Five-fraction Stereotactic Body Radiotherapy Research Articles

Executive Summary of the American Radium Society Appropriate Use Criteria for NSCLC in a Central/Ultracentral Location: Systematic Review and Guidelines

IntroductionDefinitive radiation therapy is considered standard therapy for medically inoperable early-stage NSCLC. Nevertheless, for patients with tumors located near structures such as the proximal tracheobronchial tree, esophagus, heart, spinal cord, and brachial plexus, the optimal management regimen is controversial. The objective was to develop expert multidisciplinary consensus guidelines on managing medically inoperable NSCLC located in a central or ultracentral location relative to critical organs at risk. MethodsCase variants regarding centrally and ultracentrally located lung tumors were developed by the 15-member multidisciplinary American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) expert panel. A comprehensive review of the English medical literature was performed from January 1 1946 to December 31 2023 to inform consensus guidelines. Modified Delphi methods were used by the panel to evaluate the variants and procedures, with at least three rating points from median defining agreement/consensus. The guideline was then approved by the ARS Executive Committee and released for public comment per established ARS procedures. ResultsThe Thoracic ARS AUC Panel identified 90 relevant references and obtained consensus in all variants. Radiotherapy alone was considered appropriate, with additional immunotherapy to be considered primarily in the clinical trial setting. Hypofractionated radiotherapy in eight to 18 fractions was considered appropriate for ultracentral lesions near the proximal tracheobronchial tree, upper trachea, and esophagus. For other ultracentral lesions near the heart, great vessels, brachial plexus, and spine, or for non-ultracentral but still central lesions, five-fraction stereotactic body radiation therapy was also considered an appropriate option. Intensity-modulated radiotherapy was considered appropriate and three-dimensional–conformal radiotherapy inappropriate for all variants. Other treatment planning techniques to decrease the risk of overdosing critical organs at risk were also considered. ConclusionsThe ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for various presentations of stage I NSCLC in a central or ultracentral location.

Consecutive Daily Versus Every Other Day Stereotactic Body Radiation Therapy Scheduling for Stage I Non-small Cell Lung Cancer

The optimal delivery schedule for stereotactic body radiation therapy (SBRT) in treating stage I non-small cell lung cancer (NSCLC) is unknown. This study used the National Cancer Database to examine daily versus every other day (QOD) SBRT scheduling, including trends over time and association with survival. The National Cancer Database was used to retrospectively identify patients with stage I NSCLC treated with 3-, 4-, or 5-fraction of SBRT between 2004 and 2016. Survival analysis was performed using the Kaplan-Meier method and Cox regression modeling. Of 15,269 patients, 3927 (25.7%) received SBRT daily, and 11,342 (74.3%) received treatment QOD. The use of QOD treatment increased from 63.2% in 2007 to 78.3% in 2016, and 5-fraction SBRT increased from 3.7% in 2004 to 51.4% in 2016 (both P < .0001). QOD 5-fraction became the most prevalent scheduling from 2012 to 2016 (28.5% in 2012 to 41.6% in 2016). Factors significantly associated with daily SBRT scheduling included number of fractions, race, lower income, lower comorbidities, and treatment at academic/research programs (all P ≤ .01).Median survival for daily SBRT was 37.9 months versus 38.4 months for QOD (P = .4). On multivariable analysis, no difference was found in overall survival between daily versus QOD scheduling (adjusted hazard ratio [aHR], 0.99; 95% confidence interval [CI], 0.94-1.04; P = .55). Five-fraction SBRT was associated with worse survival versus 3 fractions (aHR, 1.09; 95% CI, 1.03-1.15; P = .002). With 3-fraction SBRT, QOD treatment was associated with improved survival versus daily treatment (aHR, 0.91; 95% CI, 0.84-0.98; P = .02). With 5-fraction SBRT, QOD treatment was associated with worse survival versus daily treatment (aHR, 1.11; 95% CI, 1.02-1.22; P = .02). QOD SBRT schedules were more frequently used to treat stage I NSCLC than daily regimens by a factor of 3:1, and QOD 5-fraction SBRT became the most common dose schedule after 2012. Three-fraction QOD SBRT was associated with improved survival versus daily, whereas 5-fraction QOD SBRT was associated with worse survival versus daily.

Sinoatrial Node Irradiation in Patients Undergoing Definitive Stereotactic Body Radiation Therapy (SBRT) for Central Lung Cancers

The clinical consequences of sinoatrial node (SAN) and atrioventricular node (AVN) irradiation in patients undergoing thoracic stereotactic body radiation therapy (SBRT) remains unclear. We examined the relationship between SAN and AVN dose with survival outcomes in patients with central non-small cell lung cancer (NSCLC) tumors. A single-institutional retrospective review of patients with primary NSCLC undergoing definitive SBRT for centrally located tumors from February 2007 to December 2021 was performed. Central tumors were defined as within 2 cm of the proximal airway, mediastinum, great vessels, or spinal cord whereas ultracentral tumors were directly abutting any of the above structures. All patients underwent five-fraction SBRT to a total dose of 50 to 60 Gy. 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 non-cancer associated survival. Among 93 eligible patients, the median age was 72.5 years (Inter-Quartile Range [IQR], 66.6-78.3), median follow up was 32.4 months (IQR, 13.0-49.6), and 48 patients were female (52%). There were 49 ultracentral tumors (53%) and the median planning target volume (PTV) was 31.0 cc (IQR, 18.0-53.3). The median SAN Dmax and Dmean were 95 cGy (IQR, 37-1,072) and 58 cGy (IQR, 26-641), respectively. The median AVN Dmax and Dmean were 45 cGy (IQR, 19-506) and 34 cGy (IQR, 15-160), respectively. Candidate cutoff values for SAN Dmax and Dmean were 1,309 cGy and 814 cGy, respectively. No significant cutoff values were identified for either AVN parameter. Kaplan-Meier analysis for the proposed SAN Dmean constraint was significantly associated with overall (p = 0.016) and non-cancer associated survival (p = 0.028). The SAN Dmax constraint was significantly associated with only overall survival (p = 0.029). In a multivariate model, the SAN Dmean cutoff significantly correlated with both overall (Hazard Ratio [HR] 2.1 [1.13-3.78], p = 0.019) and non-cancer associated survival (HR 2.39 [1.12-5.10], p = 0.025) whereas the SAN Dmax cutoff was only significantly associated with overall survival (HR 1.95 [1.03-3.68], p = 0.041). SAN Dmax and Dmean were associated with significantly worse overall survival using cut-off values of 1,309 cGy and 814 cGy, respectively. SAN dose should be considered in radiation planning and further study on the consequence of SAN irradiation during SBRT is warranted.

Long-term outcomes of single and five fraction schedules of stereotactic body radiation therapy for early-stage central or peripheral NSCLC: Neither fractionation nor location matter?

8538 Background: Due to concerns with toxicity, treatment of early-stage non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT) often involves different fractionation schemes for peripheral and centrally located tumors. There is a paucity of long-term SBRT survival outcomes comparing peripheral versus central NSCLC. Methods: This is a single-institution observational cohort study of patients diagnosed with early-stage NSCLC (T1-2N0M0) who underwent 27 Gy in 1 fraction or 50 Gy in 5 fractions with heterogeneity correction at Roswell Park Comprehensive Cancer Center between September 2008 to December 2018. All patients treated with single-fraction SBRT had peripheral NSCLC and those treated with five-fraction SBRT had central NSCLC. Clinically relevant variables including age, gender, race, Karnofsky Performance Status (KPS), histology (adenocarcinoma, squamous cell carcinoma, NSCLC not otherwise specified), T stage, smoking status, tumor location, and the year of SBRT delivery were obtained retrospectively. Cox multivariable analysis (MVA), Kaplan-Meier plot, and log-rank test were performed to evaluate progression-free survival (PFS) and overall survival (OS). Fine-Gray competing risk MVA was performed to evaluate local failure (LF), nodal failure (NF), and distant failure (DF) with death as a competing event. To reduce selection bias, propensity score matching was performed between single- versus five-fraction SBRT cohorts. Results: A total of 265 patients (142 female [53.6%]; median age 77 years) met our criteria. There were 74 (27.9%) and 191 (72.1%) patients with central tumors treated with five-fraction SBRT and peripheral tumors treated with single-fraction SBRT, respectively. On Cox MVA, there was no statistically significant difference in OS (peripheral vs central tumors: adjusted hazards ratio [aHR] 1.04, 95% confidence interval [CI] 0.74-1.46, p=0.81) and PFS (peripheral vs central tumors: aHR 1.05, 95% CI 0.76-1.45, p=0.77). On Fine-Gray competing risk MVA comparing peripheral vs. central tumors, there was no statistically significant difference in LF, NF, and DF. After propensity score matching, 68 matched pairs were identified for peripheral vs. central tumors with similar results. Conclusions: Among patients with early-stage NSCLC treated with SBRT central versus peripheral location was associated with similar long-term survival and tumor recurrence outcomes.

Comparison of Survival Outcomes of Single- and Five-Fraction Schedules of Stereotactic Body Radiation Therapy for Early-Stage Central or Peripheral NSCLC

The treatment of early-stage non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT) frequently involves different fractionation schemes for peripheral and central tumors due to concerns with toxicity. We performed an observational cohort study to determine survival outcomes for patients with peripheral and central NSCLC treated with SBRT. A single-institutional database of patients with early-stage NSCLC treated with SBRT from September 2008 to December 2018 was evaluated. Outcomes were progression-free survival (PFS), overall survival (OS), local failure (LF), nodal failure (NF), and distant failure (DF). Cox multivariable analysis (MVA), Kaplan-Meier plotting, Fine-Gray competing risk MVA, and propensity score matching were performed. A total of 265 patients were included with a median follow-up of 44.2 months. There were 191 (72%) and 74 (28%) patients with peripheral and central tumors treated with single-fraction SBRT to a dose of 27 Gy and five-fraction SBRT to a dose of 50 Gy, respectively. On Cox MVA, there was no difference in OS (adjusted hazards ratio (aHR) of 1.04, 95% CI of 0.74-1.46) or PFS (aHR of 1.05, 95% CI of 0.76-1.45). On Fine-Gray competing risk MVA, there were no differences in LF, NF, or DF. Propensity matching confirmed these findings. The survival outcomes of patients treated with SBRT for early-stage NSCLC were equivalent for central and peripheral tumors.

Feasibility and Short-Term Toxicity of a Consecutively Delivered Five Fraction Stereotactic Body Radiation Therapy Regimen in Early-Stage Breast Cancer Patients Receiving Partial Breast Irradiation.

BackgroundFor appropriately selected patients with early-stage breast cancer (ESBC), accelerated partial breast irradiation (APBI) yields equivalent rates of ipsilateral breast tumor recurrence with mixed results in patient-rated cosmesis compared with whole-breast radiotherapy depending on the technique utilized. When utilizing external beam radiotherapy for APBI, techniques to reduce target margins and overall treatment volume are potentially important to decrease rates of long-term adverse cosmesis. Stereotactic body radiotherapy (SBRT) is a promising technique to deliver APBI because of its increased accuracy and sparing of uninvolved breast tissue. We report the initial results of a prospective clinical trial investigating feasibility, safety, and cosmetic outcomes of a daily five-fraction SBRT regimen for APBI.MethodsTwenty-three patients with ESBC after lumpectomy who met APBI suitability were enrolled. During lumpectomy, a bioabsorbable three-dimensional fixed array tissue marker (BioZorb™, Hologic, Marlborough, MA) was placed for enhanced visualization of the cavity boundaries. Clinical target volume (CTV) was defined as the delineable cavity plus a 1-cm isotropic expansion followed by a 3-mm isotropic planning target volume (PTV) expansion. Patients received 30 Gy delivered in five planned consecutive daily fractions in either prone or supine positioning depending on individual anatomy. Two patients completed the five-fraction treatments in 9-day interval and 11-day interval due to external circumstances. A maximum PTV of 124cc was allowed to minimize incidence of fat necrosis. Plans utilized 10-MV flattening filter–free beams delivered on a Varian Edge linear accelerator. Local control, toxicity, and nurse/patient-scored cosmesis at pre-treatment baseline, 1 month post-treatment, and at subsequent 6-month intervals were recorded.ResultsTwenty-three patients were accrued at the time of submission with median follow-up of 6 months. No patients experienced grade ≥3 acute toxicity. Of the 10 events reported probably related to SBRT, nine were grade 1 (n = 9/10, 90%). There was no evidence of difference, deterioration, or change in patient or nurse-scored cosmesis from baseline to 1 and 6 months post-treatment. One patient developed nodal failure shortly after APBI.ConclusionsAlthough longer follow-up is needed to assess long-term toxicity and local control, this study demonstrated a five-fraction SBRT regimen delivered over consecutive days is a safe, efficient, well-tolerated, and cosmetically favorable means of delivering APBI in suitable women.Clinical Trial Registrationhttps://www.clinicaltrials.gov/ct2/show/NCT03643861, NCT03643861.

Neoadjuvant Stereotactic Body Radiotherapy After Upfront Chemotherapy Improves Pathologic Outcomes Compared With Chemotherapy Alone for Patients With Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma Without Increasing Perioperative Toxicity

BackgroundPatients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) are at high risk of margin-positive resection. Neoadjuvant stereotactic body radiation therapy (SBRT) may help sterilize margins, but its additive benefit beyond neoadjuvant chemotherapy (nCT) is unclear. The authors report long-term outcomes for BRPC/LAPC patients explored after treatment with either nCT alone or nCT followed by five-fraction SBRT (nCT-SBRT).MethodsPatients with BRPC or LAPC from 2011 to 2016 who underwent resection after nCT alone or nCT-SBRT were retrospectively reviewed. Baseline characteristics were compared, and the propensity score with inverse probability weighting (IPW) was used to compare pathologic/survival outcomes.ResultsOf 198 patients, 76 received nCT, and 122 received nCT-SBRT. The nCT-SBRT cohort had a higher proportion of LAPC (53% vs 22%; p < 0.001). The duration of nCT was longer for nCT-SBRT (4.6 vs 2.9 months; p = 0.03), but adjuvant chemotherapy was less frequently administered (53% vs 67.1%; p < 0.001). Adjuvant radiation was administered to 30% of the nCT patients. The nCT-SBRT regimen more frequently achieved negative margins (92% vs 70%; p < 0.001), negative nodes (59% vs 42%; p < 0.001), and pathologic complete response (7% vs 0%; p = 0.02). In the multivariate analysis, nCT-SBRT remained associated with R0 resection (p < 0.001). The nCT-SBRT cohort experienced no significant difference in median overall survival (OS) (22.1 vs 24.5 months), local progression-free survival (LPFS) (13.5 vs. 15.4 months), or distant metastasis-free survival (DMFS) (11.7 vs 16.3 months) after surgery. After SBRT, 1-year OS was 77.0% and 2-year OS was 50.4%. Perioperative Claven-Dindo grade 3 or greater morbidity did not differ significantly between the nCT and nCT-SBRT cohorts (p = 0.81).ConclusionsDespite having more advanced disease, the nCT-SBRT cohort was still more likely to undergo an R0 resection and experienced similar survival outcomes compared with the nCT alone cohort.

Efficacy and Safety of Reirradiation with Stereotactic Body Radiation Therapy for Locally Recurrent Pancreatic Adenocarcinoma

AimsThe purpose of this study was to report on outcomes of a cohort of patients who were treated with reirradiation with stereotactic body radiation therapy (SBRT) for locally recurrent pancreatic adenocarcinoma. Materials and methodsPatients treated with SBRT reirradiation for locally recurrent pancreatic adenocarcinoma from December 2009 to April 2020 were included in the study. Descriptive statistics were used to record patient demographics, tumour and treatment characteristics. Kaplan–Meier analysis was used to evaluate overall survival, local progression-free survival (LPFS), distant metastasis-free survival and progression-free survival (PFS). ResultsIn total, 27 patients were included in the study. The median follow-up time from local recurrence was 19.7 months (range 4.2–43.1 months). Most patients received five-fraction SBRT (26/27, 96%). The median overall survival after local recurrence treatment was 18.3 months (range 3.0–42.6 months), with 6-month, 1-year and 2-year overall survival rates of 88.5%, 73.1% and 33.6%. The median LPFS after local recurrence treatment was 16.2 months (range 2.3–33.6 months), with 6-month, 1-year and 2-year LPFS rates of 95.8%, 62.9% and 27.2%. Peri-SBRT chemotherapy improved LPFS (median 17.5 versus 8.5 months; P = 0.010) and overall survival (median 19.3 versus 5.5 months; P = 0.049). Tumours ≤ 3 cm in the greatest dimension showed better local control (median LPFS 19.2 versus 10.2 months; P = 0.130). There was one case (4%) of acute grade 3 pain and one case (4%) of late grade 3 gastrointestinal toxicity. ConclusionsReirradiation with five-fraction SBRT is safe, but local control remains suboptimal. Patients with smaller tumours experienced improved outcomes, as did patients whose treatment plan included the administration of peri-SBRT chemotherapy.

Comparative Outcomes of Central and Ultracentral Lung Tumors Managed With Five-Fraction Stereotactic Body Radiation Therapy

Central (CLT) and ultracentral (UCLT) lung tumors can be at higher risk for treatment related mortality following stereotactic body radiation therapy (SBRT) and the preferred dose and fractionation is unclear. We assessed the toxicity and outcomes of patients with CLT and UCLT who underwent definitive five-fraction 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 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. Toxicity was graded by the Common Terminology Criteria for Adverse Events version 5.0. Propensity score matching was performed for gender, performance status, and history of prior lung cancer. Survival outcomes evaluated by Cox regression and Kaplan-Meier estimation.Within this cohort of 83 patients, the median age was 73.1 years with a median follow up of 29.9 months. All patients underwent 5 fraction SBRT, with dose range of 50-60 Gy. Most patients had T1 tumors (68.7%) and 43 (51.8%) were considered UCLT. In 20 (50%) patients with CLT, the proximal bronchial tree was the closest central structure while the aorta was the closest structure in 16 (37.2%) of UCLT patients. Grade 2+ toxicity was similar between the two groups, 11 (27.5%) for CLT and 13 (30.2%) (P = 0.78) for UCLT patients. Furthermore, there was no difference in grade 3 toxicity with 3 (7.5%) CLT and 4 (9.3%) UCLT patients (P = 0.77) and no observed grade 4+ events. There was no difference in crude local failure (5% vs 7.0%) (P = 0.34) or recurrence rates (22.5% vs 9.3) (P = 0.09). Multivariate analysis adjusting for gender, performance status, prior lung cancer, history of diabetes, history of heart disease, and prescription volume revealed UCLT to be associated with worse overall survival (OS) (P = 0.02) but not freedom from progression (FFP). Using propensity score match pairing, 29 match pairs were generated finding UCLT to correlate with reduced non-cancer related survival (NC-OS) and OS, but not FFP.Definitive 5 fraction SBRT yielded similar toxicity profiles for CLT and UCLT. Despite no difference in FFP, UCLT were associated with worse (NC-OS) and OS.

Simulated dose painting of hypoxic sub-volumes in pancreatic cancer stereotactic body radiotherapy

Dose painting of hypoxic tumour sub-volumes using positron-emission tomography (PET) has been shown to improve tumour control in silico in several sites, predominantly head and neck and lung cancers. Pancreatic cancer presents a more stringent challenge, given its proximity to critical gastro-intestinal organs-at-risk (OARs), anatomic motion, and impediments to reliable PET hypoxia quantification. A radiobiological model was developed to estimate clonogen survival fraction (SF), using 18F-fluoroazomycin arabinoside PET (FAZA PET) images from ten patients with unresectable pancreatic ductal adenocarcinoma to quantify oxygen enhancement effects. For each patient, four simulated five-fraction stereotactic body radiotherapy (SBRT) plans were generated: (1) a standard SBRT plan aiming to cover the planning target volume with 40 Gy, (2) dose painting plans delivering escalated doses to a maximum of three FAZA-avid hypoxic sub-volumes, (3) dose painting plans with simulated spacer separating the duodenum and pancreatic head, and (4), plans with integrated boosts to geometric contractions of the gross tumour volume (GTV). All plans saturated at least one OAR dose limit. SF was calculated for each plan and sensitivity of SF to simulated hypoxia quantification errors was evaluated. Dose painting resulted in a 55% reduction in SF as compared to standard SBRT; 78% with spacer. Integrated boosts to hypoxia-blind geometric contractions resulted in a 41% reduction in SF. The reduction in SF for dose-painting plans persisted for all hypoxia quantification parameters studied, including registration and rigid motion errors that resulted in shifts and rotations of the GTV and hypoxic sub-volumes by as much as 1 cm and 10 degrees. Although proximity to OARs ultimately limited dose escalation, with estimated SFs (∼10−5) well above levels required to completely ablate a ∼10 cm3 tumour, dose painting robustly reduced clonogen survival when accounting for expected treatment and imaging uncertainties and thus, may improve local response and associated morbidity.

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.

Simple SummaryThe optimal way to treat central (CLT) and ultracentral (UCLT) lung tumors with curative radiation is unclear. We evaluated 83 patients with CLT and UCLT who underwent a curative radiotherapy technique called stereotactic body radiation therapy (SBRT). On statistical analysis, patients with UCLT had worse overall survival. Using a cohort of patients matched for relevant variables such as gender and performance status, we evaluated radiation doses to critical central structures such as the airway and heart. In this group, patients with UCLT were more likely to exceed dose constraints as compared CLT, particularly constraints regarding the airway. Additionally, patients had worse non-cancer associated survival when radiation doses were higher than 18 Gy to 4cc’s of either the trachea or proximal bronchial tree. Based on these findings, patients with UCLT have worse outcomes which could be secondary to higher radiation doses to the trachea and proximal bronchial tree.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.

PP09 Presentation Time: 11:20 AM: High-Dose-Rate Brachytherapy Boost Combined with Ultra-Hypofractionated Radiation for Unfavorable Intermediate and High Risk Prostate Cancer

Purpose: This study aimed to evaluate outcomes associated with a single-fraction high-dose-rate (HDR) brachytherapy boost combined with five-fraction stereotactic body radiation therapy (SBRT) for patients with unfavorable intermediate- or high-risk prostate cancer.

SPARC, a phase-I trial of pre‐operative, margin intensified, stereotactic body radiation therapy for pancreatic cancer

Background and purposeFollowing resection of pancreatic cancer, risk of positive margins and local recurrence remain high, especially for borderline-resectable pancreatic cancer (BRPC). We aimed to establish the maximum tolerated dose of a margin-intensified five-fraction stereotactic body radiotherapy (SBRT) regimen designed to treat the region at risk. Materials and methodsWe conducted a prospective multicentre phase-1 rolling-six dose-escalation study. BRPC patients received pre-operative SBRT, with one dose to the primary tumour and an integrated boost to the region where tumour was in contact with vasculature. Four dose-levels were proposed, with starting dose 30 Gy to primary PTV and 45 Gy to boost volume (PTV_R), in five daily fractions. Primary endpoint was maximum tolerated dose (MTD), defined as highest dose where zero of three or one of six patients experienced dose-limiting toxicity (DLT). ResultsTwelve patients were registered, eleven received SBRT. Radiotherapy was well tolerated with all treatment completed as scheduled. Dose was escalated one level up from starting dose without encountering any DLT (prescribed 32.5 Gy PTV, 47.5 Gy PTV_R). Nine serious adverse reactions or events occurred (seven CTCAE Grade 3, two Grade 4). Two patients went on to have surgical resection. Median overall survival for SBRT patients was 8.1 months. The study closed early when it was unable to recruit to schedule. ConclusionToxicity of SBRT was low for the two dose-levels that were tested, but MTD was not established. Few patients subsequently underwent resection of pancreatic tumour after SBRT, and it is difficult to draw conclusions regarding the safety or toxicity of these therapies in combination.

Simulated daily plan adaptation for magnetic resonance-guided liver stereotactic body radiotherapy

Introduction Liver cancers are challenging to treat using image-guided radiotherapy (IGRT) due to motion and deformation of target volumes and organs at risk (OARs), as well as difficulties in visualising liver tumours using cone-beam computed tomography (CBCT) based IGRT. Liver cancer patients may thus benefit from magnetic resonance (MR)-guided daily adaptive re-planning. We evaluated the dosimetric impact of a daily plan adaptation strategy based on daily MR imaging versus CBCT-based IGRT. Methods Ten patients were studied who were treated with CBCT-guided five-fraction stereotactic body radiotherapy (SBRT) and underwent MR imaging before each fraction. Simulated reference plans were created on computer tomography (CT) images and adapted plans were created on the daily MR images. Two plan adaptation strategies were retrospectively simulated: (1) translational couch shifts to match liver, mimicking standard CBCT guidance and (2) daily plan adaptation based on reference plan clinical goals and daily target and OAR contours. Dose statistics were calculated for both strategies and compared. Results Couch shifts resulted in an average reduction in GTV D99% relative to reference plan values of 5.2 Gy (−12.5% of reference values). Daily plan adaptation reduced this to 0.8 Gy (−2.0%). For six patients who were OAR dose-limited on reference plans, couch shifts resulted in OAR dose violations in 28 out of 28 simulated fractions, respectively; no violations occurred using daily plan adaptation. No OAR dose violations occurred using either strategy for the four cases not OAR dose-limited at reference planning. Conclusions MR-guided daily plan adaptation ensured OAR dose constraints were met at all simulated treatment fractions while CBCT-based IGRT resulted in a systematic over-dosing of OARs in patients whose doses were limited by OAR dose at the time of reference planning.

Ablative Five-Fraction Stereotactic Body Radiation Therapy for Inoperable Pancreatic Cancer Using Online MR-Guided Adaptation

PurposePatients with inoperable pancreatic adenocarcinoma have limited options, with traditional chemoradiation providing modest clinical benefit and an otherwise poor prognosis. Stereotactic body radiation therapy for pancreatic cancer is limited by proximity to organs-at-risk (OAR). However, stereotactic magnetic resonance-guided adaptive radiation therapy (SMART) has shown promise in delivering ablative doses safely. We sought to demonstrate the benefits of SMART using a 5-fraction approach with daily on-table adaptation. Methods and MaterialsPatients with locally advanced, nonmetastatic pancreatic adenocarcinoma were treated with 50 Gy in 5 fractions (biologically effective dose10 100 Gy) with a prescribed goal of 95% planning target volume coverage by 95% of prescription, prioritizing hard OAR constraints. Daily online adaptation was performed using magnetic resonance-guidance and on-table reoptimization. Patient outcomes, treatment factors, and daily adaptation were evaluated. ResultsForty-four patients were treated with SMART at our institution from 2014 to 2019. Median follow-up from date of diagnosis was 16 months (range, 6.7-51.6). Late toxicity was limited to 2 (4.6%) grade 3 (gastrointestinal ulcers) and 3 (6.8%) grade 2 toxicities (duodenal perforation, antral ulcer, and gastric bleed). Tumor abutted OARs in 35 patients (79.5%) and tumor invaded OARs in 5 patients (11.1%). Reoptimization was performed for 93% of all fractions. Median overall survival was 15.7 months (95% confidence interval, 10.2-21.2), while 1-year and 2-year overall survival rates were 68.2% and 37.9%, respectively. One-year local control was 84.3%. ConclusionsThis is the first reported experience using 50 Gy in 5 fractions for inoperable pancreatic cancer. SMART allows this ablative dose with promising outcomes while minimizing toxicity. Additional prospective trials evaluating efficacy and safety are warranted.

Cost-effectiveness of upfront therapeutic options in low-volume de novo metastatic hormone-sensitive prostate cancer.

211 Background: Low-volume de novo metastatic hormone-sensitive prostate cancer (mHSPC) has historically been treated with lifelong androgen deprivation therapy (ADT). Recently, however, the addition of several advanced therapeutic options – radiation therapy (RT) to the primary, advanced hormonal therapy agents such as abiraterone acetate/prednisone (AAP), and chemotherapy – to ADT have been shown to improve survival in low-volume mHSPC. The objective of this study was to compare the cost-effectiveness of treating low-volume mHSPC patients upfront with RT+ADT, AAP+ADT, or docetaxel+ADT. Methods: A Markov-based cost-effectiveness analysis was constructed comparing three treatment strategies for low-volume mHSPC patients: (1) upfront RT+ADT --&gt; salvage AAP+ADT --&gt; salvage docetaxel+ADT; (2) upfront AAP+ADT --&gt; salvage docetaxel+ADT, and (3) upfront docetaxel+ADT --&gt; salvage AAP+ADT. Transition probabilities were calculated using data from STAMPEDE arms C/G/H, COU-AA-301, COU-AA-302, and TAX-327. RT was delivered via five-fraction stereotactic body radiation therapy. The analysis utilized a 10-year time horizon, and a $100,000/quality adjusted life year (QALY) willingness-to-pay threshold. Utilities were extracted from the literature; costs were taken from Medicare fee schedules and VA oral drug contracts. Results: At 10 years, total cost was $140K, $259K, and $189K, with total QALYs of 4.66, 5.03, and 3.72 for strategies (1) upfront RT+ADT, (2) upfront AAP+ADT, and (3) upfront docetaxel+ADT, respectively. Compared to upfront RT+ADT, upfront AAP+ADT was not cost-effective (ICER: $321K/QALY). This result remained unchanged even after modification of various model inputs in 1-way sensitivity analysis. Upfront docetaxel+ADT was both more costly and less effective than upfront RT+ADT (ICER: -$53K/QALY). Conclusions: At 10 years, RT+ADT is cost-effective compared to other advanced systemic therapy options alone, and should be considered as a viable treatment strategy in all patients with a low-burden of metastatic disease. Additional studies are needed to determine whether any benefit exists in combining RT to the primary with upfront advanced systemic therapy.

Patterns of Recurrence Following Stereotactic Body Radiation Therapy for Localized Prostate Cancer

Stereotactic body radiation therapy (SBRT) is increasingly offered for the treatment of localized prostate cancer. However, the patterns of recurrence are not well characterized. The aim of this study was to determine the recurrence rate in a large cohort of prostate cancer patients undergoing SBRT and to identity tumor and treatment factors predictive of the patterns of relapse following SBRT. Between 2007 and 2018, 1415 patients with organ-confined prostate cancer treated at a single academic institution were included in this analysis. Patients were treated with either five-fraction SBRT to a dose of 35-36.25 Gy (n=1135) or 19.5 Gy SBRT with 45-50.4 Gy intensity-modulated radiotherapy (IMRT) (n=280). PSA was monitored every 3 months during the first year, biannually for 2 years, and annually thereafter. Biochemical failure was defined using the nadir + 2 ng/mL definition. Detection of local recurrences included digital rectal examination, pelvic MRI, and/or prostate biopsy. Imaging studies such as bone scan, abdominal/pelvic CT, and more recently PET imaging were utilized to identify distant failures. Patterns of failure were classified as PSA only, local, or distant. Cox regression analysis was performed to evaluate the tumor and treatment characteristics associated with patterns of failure. Median age at diagnosis of patients was 69 years (range 42-92). The median follow-up of all patients was 36 months. Per D’Amico classification, 18% of patients had low risk disease, 57% of patients had intermediate risk disease, and 25% of patients had high risk disease. Androgen deprivation therapy (ADT) was administered to 32% of all patients. Disease free survival (DFS) for all patients at 5 years was 91.2% (low risk-99.3%, intermediate risk-91.5%, and high risk-82%). 93 patients experienced a disease recurrence with a median time to failure of 72 months (PSA only n=20; local n=30; distant n=36; and combined local and distant n=7). Median time to failure was 72 months for PSA only recurrences, 84 months for local recurrences, and 48 months for distant recurrences. Multivariate Cox regression model identified initial PSA, clinical T staging, and Gleason score (GS) as independent predictors of disease failure while controlling for ADT and supplemental IMRT. Incidence of failure following SBRT for prostate cancer remains low at 5 years. A similar number of local and distant failures were identified. Multivariate analysis identified initial PSA, clinical T staging, and GS as predictors of failure. In general, local failures occurred later than distant failures. This data supports careful monitoring of patients for early identification of salvageable local failures.

Clinical evidence for dose tolerance of the central nervous system in hypofractionated radiotherapy

Stereotactic radiosurgery (SRS), stereotactic body radiotherapy (SBRT), and stereotactic ablative body radiotherapy (SABR) are commonly used in the treatment of central nervous system (CNS) disease. This study has refined the radiation toxicity estimates for some normal tissues of the CNS based on review and analysis of the clinical evidence for single fraction radiosurgery, hypofractionated SBRT, and conventionally fractionated radiation therapy. Published guidelines and protocols are reviewed. In the past, many normal tissue tolerances were compiled based on the experience of the investigators and publications in the literature. Some tolerances were determined by modeling or calculation using the existing biological formulas, in particular the linear quadratic (LQ) model. In the present study, the estimate of risk for each dose tolerance limit in some CNS tissues is provided exclusively with normal tissue complication probability (NTCP). The clinical outcomes are compared to understand the difference in biological effect between radiosurgery and radiotherapy. Normal tissue dose tolerances and the corresponding complication rates are provided for brainstem, optic nerves, cochlea, and spinal cord, including single fraction SRS, five-fraction SBRT, and conventional radiation therapy. Calculation of biologically effective dose (BED) or single fraction equivalent dose (SFED) alone using the LQ model conveys no consensus on the biological effect across different fractionations. Comparison of conventional radiation therapy to brain and spinal cord with single fraction equivalent dose leads to even conflicting clinical outcomes. Effective differences between single fraction SRS and conventional radiotherapy need to be better understood. The existing biological model might not be valid to predict the radiosurgical outcomes based on conventionally fractionated radiotherapy. However, application of the statistical dose response models of clinical SRS and SBRT outcomes data to selected current dose tolerance guidelines into simple tables can be a clinically useful resource.

The safety and effectiveness of stereotactic body radiotherapy for central versus ultracentral lung tumors

Background and purposeRecent studies have postulated that patients undergoing lung stereotactic body radiotherapy (SBRT) for ultracentral tumors have higher toxicity and mortality rates than those with central tumors. Our aim was to compare the outcomes after lung SBRT for central versus ultracentral tumors in our own series. Material and methodsThis was a retrospective review of patients with primary and metastatic lung tumors treated with SBRT from 1 September 2009 to 30 June 2015. Patients were included if they were treated with five-fraction SBRT to central or ultracentral tumors. Central tumors were defined as tumors where the closest point was within 2 cm of (but not abutting) the proximal bronchial tree, or within 2 cm of (whether abutting or not) mediastinal structures. Ultracentral tumors were defined as tumors abutting the proximal bronchial tree. The 2-year overall survival (OS), 2-year local failure (LF), and 2-year grade ≥3 toxicity rates were compared between patients with central and ultracentral tumors. ResultsA total of 107 patients were included in this study. There were no significant differences in 2-year OS between the two groups, with 2-year OS 57.7% for central tumors, and 50.4% for ultracentral tumors (p = 0.10). There were no significant differences in 2-year LF between the two groups, with 2-year LF 3.4% for central tumors and 4.3% for ultracentral tumors (p = 0.92). There were no significant differences in 2-year grade ≥3 toxicity rate for the two groups, with 3.5% with central tumors and 8.7% with ultracentral tumors (p = 0.23). ConclusionsThere were no significant differences in OS, LF, or grade ≥3 toxicity between patients with central and ultracentral lung tumors. Although these results indicate that SBRT for ultracentral tumors may be safe, caution should be applied in selecting and treating these patients until the completion of large prospective trials.

Five-fraction SBRT for ultra-central NSCLC in-field recurrences following high-dose conventional radiation

Purpose/objectiveLocal treatment options for patients with in-field non-small cell lung cancer (NSCLC) recurrence following conventionally fractionated external beam radiation therapy (CF-EBRT) are limited. Stereotactic body radiation therapy (SBRT) is a promising modality to achieve reasonable local control, although toxicity remains a concern.Materials/methodsPatients previously treated with high-dose CF-EBRT (≥59.4 Gy, ≤3 Gy/fraction) for non-metastatic NSCLC who underwent salvage SBRT for localized ultra-central in-field recurrence were included in this analysis. Ultra-central recurrences were defined as those abutting the trachea, mainstem bronchus, or esophagus and included both parenchymal and nodal recurrences. The Kaplan-Meier method was used to estimate local control and overall survival. Durable local control was defined as ≥12 months. Toxicity was scored per the CTC-AE v4.0.ResultsTwenty patients were treated with five-fraction robotic SBRT for ultra-central in-field recurrence following CF-EBRT. Fifty percent of recurrences were adenocarcinoma, while 35% of tumors were classified as squamous cell carcinoma. The median interval between the end of CF-EBRT and SBRT was 23.3 months (range: 2.6 – 93.6 months). The median CF-EBRT dose was 63 Gy (range: 59.4 – 75 Gy), the median SBRT dose was 35 Gy (range: 25 – 45 Gy), and the median total equivalent dose in 2 Gy fractions (EQD2) was 116 Gy (range: 91.3 – 136.7 Gy). At a median follow-up of 12 months for all patients and 37.5 months in surviving patients, the majority of patients (90%) have died. High-dose SBRT was associated with improved local control (p < .01), and the one-year overall survival and local control were 77.8% and 66.7% respectively in this sub-group. No late esophageal toxicity was noted, although a patient who received an SBRT dose of 45 Gy (total EQD2: 129.7 Gy) experienced grade 5 hemoptysis 35 months following treatment.ConclusionsAlthough the overall prognosis for patients with in-field ultra-central NSCLC recurrences following CF-EBRT remains grim, five-fraction SBRT was well tolerated with an acceptable toxicity profile. Dose escalation above 35 Gy may offer improved local control, however caution is warranted when treating high-risk recurrences with aggressive regimens.