival time. Number of metastatic brain lesions of 1-3 vs. ≥4 (p = 0.051) and insurance status of Medicare/Medicaid vs. commercial insurance approached significance (13.7 vs. 6.8 months, p = 0.08). On multivariate analysis, ECOG performance status 0-1 (p < 0.001), multiple GKRS treatments (p = 0.003), and control of extracranial disease (p = 0.001) remained significant predictors of survival. CONCLUSION: ECOG score, control of extracranial disease, and multiple GKRS treatments are predictors of longer median survival following GKRS in our patient population. GKRS is an effective treatment for brain metastases, but these factors may be considered in patient selection for GKRS.

Response of T lymphocyte populations in prostate cancer patients undergoing radiotherapy: influence of neoajuvant total androgen suppression.

BACKGROUND: This study sought to better define the immunological impact of combining neoadjuvant total androgen suppression (TAS) with radiotherapy (xRT) in treating prostate cancer. MATERIALS AND METHODS: Subjects selected (n = 37) were stage I-II prostate cancer patients meeting the eligibility requirements for RTOG protocols 94-08 or 94-13. Flow cytometric monitoring of circulating T helper (Th), T suppressor/cytotoxic (Ts), natural killer (NK) and B lymphocytes was performed weekly. RESULTS: Significant reduction of all lymphocyte subsets occurred as a result of xRT. Comparison between treatment groups demonstrated that the B lymphocyte and NK lymphocyte radioresponse was not influenced by TAS, but the Th and Ts lymphocyte response was, with addition of TAS leading to less radiation-induced decline. CONCLUSION: The basis for this T cell response is unclear, but may involve a TAS-induced reduction of testosterone's immunomodulation of T cell proliferation and apoptosis and/or a direct, TAS-induced thymic stimulation. Our data suggest that addition of TAS to xRT appears to have no detrimental effects on lymphocyte subsets, and, indeed, may have favorable effects on T cells.

Lymphocyte radiosensitivity correlated with pelvic radiotherapy morbidity.

PURPOSE: To test the hypothesis that, before treatment, prostate cancer patients who demonstrate a high yield of ex vivo radiation-induced micronucleus (MN) in G(0) lymphocytes represent a patient population with a greater-than-average risk of developing radiotherapy (RT)-related morbidity. METHODS AND MATERIALS: We prospectively conducted the cytokinesis-block MN assay of peripheral blood lymphocytes (PBLs) in 38 prostate cancer patients. Before the initiation of RT, PBLs from each patient were irradiated (1-4 Gy). The mean patient age +/- SEM was 68.7 +/- 1.0 years. The clinical stage was T1 in 17, T2 in 15, and T3 in 6. The preoperative prostate-specific antigen level was < or =4 ng/mL in 5, 4-10 ng/mL in 18, and >10 ng/mL in 15. All patients underwent standardized pelvic external beam radiotherapy (range 41.4-50.4 Gy) and boost (range 16-26 Gy). The mean follow-up +/- SEM was 32.8 +/- 4.6 months. At the end of follow-up, a radiation oncologist scored the GI or GU morbidity according to the Radiation Therapy Oncology Group criteria without knowledge of the MN data. RESULTS: We found that between the average reactors (n = 25; i.e., patients who had Grade 1 or less RT-related morbidity) and over reactors (n = 13; i.e., patients who developed Grade 2 or greater RT-related morbidity), the differences in the ex vivo radiation dose-response relationship of MN yield in PBLs were highly significant, especially at doses of > or =2 Gy. Also, the development of RT-related morbidity correlated with the radiation dose-response relationship of MN yield in PBLs before treatment, but did not correlate with any of the patients' clinical variables. CONCLUSION: Our findings suggest that the pre-RT ex vivo radiation dose-response relationship of MN yield in PBLs may be a significant predictive factor for the development of GI or GU morbidity in prostate cancer patients after pelvic RT.

Stress reactivity, health behaviors, and compliance to medical care in breast cancer survivors.

PURPOSE/OBJECTIVES: To explore relationships among quality of life (QOL), stress reactivity, health behaviors, and compliance to medical care in breast cancer survivors. DESIGN: One-time descriptive laboratory study. SETTING: A visual motor laboratory at a rural university in the southeastern United States. SAMPLE: 25 breast cancer survivors. METHODS: Participants were subjected to the Trier Social Stress Test (TSST) in a laboratory setting and completed questionnaires at home prior to and after the laboratory session. main research variables: Changes in heart rate variability (HRV), salivary cortisol, and state anxiety from the State-Trait Anxiety Inventory (STAI) estimated stress reactivity. Health behaviors, QOL, and trait anxiety were determined by questionnaires. Compliance to medical care was determined from medical records. FINDINGS: Analyses of variance (ANOVAs) indicated that QOL scores were higher for participants with lower compared to higher stress reactivity (p < 0.05). In addition, ANOVAs revealed that participants high in compliance to medical care indicated a lower stress response as determined by HRV (p < 0.01) and the STAI (p < 0.05) compared to those low in compliance. No significant differences were noted in any of the health behaviors based on stress reactivity. CONCLUSIONS: The data suggest that breast cancer survivors who indicate the greatest stress reactivity tend to have the poorest compliance to medical care and lowest QOL. IMPLICATIONS FOR NURSING: Nurses may wish to provide additional support to breast cancer survivors who indicate high stress reactivity in the hopes of improving compliance to medical care and QOL. KNOWLEDGE TRANSLATION: The data suggest that supportive care strategies that reduce stress could potentially improve compliance to medical care in breast cancer survivors. In addition, strategies for managing stress may result in improvements in QOL. Health behaviors, according to the data, do not seem to be influenced by stress reactivity.

Exercise programming and counseling preferences of breast cancer survivors during or after radiation therapy.

PURPOSE/OBJECTIVES: To explore exercise programming and counseling preferences and exercise-related beliefs in breast cancer survivors during and after radiation therapy, and to compare differences based on treatment and insurance status. DESIGN: Cross-sectional survey. SETTING: Ambulatory cancer center in a rural community in eastern North Carolina. SAMPLE: 91 breast cancer survivors during or after radiation therapy. METHODS: The researchers administered the questionnaire to participants. MAIN RESEARCH VARIABLES: Exercise programming and counseling preferences and exercise beliefs moderated by treatment status (on-treatment, early, and late survivors) and insurance status (Medicaid, non-Medicaid). FINDINGS: Chi-square analyses indicated that fewer Medicaid users were physically active and reported health benefits as an advantage of exercise compared to non-Medicaid users (p < 0.05). In addition, more Medicaid users preferred exercise programming at their cancer center compared to non-Medicaid users (p < 0.05). More on-treatment and early survivors listed health benefits as advantages to exercise, but fewer indicated weight control as an advantage compared to late survivors (p < 0.05). Early survivors were more likely than on-treatment survivors to indicate that accessible facilities would make exercising easier for them (p < 0.05). CONCLUSIONS: Medicaid users are less active, less likely to identify health benefits as an advantage for exercising, and more likely to prefer cancer center-based exercise programming compared to non-Medicaid users. In addition, on-treatment and early survivors are more likely to list health benefits and less likely to indicate weight control as advantages of exercising compared to late survivors. IMPLICATIONS FOR NURSING: The low activity levels of Medicaid users may be best targeted by providing cancer center-based exercise programming. Exercise interventions may be most effective if tailored to the unique needs of treatment status.