Stereotactic Body Radiotherapy For Lung Cancer Research Articles

Quantifying day-to-day variations in 4DCBCT-based PCA motion models

The aim of this paper is to quantify the day-to-day variations of motion models derived from pre-treatment 4-dimensional cone beam CT (4DCBCT) fractions for lung cancer stereotactic body radiotherapy (SBRT) patients. Motion models are built by (1) applying deformable image registration (DIR) on each 4DCBCT image with respect to a reference image from that day, resulting in a set of displacement vector fields (DVFs), and (2) applying principal component analysis (PCA) on the DVFs to obtain principal components representing a motion model. Variations were quantified by comparing the PCA eigenvectors of the motion model built from the first day of treatment to the corresponding eigenvectors of the other motion models built from each successive day of treatment. Three metrics were used to quantify the variations: root mean squared (RMS) difference in the vectors, directional similarity, and an introduced metric called the Euclidean Model Norm (EMN). EMN quantifies the degree to which a motion model derived from the first fraction can represent the motion models of subsequent fractions. Twenty-one 4DCBCT scans from five SBRT patient treatments were used in this retrospective study. Experimental results demonstrated that the first two eigenvectors of motion models across all fractions have smaller RMS (0.00017), larger directional similarity (0.528), and larger EMN (0.678) than the last three eigenvectors (RMS: 0.00025, directional similarity: 0.041, and EMN: 0.212). The study concluded that, while the motion model eigenvectors varied from fraction to fraction, the first few eigenvectors were shown to be more stable across treatment fractions than others. This supports the notion that a pre-treatment motion model built from the first few PCA eigenvectors may remain valid throughout a treatment course. Future work is necessary to quantify how day-to-day variations in these models will affect motion reconstruction accuracy for specific clinical tasks.

Pretreatment Factors Influencing Radiation Pneumonitis after Stereotactic Body Radiation Therapy in the Treatment of Lung Cancer

ObjectiveRadiation pneumonitis (RP) is a dose-limiting toxicity that affects the treatment of lung cancer. Data on factors predictive of developing symptomatic RP after stereotactic body radiation therapy (SBRT) are limited. We reviewed data to identify pretreatment factors predictive of the development of symptomatic RP in patients’ lung cancer treated with SBRT.MethodsData were collected on 296 patients treated with SBRT for lung cancer. Factors available at time of consultation were analyzed for the development of symptomatic RP, defined as CTCAE v. 4.0 ≥ Grade 2. The factors analyzed included patient demographic, tumor-specific, and pretreatment pulmonary function data. Univariate and multivariate analyses were performed to assess for predictive factors.ResultsMedian follow-up was 22 months. The rate of symptomatic RP was 16%. Univariate analysis showed an increased rate of symptomatic RP with treatments to the right lung (22% vs. 9%, p = 0.007), driven primarily by an increased rate of symptomatic RP when treating the right lower lobe (RLL) vs. other lobes (31 vs. 13%, p = 0.03). Patients with a history of prior lung directed therapy were also more likely to develop symptomatic RP (12% vs. 24%, p = 0.008). These statistical differences were retained on multivariate analysis.ConclusionSBRT to the right lung, especially the RLL, and to patients with a history of prior lung-directed therapy increases the risk of developing symptomatic RP after SBRT. Further studies on ways to predict and prevent symptomatic RP are needed.

Stereotactic Image Guided Lung Radiation Therapy for Clinical Early Stage Non-Small Cell Lung Cancer: A Long-Term Report From a Multi-Institutional Database of Patients Treated With or Without a Pathologic Diagnosis

PurposeEarly stage lung cancer is treated with stereotactic body radiation therapy (SBRT) in patients who are unable or unwilling to undergo surgical resection. Some patients’ comorbidities are so severe that they are unable to even undergo a biopsy. A clinical diagnosis without biopsy before SBRT has been used, but there are limited data on its efficacy. Methods and MaterialsData on patients treated with SBRT for non-small cell lung cancer, with and without tissue confirmation, were collected from multiple institutions across Europe, Canada, and the United States. Patients with a minimum of 2 years of comprehensive follow up were selected for analysis. Treatment and patient characteristics were compared. Overall survival (OS), disease-free survival (DFS), cause-specific survival (CSS), and rates of local recurrence (LR), regional recurrence (RR), and distant metastasis (DM) were calculated and analyzed. ResultsA total of 701 patients were identified, of which 67% had tissue confirmation of their tumors. The 3- and 5-year outcomes for OS, CSS, and DFS were 83.8%, 93.1%, 69%, and 60.6%, 86.7%, 45.5%, respectively. The rates for LR, RR, and DM at 3 and 5 years were 6.4%, 9.3%, 14.3%, and 10.5%, 14.3%, 19.7%, respectively. There were no statistically significant differences in survival outcomes or recurrences between the biopsy and no-biopsy cohorts. ConclusionsSBRT for clinically diagnosed lung cancers is efficacious in appropriately selected patients, with similar outcomes as those with a pathologic diagnosis. Thorough clinical and radiographic evaluations in a multidisciplinary setting are critical to the management of these patients.

Patterns of stereotactic body radiation therapy: The influence of lung cancer treatment on prostate cancer treatment

IntroductionTechnology availability and prior experience with novel cancer treatments may partially drive their use. We sought to examine this issue in the context of stereotactic body radiation therapy (SBRT) by studying how its use for an established indication (lung cancer) impacts its use for an emerging indication (prostate cancer). MethodsUsing SEER-Medicare from 2007 to 2011, we developed prostate cancer-specific physician-hospital networks. Our primary dependent variable was SBRT use for prostate cancer and our primary independent variable was SBRT use for lung cancer, both at the network level. To assess the influence of SBRT availability and experiential use, we generated predicted probabilities of SBRT use for prostate cancer stratified by a network's use of lung cancer SBRT, adjusting for network characteristics. To assess intensity of use, we examined the correlation between the proportion of prostate cancer patients and lung cancer patients receiving SBRT within a network. ResultsWe identified 316 networks that served 41,034 prostate cancer and 83,433 lung cancer patients. A network was significantly more likely to use SBRT for prostate cancer if that network used SBRT for lung cancer (e.g., in 2011, odds ratio [OR] 12.7; 95% confidence interval [CI] 3.9-41.8). The Pearson's correlation between the proportion of prostate cancer patients and lung cancer patients receiving SBRT in a network was 0.34, which was not statistically significant (P = 0.12). ConclusionsSBRT availability and experiential use for lung cancer influences its use for prostate cancer, but intensity of use for one does not relate to intensity of use for the other.

Radiation-induced lung injury patterns and the misdiagnosis after SBRT of lung cancer

PurposeTo analyze radiation-induced lung injury (RIL) after stereotactic body radiotherapy (SBRT) of lung cancer and the subsequent clinical problems. Methods106 lung cancer patients treated with SBRT were included, their computed tomography (CT) scans were reviewed. Late injury pattern was classified by Koening’s, radiologist’ diagnosis reports for RIL was reviewed. Logistic regression was used to analyze the predictive model of injury pattern, which was also validated by ROC curve. ResultsRadiographic late injury within at least 6 months after SBRT was concluded. The majority of late RIL was mass-like pattern, not the modified conventional pattern. 36.8% patients showed acute injury, which trend to occur late lung injury earlier than patients who were not found acute injury (p = 0.0185). 24.5% RIL cases were misdiagnosed to tumor progression by radiologists. Most misdiagnosis occurred among mass-like pattern. Per fraction dose (p < 0.0001), prescription isodose line (p = 0.027) and age (p = 0.089) trend to associate with the occurrence of mass-like injury pattern. Nomogram was established based on these parameters, ROC curve showed that area under the ROC curve (AUC) of the nomogram was 0.767 (95% CI = 0.677-0.857), which was better than any factors along. ConclusionSBRT for lung cancer patients was safe, the majority of late RIL was mass-like pattern. This injury was difficult to be distinguished from tumor progression, which leaded to misdiagnosis of 24.5% patients receiving SBRT. A nomogram based on age, per fraction dose and the prescription isodose line may assist the diagnosis in clinical practice.

Clinical experience with lung-specific electromagnetic transponders for real-time tumor tracking in lung stereotactic body radiotherapy.

Motion management is crucial for optimal stereotactic body radiotherapy (SBRT) of moving targets. We aimed to describe our clinical experience with real-time tracking of lung-specific electromagnetic transponders (EMTs) for SBRT of early stage non-small cell lung cancer in free-breathing (FB) or deep inspiration breath-hold (DIBH). Seven patients were implanted with EMTs. Simulation for SBRT was performed in FB and in DIBH. We prescribed 60Gy in 3, 5 or 8 fractions to the tumor and delivered SBRT with volumetric modulated arcs and a 6MV flattening filter free photon beam. Patients' setup at the linac was performed using EMT positions and cone-beam CT (CBCT) verification. Four patients were treated in DIBH because of a dosimetric benefit. We analysed patient alignment and treatment delivery parameters using DIBH or FB and EMT real-time tracking. There were no complications from the EMT implantation. Visual inspection of CBCT before and/or after SBRT revealed good alignment of structures and EMTs. The median setup time was 9.8min (range: 4.6-34.1min)and the median session time was 14.7min (range: 7.3-36.5min). EMT positions in lungs remained stable during overall treatment and allowed real-time tracking both in FB and in DIBH SBRT. The treatment beam was gated when EMT centroid position exceeded tolerance thresholds ensuring correct delivery of radiation to the tumor. Using EMTs for real-time tracking of tumor motion during lung SBRT proved to be safe, accurate and easy to integrate clinically for treatments in FB or DIBH.

JCSE01.17 Modelling the Immunosuppressive Difference of SBRT and CRT by Simulating the Dose to Circulating Lymphocytes in Non-Small Cell Lung Cancer

Radiation-dose delivered to circulating lymphocyte (CL) has detrimental effect on immune system for cancer patients. Our study established a model to compare the cumulative dose on CL of patients with conventional fractionation radiotherapy (CRT) and stereotactic body radiation therapy (SBRT) in lung cancer with different target volume. The improved model is based on convolution algorithm suggested by Yovino (Cancer Investigation, 2013). The current blood DVHs of each organ were multiplied with treatment field DVH to generate original DVHs. During one second, 0.6% of whole-body blood circulates through each organ and rest body according to blood circulating pattern and then new DVHs of organ were generated. The new DVHs would be used for next second’s calculation with treatment field DVH. Conventional fractionated non-small cell lung cancer plan 60Gy (30 fractions*2.0Gy) and SBRT plan 50Gy (5fractions*10Gy) are constructed for three patients with different target volumes. The primary endpoint is peak cumulative blood dose (PCBC). PCBC of three patients with CRT and SBRT were calculated as Figure 1. PCBC with CRT to circulating lymphocyte (CL) were 2.5Gy, 5.6Gy, 9.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. And PCBC with SBRT to circulating lymphocyte (CL) were 2.1Gy, 2.9Gy, 6.0Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. PCBC gap of SBRT to circulating lymphocyte (CL) was decreased 0.4Gy, 2.7Gy, 3.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. An improved simulation-model was established, SBRT, compared to CRT, will lead to decreased cumulative dose on CL, which may cause less impact on immune system with the enlargement of PTV-volume.

P1.04-69 Modelling the Immunosuppressive Difference of SBRT and CRT by Simulating the Dose to Circulating Lymphocytes in Non-Small Cell Lung Cancer

Radiation-dose delivered to circulating lymphocyte (CL) has detrimental effect on immune system for cancer patients. Our study established a model to compare the cumulative dose on CL of patients with conventional fractionation radiotherapy (CRT) and stereotactic body radiation therapy (SBRT) in lung cancer with different target volume. The improved model is based on convolution algorithm suggested by Yovino (Cancer Investigation, 2013). The current blood DVHs of each organ were multiplied with treatment field DVH to generate original DVHs. During one second, 0.6% of whole-body blood circulates through each organ and rest body according to blood circulating pattern and then new DVHs of organ were generated. The new DVHs would be used for next second’s calculation with treatment field DVH. Conventional fractionated non-small cell lung cancer plan 60Gy (30 fractions*2.0Gy) and SBRT plan 50Gy (5fractions*10Gy) are constructed for three patients with different target volumes. The primary endpoint is peak cumulative blood dose (PCBC). PCBC of three patients with CRT and SBRT were calculated as Figure 1. PCBC with CRT to circulating lymphocyte (CL) were 2.5Gy, 5.6Gy, 9.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. And PCBC with SBRT to circulating lymphocyte (CL) were 2.1Gy, 2.9Gy, 6.0Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. PCBC gap of SBRT to circulating lymphocyte (CL) was decreased 0.4Gy, 2.7Gy, 3.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. An improved simulation-model was established, SBRT, compared to CRT, will lead to decreased cumulative dose on CL, which may cause less impact on immune system with the enlargement of PTV-volume.

Questionnaire survey comparing surgery and stereotactic body radiotherapy for lung cancer: lessons from patients with experience of both modalities.

Currently, there is some controversy regarding indications for stereotactic body radiotherapy (SBRT) for lung cancer patients. We investigated the treatment preferences of patients with experience of both surgery and SBRT using a questionnaire survey. Of lung cancer patients treated with SBRT between 2005 and 2017, we identified those who also previously underwent surgery for lung cancer. These patients were asked about their experiences of surgery and SBRT including perceived condition, distress, stress, convenience, adverse effects, and satisfaction during and after treatment. Participants were also asked about treatment decision-making for hypothetical scenarios. Of 653 lung cancer patients treated with SBRT, 149 also underwent surgery for lung cancer, 52 of whom participated in this questionnaire. The median age at the time of this survey was 76 years (range, 59-91 years). Significantly more participants had a favorable impression of SBRT during and after treatment (all question items; P<0.01). In terms of overall satisfaction, 27 patients preferred SBRT and three patients preferred surgery. In a hypothetical scenario (equivalent treatment outcomes) aged 70 years and faced with decision-making for first-time lung cancer treatment, significantly more patients selected SBRT (P<0.01): 38 patients selected SBRT. In a scenario with 20% better survivals for surgical resection, 14 patients selected SBRT, 12 selected surgery, and 26 were indecisive (P=0.47). In a scenario at age 80 years, significantly more patients selected SBRT (P<0.01). Most patients with experience of both surgery and SBRT for lung cancer prefer SBRT. This information would be helpful at treatment decision-making.

Maximum standardized uptake value at pre-treatment PET in estimating lung cancer progression after stereotactic body radiotherapy.

PurposeThis study aimed to identify the feasibility of the maximum standardized uptake value (SUVmax) on baseline 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) as a predictive factor for prognosis in early stage primary lung cancer treated with stereotactic body radiotherapy (SBRT).Materials and MethodsTwenty-seven T1-3N0M0 primary lung cancer patients treated with curative SBRT between 2010 and 2018 were retrospectively evaluated. Four patients (14.8%) treated with SBRT to address residual tumor after wedge resection and one patient (3.7%) with local recurrence after resection were included. The SUVmax at baseline PET/CT was assessed to determine its relationship with prognosis after SBRT. Patients were divided into two groups based on maximum SUVmax on pre-treatment FDG PET/CT, estimated by receiver operating characteristic curve.ResultsThe median follow-up period was 17.7 months (range, 2.3 to 60.0 months). The actuarial 2-year local control, progressionfree survival (PFS), and overall survival were 80.4%, 66.0%, and 78.2%, respectively. With regard to failure patterns, 5 patients exhibited local failure (in-field failure, 18.5%), 1 (3.7%) experienced regional nodal relapse, and other 2 (7.4%) developed distant failure. SUVmax was significantly correlated with progression (p = 0.08, optimal cut-off point SUVmax > 5.1). PFS was significantly influenced by pretreatment SUVmax (SUVmax > 5.1 vs. SUVmax ≤ 5.1; p = 0.012) and T stage (T1 vs. T2-3; p = 0.012).ConclusionSUVmax at pre-treatment FDG PET/CT demonstrated a predictive value for PFS after SBRT for lung cancer.

Pleural contact decreases survival in clinical T1N0M0 lung cancer patients undergoing SBRT

BackgroundClinical staging, as used for patients treated with stereotactic body radiotherapy (SBRT) for early-stage lung cancer, inadequately accounts for pleural invasion, which is a pathologic criteria. Considering the current situation, we analyzed effects of relationships between tumors and the pleura on treatment outcomes of SBRT for early-stage lung cancer. Materials and methodsAmong consecutive patients treated with SBRT between 2006 and 2017, we retrospectively identified non-small cell lung cancer patients with primary tumor diameters ≤4 cm and N0M0. The relationships between tumors and the pleura were investigated. The effects of these findings on treatment outcomes were analyzed. ResultsWe identified 386 patients which met the inclusion criteria. Among these patients, 323 patients were with tumors of 0.1–3.0 cm (T1-size), and 63 patients were with tumors of 3.1–4.0 cm (T2a-size). Among patients with T1-size tumors, 120, 134, and 23 had findings of pleural contact, pleural indentation, and pleural thickening, respectively. When we divided T1-size patients into 2 groups based on pleural contact (contact− or contact+), the 3-year cause-specific mortality and overall survival in patients with T1-size & contact+ were significantly worse than those in patients with T1-size & contact− (17.6% (95% confidence interval (CI), 10.7–25.9%) vs. 6.6% (95% CI, 3.5–11.1%), p < 0.01), and 58.2% (95% CI, 47.6–67.5%) vs. 77.6% (95% CI, 70.5–83.2%), p < 0.01). Local recurrence, regional recurrence, pleural cavity recurrence, and distant metastasis were associated with worse cause-specific mortality and overall survival. On multivariate analysis, pleural contact was associated with cause-specific mortality (hazard ratio (HR), 1.96; 95% CI, 1.09–3.52; p = 0.03) and overall survival (HR, 1.59; 95% CI, 1.08–2.34; p = 0.02). ConclusionPleural contact in clinical T1N0M0 lung cancer patients was associated with significantly worse survivals.

Dosimetric Effect of Intrafraction Tumor Motion in Lung Stereotactic Body Radiotherapy Using CyberKnife Static Tracking System.

Purpose:We investigated the dosimetric effect of intrafraction tumor motion in lung stereotactic body radiotherapy using the CyberKnife static tracking system.Methods:Four-dimensional computed tomography scans of a dynamic thorax phantom were acquired. Two motion ranges, 3 collimator sizes, and 4 treatment starting phases were investigated. Monte Carlo dose distributions were calculated on internal target volume with a treatment-specific setup margin for 6 Gy/1 fraction. Dosimetric effects of intrafractional tumor motion were assessed with Gafchromic films. γ (5%/3 mm), dose differences, and distance to agreement were analyzed.Results:With 30 mm collimator plans, the measured dose passed the criteria γ (5%/3 mm) in all tumor motion ranges. The γ passing rates of the plans using 20 mm or 20+35 mm collimators were much lower than that with 30 mm collimator, especially with the 30 mm tumor motion range. The measured dose of 10 mm tumor motion ranges all passed the 90% criteria of γ (5%/3 mm), the results being much better than those of 30 mm tumor motion ranges, which were below 80%. The results of same delivered plan but treated with different starting phases varies greatly.Conclusion:Xsight Lung Tracking technique should be used with caution in lung cancer stereotactic body radiation therapy because the temporal dose variations can be significant.

Pattern of recurrence after CyberKnife stereotactic body radiotherapy for peripheral early non-small cell lung cancer.

The treatment efficacy after CyberKnife stereotactic body radiotherapy (SBRT) have not been adequately addressed. The purpose of this study was to investigate pattern of recurrence according to irradiation field after CyberKnife SBRT for early-stage non-small cell lung cancer (NSCLC). This retrospective study included patients with peripheral cT1/2N0M0 NSCLC that was treated with SBRT using a CyberKnife between May 2013 and March 2016 at single institute and followed up by more than two imaging examinations. Both operable and inoperable patients were included. Overall survival (OS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method with 95% confidence intervals (CI). Cumulative incidence curves of recurrence were calculated and compared using the Gray's test. Total 71 patients were included and analyzed in this study. The median follow-up period for surviving patients was 34 months (range, 7-64 months). The 2-year OS and PFS rate were 93% (95% CI: 83-97%) and 77% (95% CI: 65-86%), respectively. The 2-year cumulative incidence rate of infield recurrence and out-of-field recurrence were 6% (95% CI: 2-14%) and 17% (95% CI: 9-27%), respectively. Gross tumor volume (GTV) ≥9 mL and diagnosis-to-treatment interval (DTI) ≥90 days were significantly associated with infield recurrence (P<0.001 and P=0.007), and epidermal growth factor receptor (EGFR) mutation was significantly associated with out-of-field recurrence (P=0.014). Treatment efficacy after CyberKnife SBRT for peripheral early-stage NSCLC was identical to previous conventional linac-based SBRT reports. With short follow-up period, it was found that GTV and DTI were the significant predictive factor of infield recurrence, and EGFR mutation was the significant predictive factor of out-of-field recurrence.

Comorbidity indexing for prediction of the clinical outcome after stereotactic body radiation therapy in non-small cell lung cancer

PurposeTo determine the prognostic impact of comorbidity and age in medically inoperable early-stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT) using the age-adjusted Charlson Comorbidity Index (aCCI).Patients and methodsBetween November 2008 and January 2015, 196 consecutive patients with medically inoperable NSCLC were treated with SBRT at a single institution. The prescribed isocenter dose was either 60.0 Gray (Gy) in six fractions for central lung cancer or 56.25 Gy in three fractions for peripheral lung cancer. Baseline comorbidities were retrospectively retrieved according to available outclinic medical records as well as the hospital information system. The aCCI was scored for each patient and subjected according to outcome and toxicity as well as all of the single items of the aCCI and other clinical parameters using univariate and multivariate analysis.ResultsThirty-one point 6 % (62/196) of patients were deceased, of whom 17.3% (34/196) died due to lung cancer and 14.3% (28/196) due to comorbidities. The median overall survival (OS) was 15.0 months (95% CI [11.9–18.1]), whereas the median cancer-specific survival (CSS) was not reached. An aCCI ≥7 compared with an aCCI ≤6 was significantly associated with an increased risk of death (HR 1.79, 95% CI [1.02–2.80], p = 0.04) and cancer-specific death (HR 9.26, 95% CI [4.83–24.39], p < 0.001), respectively. Neither OS nor CCS were significantly associated with age, sex, side (left vs. right), lobe, localization (central vs. peripheral), packyears, TNM, or any item of the aCCI. Considering the 14.3% (28/196) of deceased patients who died due to comorbidities, aCCI ≥9 was significantly associated with non-cancer-related death (HR 3.12, 95% CI [1.22–8.33], p = 0.02). The observed cumulative rate of radiation pneumonitis (RP) ≥2 was 12.7% (25/196). The aCCI had no statistical association with RP.ConclusionAdvanced age and numerous comorbidities characterizing this patient population were successfully assessed using the aCCI in terms of survival. Therefore, we recommend that age and comorbidity be indexed using the aCCI as a simple scoring system for all patients treated with SBRT for lung cancer.

Clinical outcomes of stereotactic body radiotherapy for de novo pulmonary tumors in patients with completely resected early stage non-small cell lung cancer.

PurposeFollowing surgery for early stage non-small-cell lung cancer (NSCLC), de novo pulmonary tumors are common. This study aimed to assess the efficacy, patterns of failure, and toxicity of stereotactic body radiotherapy (SBRT) in the treatment of de novo pulmonary tumors following curative resection of early stage NSCLC.Patients and methodsWe reviewed the medical data of patients who had received definitive intent SBRT for small lung cancer at Zhongshan Hospital, Fudan University, between June 2011 and December 2017. Patients who had experienced complete resection for prior early stage NSCLC before SBRT were identified for further analysis. Incidences of locoregional recurrence (LR) and distant metastasis (DM) were evaluated using the alternative cumulative incidence competing risk method. The probability of survival was estimated using the Kaplan–Meier method.ResultsA total of 33 patients with 36 lesions were eligible and included in this study. The median follow-up time was 32 months. Estimated incidences of LR and DM were 37.62% and 15.92%, respectively, at 1 year and 48.02% and 21.23%, respectively, at 2 years. The progression-free survival and overall survival of all patients were 62.40% and 90.30%, respectively, at 1 year and 52.00% and 69.90%, respectively, at 2 years. In all, 26 patients experienced grade 1 SBRT-related toxicity, 11 patients experienced grade 2 SBRT-related toxicity, and three patients experienced grade 3 toxicity. There were no grade 4/5 toxicities or SBRT-related deaths during the follow-up period.ConclusionSBRT appears to be a safe and potentially effective alternative therapeutic option for de novo pulmonary tumors following early stage NSCLC radical resection, despite impaired pulmonary reserve.

Treatment-Related Lymphopenia is an Independent Predictor of Survival in Patients with Lung Cancer Treated via Stereotactic Body Radiation Therapy

Treatment-related lymphopenia (TRL) is frequently associated with radiation therapy. Multiple prior studies have shown associations between TRL and inferior outcomes in various solid tumors, including patients treated with conventionally fractionated radiation therapy for lung cancer. TRL was recently shown to occur in patients with lung cancer treated with stereotactic body radiation therapy (SBRT), but the survival impact of TRL in this setting remains unknown. We seek to evaluate the impact of severe TRL in the setting of lung cancer treated with SBRT on overall survival and evaluate potential strategies to minimize TRL. We retrospectively identified 346 patients treated with thoracic SBRT between 2008 and 2016. Of these patients, 137 had complete blood counts with differentials within 12 months preceding and following SBRT. This was further refined to exclude patients who received prior radiation therapy to the head, neck or thorax; patients who received chemotherapy; and patients with pre-treatment absolute lymphocyte counts less than 500x106 cells/L. The remaining 91 patients were included in the analyses. All patients were treated with 5 fraction regimens, following RTOG 0813 or 0915 as appropriate. We defined severe TRL as an absolute lymphocyte count less than 500x106 cells/L. Kaplan-Meier curves, log-rank analysis and cox regression were performed to assess for survival differences associated with severe TRL using statistical software. Of the 91 included patients, median age was 71.9 years, 55% were female, and 39% had central lung lesions. Planning target volumes ranged from 4.3-183 cm3. Patients with severe TRL had worse overall survival (log rank, 2=7.62, p=0.006). On univariate cox regression, minimum absolute lymphocyte count was directly related to survival, with a hazard ratio of 0.353 (p=0.002). Flattening filter free-arcs were associated with less lymphocyte depletion compared to step and shoot IMRT, with a mean difference in depletion of 211x106 cells/L between modalities (p=0.04). PTV size also had a statistically significant positive correlation with lymphopenia. Severe TRL after lung cancer SBRT is associated with worse overall survival. The use of flattening filter free-arcs reduced lymphocyte depletion compared to step and shoot IMRT.

Effects of Circumferential Bronchial Tree Irradiation on the Development of Radiation Pneumonitis Following Lung SBRT

Stereotactic body radiation therapy (SBRT) may result in the development of serious lung toxicity, including death. There is evidence that increased fractionation, lower daily doses, and non-sequential daily treatments can mitigate this risk. However, a subset of patients will still develop radiation pneumonitis (RP). This study investigated alternative dosimetric parameters beyond those previously reported for lung and proximal bronchial tree (PBT) to test their association with development of RP. We hypothesize that target dose conformity can be adversely affected by tightly constraining dose to an unspecified volume of PBT, which could result in paradoxical adverse lung toxicity. A cohort of 27 consecutively treated patients who underwent static-beam SBRT for lung cancer between 2010 and 2015 were identified at one institution. Clinical RP was coded on a scale from 0-5 using the RTOG Toxicity Criteria version 2 guidelines for late radiation morbidity occurring with a minimum follow-up of 10 months. For analysis, we grouped grades 0-1 and grades 2-3 RP. There was no grade 4-5 RP in this cohort. A treatment planning radiotherapy software was used to collect planning parameter data. Irradiation of the contoured PBT was evaluated by examining abutment or circumferential overlap of fractionation-specific isodose lines, chosen based on the “trachea and large bronchus” section of RTOG dose planning parameters. These reference isodose lines were 15, 16, and 18 Gy, corresponding to the PBT D4cc dose limit for 3x18 Gy, 4x12 Gy, and 5x10 Gy fractionation schemes, respectively. Overlap of the PBT was analyzed for association with RP. Statistical analyses were performed with the chi-square test. There was a significant association between circumferential radiation of the PBT and RP (p = 0.02) with 81.8% of patients having circumferential radiation classified by grade 2-3 RP versus grade 0-1. Neither PBT D4cc nor abutment of the isodose line with the PBT was significantly associated with RP (p = 0.19). Grade 2-3 RP was observed in 80% of patients with mean lung dose (MLD) > 4 Gy, compared with 33% of patients with MLD ≤ 4 Gy (p = 0.01) and noted in 80% of patients with lung V5 > 20% compared to 33% of patients with V5 ≤ 20% (p = 0.01). There was not a significant association between lung V20, D1000, or D1500 and the RP clinical grade. Circumferential PBT irradiation beyond the RTOG planning parameters for the D4cc dose limit is significantly associated with RP clinical grade for lung cancer patients treated with SBRT in this cohort. Our results also point to the potential limitations of published RTOG dose parameters as predictors of RP. We suggest establishing a circumferential dose limit for the PBT within ongoing clinical trials investigating the safety of treating centrally located lung tumors with SBRT.

MA01.07 Validation of RTOG 0813 Normal Tissue Constraints for Pulmonary Toxicity in SBRT for Central Non-Small Cell Lung Cancer

Stereotactic body radiation therapy (SBRT) yields excellent local control rates for medically inoperable early stage "central" non-small cell lung cancer. Normal tissue constraints provided in RTOG 0813, which tested safety and efficacy of lung SBRT for central tumors, were largely based on expert estimates, and clinical validation of constraints is limited. We sought to identify the sensitivity and specificity of the current RTOG constraints for predicting pulmonary toxicity in a large institutional data set. We identified 136 lesions within 2 cm of the proximal bronchial tree (PBT), treated from 2005 to 2014 from a prospective registry of 1,462 patients. Dose was 50 or 60 Gy given in 5 fractions. Pulmonary toxicity was categorized as pneumonitis or non-pneumonitis (fistula, bronchial stenosis or necrosis, atelectasis, hemoptysis, or clinically significant pleural effusion). A series of dose endpoints for the PBT was generated based on dose volume histograms, where dose levels ranged from 0 Gy to 80 Gy in increments of 0.1 Gy, and volumes ranged from 0.03 cc to 50 cc in increments of 0.03cc. A total of 1,333,600 dosimetric endpoints were analyzed. The sensitivity and specificity of these endpoints in predicting pulmonary toxicity was calculated. The optimal dosimetric endpoint was chosen by identifying the highest F-score. We observed nine Grade 2 pneumonitis and 10 Grade ≥ 2 non-pneumonitis toxicities, of which three were Grade 5 (broncho-pleural fistula, left mainstem bronchus necrosis, and bronchial stenosis). The optimal dosimetric endpoint to avoid Grade 2-5 non-pneumonitis toxicity was D0.03cc<50 Gy to the PBT, with 90% sensitivity and 77% specificity. The optimal point dose to avoid Grade 3-5 non-pneumonitis toxicity was D0.3cc<46.5 Gy, with 100% sensitivity and 85% specificity. Applying PBT RTOG constraints to our dataset achieved 18% sensitivity and 91% specificity for D4cc<18 Gy and 29% sensitivity and 93% specificity for D0.03cc<52.5 Gy. Clinical results from this large institutional data set validate current RTOG constraints for PBT as predictive for pulmonary toxicity. The results also suggest that RTOG constraints D4cc<18 Gy and D0.03cc<52.5 Gy to PBT have moderate sensitivity but excellent specificity for pulmonary toxicity. We identified D0.03cc <50 Gy to PBT as having the largest sensitivity and specificity for toxicity prediction, and this value parallels current RTOG constraint of D0.03cc <52.5 Gy. This analysis suggests that an additional volume/dosimetric constraint of D0.3cc<46.5 Gy may be considered for avoidance of Grade 3-5 non-pneumonitis pulmonary toxicity.

Cardiac radiation dose distribution, cardiac events and mortality in early-stage lung cancer treated with stereotactic body radiation therapy (SBRT).

The impact of radiation dose to the heart in early-stage lung cancer patients treated with definitive stereotactic body radiation therapy (SBRT) is not well known. We, therefore, analyzed whether higher radiation dose to the heart would lead to an increase in cardiac toxicity and overall mortality. Seventy-four patients with 75 tumors treated definitively with SBRT for early-stage non-small cell lung cancer (NSCLC) and two cases of limited-stage small cell lung cancer (SCLC) with an average follow-up of 35 months (range, 1-130 months) were retrospectively analyzed. The whole heart and cardiac substructures including atria, ventricles, heart valves, atrioventricular (AV) node and four major coronary artery branches were contoured using commercial treatment planning software. For each structure, multiple dose-volume parameters were recorded. The relation between radiation doses to the heart, tumor location, and preexisting medical conditions with the development of cardiac events and mortality was assessed. Overall, there was large variability in dose to cardiac substructures: mean heart dose (MHD) averaged 1.90 Gy (range, 0.04-11.00 Gy) equivalent 2 Gy dose (EQD2) and average max dose to the left anterior descending artery (LAD) was 5.67 Gy (range, 0.04-48.60 Gy) EQD2. Patients with tumor location in the upper lobes received higher cardiac radiation dose compared to other lobes (P<0.0001). There was no difference in MHD between central and peripheral tumor locations. The distance between heart and tumor was negatively associated with MHD (r=-0.61, P<0.0001). Eighteen patients developed cardiac complications including the need for defibrillator placement, arrhythmia development and worsening heart failure. Preexisting cardiac disease was associated with an increased number of cardiac events after radiotherapy (P=0.039). However, neither radiation dose to the whole heart or the cardiac substructures, nor comorbidities such as diabetes, hypercholesterolemia, hypertension or COPD were associated with the number of cardiac events or overall mortality. Radiation doses to the heart and its substructures show large variability. Cardiac events occurred more frequently in patients with a history of heart problems. At present, the effect of radiation dose on cardiac toxicity is unclear in patients undergoing SBRT for early-stage lung cancer. Longer follow-up and a larger cohort are needed to assess for late cardiac sequelae.

SBRT for early stage lung cancer: outcomes from biopsy-proven and empirically treated lesions.

Aim:Herein, we compare outcomes in patients treated with lung stereotactic body radiotherapy (SBRT) with and without tissue confirmation.Methods:We reviewed 196 patients that underwent lung SBRT for presumed (100 patients) or proven non-small-cell lung cancer (96 patients) over a 10-year period and compared outcomes.Results:A total of 196 patients with a median age of 76 underwent lung SBRT to a median dose of 48 Gy in four fractions. Median follow up was 17 months. Local control and overall survival at 3 years was 94 and 58% for the entire group. There was no difference in overall survival, local control, regional control or distant control between the cohorts.Conclusion:SBRT is a safe and effective treatment for patients with non-small-cell lung cancer that are medically inoperable with comparable results in empirically treated patients.