Fraction Stereotactic Body Radiation Therapy Research Articles

A phase III randomized-controlled, single-blind trial to improve quality of life with stereotactic body radiotherapy for patients with painful bone metastases (ROBOMET)

BackgroundBone metastases represent an important source of morbidity in cancer patients, mostly due to severe pain. Radiotherapy is an established symptomatic treatment for painful bone metastases, however, when conventional techniques are used, the effectiveness is moderate. Stereotactic body radiotherapy (SBRT), delivering very high doses in a limited number of fractions in a highly conformal manner, could potentially be more effective and less toxic.MethodsThis is a phase III, randomized-controlled, single-blind, multicenter study evaluating the response rate of antalgic radiotherapy for painful bone metastases and the acute toxicity associated with this treatment. A total of 126 patients will be randomly assigned to receive either the standard schedule of a single fraction of 8.0 Gy delivered through three-dimensional conformal radiotherapy or a single fraction of 20.0 Gy delivered through SBRT. Primary endpoint is pain response at the treated site at 1 month after radiotherapy. Secondary endpoints are pain flare at 24–48-72 h after radiotherapy, duration of pain response, re-irradiation need, acute toxicity, late toxicity, quality of life and subsequent serious skeletal events. In a supplementary analysis, patient-compliance for a paper-and-pencil questionnaire will be compared with an electronic mode.DiscussionIf a dose-escalated approach within the context of single fraction stereotactic body radiotherapy could improve the pain response to radiotherapy and minimize acute toxicity, this would have an immediate impact on the quality of life for a large number of patients with advanced cancer. Potential disadvantages of this technique include increased pain flare or a higher incidence of radiation-induced fractures.Trial registrationThe Ethics committee of the GZA Hospitals (B099201732915) approved this study on September 4th 2018. Trial registered on Clinicaltrials.gov (NCT03831243) on February 5th 2019.

Impact of intrafraction prostate motion on clinical target coverage in proton therapy: A simulation study of dosimetric differences in two delivery techniques.

PurposeTo investigate the dosimetric impact of prostate intrafraction motion on proton double‐scattering (DS) and uniform scanning (US) treatments using electromagnetic transponder‐based prostate tracking data in simulated treatment deliveries.MethodsIn proton DS delivery, the spread‐out Bragg peak (SOBP) is created almost instantaneously by the constant rotation of the range modulator. US, however, delivers each entire energy layer of the SOBP sequentially from distal to proximal direction in time, which can interplay with prostate intrafraction motion. This spatiotemporal interplay during proton treatment was simulated to evaluate its dosimetric impact. Prostate clinical target volume (CTV) dose was obtained by moving CTV through dose matrices of the energy layers according to prostate‐motion traces. Fourteen prostate intrafraction motion traces of each of 17 prostate patients were used in the simulated treatment deliveries. Both single fraction dose‐volume histograms (DVHs) and fraction‐cumulative DVHs were obtained for both 2 Gy per fraction and 7.25 Gy per fraction stereotactic body radiotherapy (SBRT).ResultsThe simulation results indicated that CTV dose degradation depends on the magnitude and direction of prostate intrafraction motion and is patient specific. For some individual fractions, prescription dose coverage decreased in both US and DS treatments, and hot and cold spots inside the CTV were observed in the US results. However, fraction‐cumulative CTV dose coverage showed much reduced dose degradation for both DS and US treatments for both 2 Gy per fraction and SBRT simulations.ConclusionsThis study indicated that CTV dose inhomogeneity may exist for some patients with severe prostate intrafraction motion during US treatments. However, there are no statistically significant dose differences between DS and US treatment simulations. Cumulative dose of multiple‐fractions significantly reduced dose uncertainties.

Early Stage NSCLC (ES-NSCLC) with Gross Endobronchial Disease (GED) Predicts for Worse Overall Survival (OS) after Treatment with 5-Fraction Stereotactic Body Radiation Therapy (SBRT)

SBRT is an effective treatment for ES-NSCLC. Central tumors however pose a therapeutic challenge due to proximity to critical organs such as central airways. Five fraction approaches have been advocated to limit treatment induced toxicity. In this report, we evaluate the dosimetric parameters of central airways and identify GED as a predictor of poor overall survival in a diverse cohort of patients. Medically inoperable ES-NSCLC patients were treated with robotic SBRT per institutional protocol. The majority (n=41) underwent bronchoscopy for mediastinal staging, biopsy, fiducial placement and identification of GED. Proximal bronchial tree (PBT) was contoured based on the RTOG atlas, and included trachea (T), mainstem bronchus (MB) and secondary bronchi (SB). Dosimetry for PBT and each of the three subvolumes was analyzed. An additional structure, eval-PBT, was created as the subtraction of GTV from PBT. From December 2010 to December 2015, 50 patients with biopsy proven ES-NSCLC (stage I - 31; stage II – 19) with median age of 75 were treated (50 Gy in 5 fractions). At median follow up of 36 months, OS did not differ between peripheral (n=39) and central tumors (n=11) (54% vs 46%; p=0.41). Local control for peripheral tumors was significantly better than central tumors (94% vs. 60% p=0.018). Of 41 patients who underwent bronchoscopy, five central tumors were found to have GED involving the RUL (n=2), RLL (n=1), LUL (n=1) and LLL (n=1). LC and OS for tumors with GED was 66% and 20%. Cox regression analysis identified GED as a predictor of OS (HR: 4.216, p=0.009). Three patients with GED likely experienced grade 5 bronchial strictures. Median Dmax to PBT was 62.3 Gy (33.7-68) in central tumors. This represented the Dmax to SB, however median Dmax to T and MB were 12.1 Gy (1.1-37.1) and 30.8 Gy (15.2-68). Median Dmax to PBT in central tumors with GED was higher than those without GED (64.8 vs 59.1 p=0.17). Dmax to eval-PBT was lower 60.2 Gy (56.3-66.9). Patients who likely experienced grade 5 bronchial strictures had higher median Dmax to PBT and eval-PBT (67.3 and 66.9 Gy) than other central tumors (62.3 Gy). Presence of GED was associated with higher V18 (16.7cc vs 4.1 cc p=0.03) and V16.5 (20.7cc vs. 5.6 cc, p=0.05). ES-NSCLC with GED predicts for worse OS following treatment with 5-fraction SBRT. Despite high Dmax delivered to PBT, LC remained relatively poor for central tumors. Furthermore, it is likely that high Dmax delivered to PBT resulted in Grade 5 toxicity for central tumors with GED. Future ES-NSCLC SBRT trials should require pretreatment bronchoscopy for central tumors to confirm these preliminary findings and to hone PBT dosimetric constraints.

Do Health Insurance and Other Psychosocioeconomic Determinants of Health Impact Survival Through Treatment Delays with Stereotactic Body Radiation Therapy in Borderline Resectable and Locally Advanced Pancreatic Cancer Patients?

The biopsychosocial model of health suggests that focusing only on the biologics of disease neglects areas for improvement that may affect outcomes. Costs of stereotactic body radiation therapy (SBRT) for borderline resectable (BRPC) and locally advanced (LAPC) pancreatic cancer may be prohibitive for insurance companies to approve in a timely fashion given the debated necessity of neoadjuvant SBRT. We hypothesized that psychosocioeconomic factors contribute to delayed initiation of SBRT, which leads to poor survival outcomes. Retrospective analysis of an IRB approved database of BRPC and LAPC patients treated with SBRT yielded 223 patients that met our selection criteria from 2009-2016. Patients were treated according to an institutional treatment pathway, with systemic therapy regimens based on the discretion of the treating medical oncologist consisting of either gemcitabine-based regimens or FOLFIRINOX. This was followed by 5 fraction SBRT. All patients undergoing SBRT were assessed for psychosocial needs prior to therapy. Delayed initiation of SBRT was defined as >21 days from the end of chemotherapy to the first day of SBRT. Delayed start of SBRT (18.4 vs 12.0 months, p<0.001), no secondary insurance prior to SBRT treatment (12.0 vs 16.5 months, p=0.009), and no reliable transportation (11.5 vs 15.0 months, p=0.045) were all independently associated with poor overall survival. Delayed SBRT starts were associated with not having private insurance (p=0.005), not having United (p=0.020), having financial concerns (p=0.041), and living in a lower valued home (p=0.008). Proxies of lower socioeconomic status are associated with delayed SBRT starts, which, in this cohort, is also tied to poor overall survival. As stewards of the healthcare system, it is imperative for clinicians to holistically assess patients that may be vulnerable to these non-biologic factors, as this may impede time sensitive treatments. Referral for radiation oncology evaluation prior to or shortly after initiation of systemic therapy may allow earlier identification of these factors so that these issues can be addressed proactively, mitigating potential delays in SBRT delivery.

CA 19-9 Maintains Prognostic Value for Inoperable Pancreatic Cancer Patients Receiving Definitive Hypofractionated or Stereotactic Body Radiation Therapy

Use of carbohydrate antigen 19-9 (CA 19-9) in patients with resectable pancreatic cancer is well-established. The role of CA 19-9 in management of patients with inoperable pancreatic cancer receiving treatment with definitive hypofractionated or stereotactic body radiation therapy (SBRT) is less clear. Eligible patients for this IRB approved retrospective study included patients diagnosed with inoperable pancreatic cancer who received a definitive course of radiation therapy (RT) in either 50 – 52 Gy in 5 fractions or 50.7 – 67.5 Gy in 15 fractions. Patients were also required to have a recorded CA 19-9 value at diagnosis. Available CA 19-9 values were also recorded prior to radiation (within one month) and after RT (within 3 months). CA 19-9 levels were adjusted for bilirubin >2 mg/dL by dividing CA 19-9 level by bilirubin level. Overall survival (OS) was calculated from start date of RT. Patients were grouped based on CA 19-9 cutoff value of 90 U/mL (derived from literature). Kaplan-Meier curves were generated and differences between groups were determined using the log-rank method. Fisher’s Exact testing was performed to test correlation between CA 19-9 levels and likelihood of receiving a pancreatectomy. A total of 55 patients were eligible for this study (40 patients with locally advanced disease, 10 patients with borderline-resectable disease, and 5 patients who were medically inoperable). Median follow up was 13 months. Treatments included 5 fraction SBRT (n=15) or 15 fraction hypofractionated regimen (n=40). CA 19-9 levels were available for 51 patients prior to RT and 50 patients after RT. Median CA 19-9 levels were 121 U/mL (range: 1 – 9674) at diagnosis, 50 U/mL (1 – 29690) prior to RT, and 43 U/mL (1 – 28925) after RT. OS at 1 year was significantly improved with CA 19-9 level ≤ 90 U/mL at diagnosis (75% vs 59%, P=0.04), before RT (73% vs 48%, P=0.04), and within 3 months after RT (83% vs 25%, P<0.01). Fisher’s Exact testing did not identify significant correlation between likelihood of pancreatectomy and CA 19-9 levels at diagnosis (P=0.75), before (P=1.00) or after (P=0.46) RT (analysis excluded medically inoperable cases). CA 19-9 demonstrated a role as a prognostic marker for patients with inoperable pancreatic cancer receiving definitive hypofractionated/SBRT courses. CA 19-9 values do not appear to impact likelihood of undergoing a pancreatectomy after RT.

Invasive Nodal Staging May Not Reduce Regional and Distant Recurrence Rates for Patients Treated with SBRT for Inoperable Stage I NSCLC

In patients receiving definitive stereotactic body radiation therapy (SBRT) for presumably node-negative, early-stage non-small cell lung cancer (NSCLC), many patients are staged with PET-CT alone. The role of invasive nodal staging with either bronchoscopy plus endobronchial ultrasound (EBUS) or mediastinoscopy in patients undergoing PET prior to definitive lung SBRT is uncertain. We sought to characterize the impact of nodal staging modality on clinical outcomes after SBRT for early NSCLC. Patients receiving definitive SBRT for T1-2N0 NSCLC that were determined to be node-negative by either PET plus invasive nodal staging (EBUS or mediastinoscopy) or PET alone were identified using a single-institution prospective registry. All patients received 3-5 fraction SBRT with a biologically effective dose (BED10) of ≥ 100 Gy. Patients who did not undergo pre-SBRT PET, received adjuvant systemic therapy, or who were treated with additional SBRT courses for synchronous or metachronous NSCLC were excluded from the current study. Multivariable logistic regression was performed to identify which variables were independently associated with invasive mediastinal staging. Variables evaluated included staging, age, gender, ethnicity, central versus peripheral location, stage, and histology. A total of 651 patients treated from 2005 – 2016 met the above inclusion criteria. Invasive nodal staging was performed in 15.2% of patients (n=99) with either EBUS (n= 78) or mediastinoscopy (n= 21). Median age at SBRT was 75.3 years (range, 49.3 – 88.8). Median follow up was 19.4 months, and median survival was 28.5 months for all patients. Factors predictive of increased likelihood to receive invasive nodal staging on multivariable analysis were young age (OR for increasing age 0.968; 95% CI 0.945 – 0.990), white race (OR for non-white 0.540; 0.304 = 0.958), female patients (OR 1.629; 95% CI 1.031 – 2.575), central location (OR 1.978; 95% CI 1.218 – 3.211) and squamous histology (OR 2.564; 95% CI 1.243 – 5.287). On multivariable analysis, nodal and/or distant failure was not significantly different between PET alone (crude failure rate, 23.6%) versus invasive nodal staging (25.4%, p=0.714) in this patient cohort. Most patients with early stage NSCLC treated with definitive SBRT did not undergo invasive nodal staging, and we identify several factors predictive of its use. There was no significant difference in nodal or distant failure based on type of nodal staging utilized.

Prospective Case Series in the Use of Abdominal and Pelvic SBRT in the Context of Oligo-Progressive Disease

There is emerging evidence for the “Oligometastatic” state where local therapy for a limited number of metastatic lesions may have benefits for progression free survival (PFS), overall survival (OS) and potentially quality of life. The “Oligo-progressive” state occurs when a patient has several metastatic deposits in which a small number are progressing either on systemic therapy or having just completed a line of treatment. Controlling such lesions with Stereotactic Body Radiotherapy (SBRT) is theorized to extend PFS by either extending an existing chemotherapy course or by delaying the need for commencing a new course. Limited information has been published for treating such lesions in the abdomen and pelvis. We analyzed all oligo-progressing patients treated with 5-fraction SBRT to the abdomen and pelvis 2014-2018. Patients were treated with VMAT using Varian planning software over 2 weeks with abdominal compression employed to reduce breathing amplitude for upper abdominal targets. Patients were categorized in terms of primary diagnosis, target location, target size, dose delivered, PFS and OS from SBRT and time to next treatment. Oligo-progression was defined using an in-house protocol as metastatic patients who progressed radiologically in 1-2 lesions on systemic treatment or within 6 months of completing a course. Local control was evaluated using cross–sectional imaging. Toxicity assessment used CTCAE version 4. Data analysis was conducted as part of an institutional Quality Assurance Process. A total of 35 patients with 42 SBRT courses met inclusion criteria, mean age 62 (range 31–87 years). Their primary tumor types included colorectal 11 (31%), breast 8 (23%), endometrial 4 (11%), lung 4 (11%), and other types 8 (23%). SBRT target organs included liver 26 (62%), para-aortic lymph nodes 5 (12%), adrenal gland 4 (9%), iliac nodes 4 (9%) and others 3 cases (7%). Median PTV prescription dose was 40Gy in 5 fractions (range 25-50Gy) with mean ITV size 98cc (range 0.73-613cc). Median follow-up 300 days. Estimated local control rate was 69% at 1 year and 51% at 2 years, respectively. Median PFS following SBRT was 111 days (95% CI 60-161 days), with estimated 1 year PFS 25%. Median OS was 663 days (95% CI 281-1044 days), with estimated 1-year OS of 67%. Median chemotherapy-free time following SBRT was 133 days (95% CI 61-205 days). One patient developed a grade 4 GI toxicity with a gastro-hepatic fistula, resolved with conservative management. No other grade ≥3 toxicities were observed. There was no association between local control rate or PFS with cancer type, ITV size or prescribed dose. Abdominal and Pelvic SBRT to oligo-progressive targets was well tolerated in this series and could allow either a period of time off chemotherapy or the continuation of existing systemic therapy thereby potentially increasing the remaining chemotherapy options.

Single Fraction Stereotactic Body Radiation Therapy After Surgery in Treating Patients With Non-small Cell Lung Cancer

Single Fraction Stereotactic Body Radiation Therapy After Surgery in Treating Patients With Non-small Cell Lung Cancer

A mid-treatment break and reassessment maintains tumor control and reduces toxicity in patients with hepatocellular carcinoma treated with stereotactic body radiation therapy

Background and purposePatients with hepatocellular carcinoma (HCC) commonly have underlying liver dysfunction with variable tolerance to liver stereotactic body radiation therapy (SBRT). We hypothesized that insertion of a 1-month mid-treatment break would allow us to adapt treatment to the individual patient response, thereby reducing toxicity without compromising local control (LC). Materials and methodsWe analyzed HCC patients receiving 3–5 fraction SBRT at our institution from 2005 to 2017. Over this time, patients were offered enrollment on prospective trials assessing individualized adaptive SBRT. Based on normal tissue complication probability and modeling of changes in liver function following a 1-month treatment break between fractions 3 and 4, patients could receive a total of 3 or 5 fractions. Patients not on trial received 3 or 5 fractions without a break. Toxicity was defined as a ≥2 point rise in Child–Pugh (CP) score within 6 months of SBRT. Results178 patients were treated with SBRT to 263 HCCs. Median follow-up was 23 months. 86 treatments had a 1-month break. 1-Year LC was 95.4%; this was not different between patients treated with or without a break (p = 0.14). Controlling for tumor size and dose a break was not associated with inferior LC (HR: 0.58, 95%CI: 0.1–3.34, p = 0.54). 54 patients experienced a ≥2 point rise in CP score. Controlling for the number of prior liver directed therapies and mean liver dose, a treatment break reduced the odds of toxicity (OR: 0.42, 95% CI: 0.17–1.03, p = 0.06). ConclusionA one-month mid-treatment break and reassessment may reduce the odds of treatment related toxicity without compromising LC.

Intratumoural renal cell carcinoma haemorrhage following stereotactic radiotherapy: a case report

BackgroundStereotactic radiotherapy is an emerging treatment option for patients with inoperable renal cell carcinoma (RCC). Haemorrhage has not previously been reported to occur as a result of Stereotactic Body Radiotherapy (SBRT) to the kidney for primary RCC. We report an acute haemorrhage in a patient who received only one of three planned fractions of SBRT as part of a clinical trial.Case presentationA 74 year old female had a left renal mass under observation for 4 years, during which time she was imaged repeatedly using ultrasound and CT scans. There has been no evidence of metastases, and the lesion has demonstrated a steady pattern of growth over the 4-year period. Fine needle aspiration histologically confirmed RCC.Following a multidisciplinary review, the patient was recommended for SBRT as she was not considered a surgical candidate. Treatment was planned for an ablative 42Gray (Gy) to be delivered in 3 fractions at 14Gy/fraction as part of a clinical trial. Our patient presented to the emergency department (ED) suffering left flank pain, fever and vomiting within 3 h of the first fraction of SBRT. CT showed the mass to have markedly increased in size, measuring 8.7 × 8.1 × 7.0 cm, from 6.5 × 5.4 × 5.6 cm. It was reported as an internal haemorrhage into the malignancy. The patient was admitted for analgesia, anti-pyretics, and transfusion of 2 units of packed red blood cells. The patient recovered without any further intervention but radiotherapy was discontinued. The patient was alive and free from disease progression two years after the aborted treatment.ConclusionSuch events, though rare, are potentially serious, and therefore clinicians should be aware of such treatment related complications.

Adaptive Dose Escalation Trial of Stereotactic Body Radiation Therapy (SBRT) in combination with GC4419 in pancreatic cancer.

TPS4164 Background: Local progression causes up to 30% of deaths from pancreatic cancer (PC) and is also a significant source of morbidity. Stereotactic body radiotherapy (SBRT) offers the potential for improved therapeutic index over standard fractionation, but current regimens of 5-7 Gy/fraction x 5 are constrained by nearby organ tolerance and offer only palliation without improving survival. Safe dose escalation is necessary to improve SBRT efficacy. GC4419, a superoxide dismutase mimetic, selectively converts superoxide (O2•-) to hydrogen peroxide (H2O2) and oxygen. O2•-initiates normal tissue damage due to RT. GC4419 is in a Phase 3 trial (NCT03689712) to reduce RT-induced oral mucositis in head and neck cancer, based on positive results in a randomized Phase 2 trial for that indication (Anderson, ASCO 2018). GC4419 improved the survival of mice receiving 8.5 Gy x 5 to the upper abdomen. Cancer cells are less tolerant to elevated H2O2, and more tolerant to elevated O2•-, than normal cells, and GC4419 demonstrated mechanism-dependent synergy with high dose-fraction RT in a human tumor xenograft with inducible expression of catalase (Sishc, AACR 2018). Thus, adding GC4419 to SBRT may increase both the efficacy and the safety of the latter. Methods: 48 patients with localized, unresectable PC without frank duodenal invasion, who have received 3+ cycles of induction chemotherapy, are to be randomized 1:1 to placebo or GC4419, 90 mg IV, prior to each of 5 consecutive daily (M-F) SBRT fractions. A phase I/II Late Onset Efficacy/ Toxicity tradeoff (LO-ET) based adaptive design adaptive model drives SBRT dose escalation in each arm based on a dual endpoint (Gr 3-4 GI toxicity or death ;stable disease or better) by 90 days post SBRT. The planned dose levels are 10, 11 and 12Gy x 5 fractions (BED10=100,112.5 and 132Gy, respectively) as an integrated boost to the gross tumor volume (GTV). Primary endpoint: Maximum tolerated dose of SBRT with GC4419 or placebo. Exploratory endpoints include change in tumor radiographic resectability, correlative studies (ctDNA, exosomal DNA, tumor exome/transcriptome sequencing, immune profiling). Supported by Galera Therapeutics, Inc. Clinical trial information: NCT03340974.

Assessment of the accuracy of truebeam intrafraction motion review (IMR) system for prostate treatment guidance.

Intrafraction motion review (IMR), a real-time 2D, motion management feature of the Varian Truebeam™ incorporates triggered imaging, automatic fiducial marker detection and automatic beam hold. With the increasing adoption of high dose per fraction stereotactic body radiotherapy (SBRT) this system provides a potential means to ensure treatment accuracy. The goal of this study was therefore to investigate and quantify key performance characteristics of IMR for prostate treatment guidance. Phantom experiments were performed with a custom Computerized Imaging Reference Systems, Inc (CIRS) pelvis phantom with implanted gold seeds and the Hexamotion™ 5D motion platform. The system accuracy was assessed statically and under typical prostate motion trajectories. The IMR functionality and marker detectability was tested under different anatomical conditions and with different imaging acquisition modes. Imaging dose for triggered imaging modes was determined using an ionisation chamber based on IPEMB dose calibration protocol for kV energies. For zero displacement, the IMR demonstrated submillimeter agreement with the known position. Similarly, dynamic motion differences between the IMR reported position and 2D trajectory displacement were within 1mm. Static displacement in the anterior direction was reported by IMR as sinusoidal motion on the x-axis (kV angle). The 2D nature of IMR limits the ability to detect motion out of the plane of the kV image detector. Using typical clinical imaging settings, imaging dose determined at the patient surface was 2.58mGy/frame and the corresponding IMR displayed dose was 2.63mGy/frame. The methodology used was able to quantify the accuracy of the IMR system. The IMR was able to accurately and consistently report fiducial positions within the limitations inherent of a 2D system. IMR is fully integrated with the Truebeam system with an easy to use and efficient workflow and is clinically beneficial especially within the context of SBRT.

Hypoxia Induced by Vascular Damage at High Doses Could Compromise the Outcome of Radiotherapy.

This study investigated the impact of temporary vascular collapse on tumour control probability (TCP) in stereotactic body radiotherapy (SBRT), taking into account different radiosensitivities of chronically and acutely hypoxic cells. Three-dimensional tumours with heterogeneous oxygenation were simulated assuming different fractions of collapsed vessels at every treatment fraction. The modelled tumours contained a chronically hypoxic subvolume of 30-60% of the tumour diameter, and a hypoxic fraction ≤5 mm Hg of 30-50%. The rest of the tumours were well-oxygenated at the start of the simulated treatment. For all simulated cases, the largest reduction in TCP from 97% to 2% was found in a tumour with a small chronically hypoxic core treated with 60 Gy in eight fractions and assuming a treatment-induced vascular collapse of 35% in the well-oxygenated region. The timing of SBRT fractions should be considered together with the tumour oxygenation to avoid loss of TCP in SBRT.

Inoperable Pulmonary Carcinoid Tumors: Local Control Rates With Stereotactic Body Radiotherapy/Hypofractionated RT With Image-Guided Radiotherapy

IntroductionSurgery is the standard of care for pulmonary carcinoid tumors; however, options for inoperable patients are few. We report the outcomes of inoperable pulmonary carcinoid patients treated with stereotactic body radiotherapy (SBRT). Patients and MethodsFrom an institutional database, we retrospectively identified patients treated with SBRT for pulmonary carcinoid tumors from 2007 to 2017. Additional inclusion criteria were previous histopathologic diagnosis, age older than 18 years and Karnofsky performance status ≥ 70. ResultsTen patients were treated for 12 pulmonary carcinoid lesions with 5 to 10 fractions of SBRT. Their median age was 66.5 years (range, 40-83 years) and most presented with nonspecific symptoms of cough, shortness of breath, or hemoptysis. Pathology revealed typical carcinoid for 9 patients, with the 10th with atypical histology. The median prescription dose for all patients was 50 Gy in 5 to 10 fractions (range, 40-60 Gy) with SBRT/hypofractionated radiation with daily image-guided radiotherapy (IGRT) delivered using a linear accelerator with respiratory monitoring. Four patients received 10-fraction hypofractionated radiation with daily IGRT and 6 others received 5-fraction SBRT. The follow-up after SBRT/hypofractionated IGRT ranged from 6 to 56 months (median, 25 months). Four patients were alive with stable disease at their last follow-up. Two patients died from disease progression in the mediastinal lymph nodes as well as in the lung. Both opted for palliative treatment. The other 4 patients died from their comorbid medical conditions, but had stable disease at their last follow-up. Median overall survival was 27.1 months (range, 5.5-56 months). ConclusionPulmonary carcinoid tumors treated with SBRT have a promising tumor control rate and survival.

Impact of neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT) on R0 resection rate for borderline resectable and locally advanced pancreas cancer.

370 Background: Management for borderline resectable pancreas cancer (BRPC) and locally advanced pancreas cancer (LAPC) is controversial. Multiagent chemotherapy (CT) followed by SBRT may allow for tumor downstaging and the ability to perform an R0 resection. Methods: We retrospectively evaluated BRPC and LAPC patients (pts) treated on our multidisciplinary treatment pathway. Pts underwent 2-3 months of CT. Pts without systemic progression received five fractions of SBRT, delivered every other day, to a dose of 30-33 Gy. After restaging, pts underwent surgery if resectable. Overall survival (OS), distant metastasis free survival (DMFS) and local progression free survival (LPFS) were estimated and compared by Kaplan-Meier and log-rank methods. Results: We identified 80 pts with BRPC (65) or LAPC (15) treated with neoadjuvant CT + SBRT between 2011-2017. Median follow up was 20 months. CT primarily included FOLFIRINOX (65%) and gemcitabine/nab-paclitaxel (30%). Of pts completing CT + SBRT, 67 (84%) went to surgery and 53 (79%) of those pts underwent definitive surgery including seven LAPC patients. The remaining 14 pts underwent palliative or exploratory surgery due to intraoperative metastases (43%) or vascular involvement (57%). Of pts undergoing definitive surgery, 51 had R0 resection (96%) and 5 (9%) had a complete pathologic response (PR) to CT + SBRT. The R0 resection rate of the cohort was 64%. OS was 24.5 months. Pts with a complete or marked (14%) PR had significantly better OS than those with a moderate (40%) PR (41.3 vs 30 months, p = 0.04) and pts unable to undergo definitive surgery (18.2 months, p &lt; 0.001). Zero of 11 pts who had a marked or complete PR had local progression, significant compared to those with moderate PR (p = 0.012). DMFS between these two groups was not statistically significantly different. Conclusions: Neoadjuvant CT + SBRT are associated with favorable PR rates and R0 resection rates. Marked or complete PR was associated with improved LPFS and OS compared to moderate PR and pts who did not undergo definitive surgery. DMFS was not significantly different between complete and marked PR compared to those with moderate PR.

Long-term Clinical Outcomes and Safety Profile of SBRT for Centrally Located NSCLC

PurposePrevious studies suggest that stereotactic body radiation therapy (SBRT) is associated with higher toxicity rates for central lung tumors relative to peripheral tumors when using 3 fraction SBRT. The initial results from Radiation Therapy Oncology Group study 0813 suggest a safe toxicity profile of SBRT administered in 5 fractions for central non-small cell lung cancer (NSCLC). We reviewed our institutional data to evaluate the safety and efficacy of SBRT for central NSCLC.Methods and materialsWe reviewed our prospectively collected SBRT database for patients with central NSCLC who received SBRT between 2008 and 2014. The most frequent dose and fractionations were 50 Gy in 5 fractions (59%) and 48 Gy in 4 fraction (30%). Local control (LC), regional control, metastasis-free survival, and overall survival were calculated using Kaplan-Meier estimates. The National Cancer Institute Common Terminal Criteria for Adverse Events were used for toxicity grading.ResultsA total of 110 central lung tumors in 103 patients were included. The median age was 74 years (range, 40-95 years), and the median follow-up time of living patients was 50 months. The mean tumor size was 20 mm (range, 5-70 mm). The 5 year rate of LC, regional control, and distant control was 89%, 77%, and 82%, respectively. The median and 5-year overall survival were 3.5 years and 35%, respectively. No treatment variables were associated with tumor control or other clinical outcomes. A single patient experienced grade 3 radiation pneumonitis (0.97%). The rate of late toxicity grade ≥3 was 9.7% (grade 3, 7.7%; grade 4, 0.97%; grade 5, 0.97%) and included pneumonitis (3.9%), bronchial necrosis (2.9%), myocardial dysfunction (1.9%), and worsening heart failure (0.97%).ConclusionsSBRT for central NSCLC provides high rates of LC. Despite excellent LC, patients remain at risk for regional and distant failure. The rate of grade 3 pneumonitis was consistent with that of prior reports. We observed low rates of grade 4-5 toxicity potentially attributable to SBRT. Our results contribute to the growing body of data in support of the safety of SBRT for central NSCLC.

Breathing-motion induced interplay effects for stereotactic body radiotherapy of liver tumours using flattening-filter free volumetric modulated arc therapy

The purpose of this study was to investigate breathing-motion induced interplay effects for stereotactic body radiotherapy (SBRT) of liver tumours treated with flattening-filter free (FFF) volumetric modulated arc therapy (VMAT).Ten patients previously treated with liver SBRT were included in this study. All patients had four-dimensional computed tomography (4DCT) scans acquired prior to treatment. The 4DCT was sorted into 8–10 phases covering an equal time interval. A FFF VMAT plan was created for one fraction in the mid-ventilation phase for each patient. To generate dose distributions including both interplay effects and dose blurring, a sub-plan was calculated for each phase. The total dose distributions were accumulated to the mid-ventilation phase using the deformed vector fields (DVF) from deformable image registration between the corresponding CT and the mid-ventilation phase CT. A blurred dose distribution, not including interplay effects, was also obtained by distributing the delivery of the whole plan uniformly on all phases, and was similarly accumulated to the mid-ventilation phase. To isolate interplay effects, this blurred dose distribution was subtracted from the total dose distribution with interplay effects. The near minimum dose (D98%), mean dose (Dmean), heterogeneity index (HI), and the near minimum dose difference (ΔD98%) between the accumulated dose distributions with and without interplay effects were calculated within the gross tumour volume (GTV) for each patient.Comparing the accumulated dose distributions with and without interplay effects, the D98% decreased for nine of the ten patients and the HI increased for all patients. The median and minimum differences in D98% were −2.1% and −5.0% (p = 0.006), respectively, and the median HI significantly increased from 6.2% to 12.2% (p = 0.002). The median ΔD98% was −4.0% (range −7% to −1.5%).In conclusion, statistically significant breathing-induced interplay effects were observed for a single fraction of FFF VMAT liver SBRT, resulting in heterogeneous dose distributions within the GTV.

Sparing the surgical area with stereotactic body radiotherapy for combined treatment of spinal metastases: a treatment planning study

Introduction: Decreasing the radiation dose in the surgical area is important to lower the risk of wound complications when surgery and radiotherapy are combined for the treatment of spinal metastases. The purpose of this study was to compare the radiation dose in the surgical area for spinal metastases between single fraction external beam radiotherapy (EBRT), single fraction stereotactic body radiotherapy (SBRT) and single fraction SBRT with active sparing (SBRT-AS) of the posterior surgical area.Methods: Radiotherapy treatment plans for EBRT, SBRT and SBRT-AS of the posterior surgical area were created for 13 patients with spinal metastases. A single fraction of 8Gy was prescribed to the spinal metastasis in the EBRT plan. For the SBRT treatment plans, a single fraction of 18Gy was prescribed to the metastasis and 8Gy to the rest of the vertebral body. For the SBRT plan with active sparing the dose in the designated surgical area was minimized without compromising the dose to the organs at risk.Results: The median dose in the surgical area was 2.6Gy (1.6–5.3Gy) in the SBRT plan with active sparing of the surgical area compared to a median dose of 3.7Gy (1.6–6.3Gy) in the SBRT plan without sparing and 6.5Gy (3.5–9.1Gy) in the EBRT plans (p < .001). The radiation doses to the spinal metastases and organs at risk were not significantly different between the SBRT plan with and without sparing the surgical area.Conclusions: The radiation dose to the surgical area is significantly decreased with the use of SBRT compared to EBRT. Active sparing of the surgical area further decreased the mean radiation dose in the surgical area without compromising the dose to the spinal metastasis and the organs at risk.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blocker use During Stereotactic Body Radiation Therapy Associated with Decreased Pneumonitis: A Multi-center Analysis

Radiation pneumonitis (RP) is a serious adverse effect associated with lung radiation therapy (RT). The use of angiotensin-converting enzyme inhibitors (ACEI) is associated with a lower risk of RP in the setting of conventional lung RT. However, whether ACEI use during stereotactic body radiation therapy (SBRT) has protective properties against RP is unknown. Similarly, the effect of angiotensin receptor blockers (ARB) use on the incidence of RP is not known. The purpose of this study is to examine the impact of ACEI and ARB use during lung SBRT treatment on the development of RP. Under an Institutional Review Board-approved protocol, the records of 252 consecutive patients from 2009 – 2015 at 4 related academic institutions with lung cancer treated with SBRT were reviewed. Presence of RP was determined using all available records, including follow-up data from radiation oncology, pulmonology, medical oncology, and hospitalizations, and graded using the Common Terminology Criteria for Adverse Events Version 4.0. Univariate and multivariate analysis was performed to identify factors associated with clinical outcomes. Kaplan-Meier methods were used to determine OS. A total of 208 patients were used for the analysis with a median follow-up time of 23 months. Median age was 71 years old. Median tumor size was 2.1cm, and 63% of the tumors were peripheral in location. 68% of the tumors were T1, 48% were T2, 7% were T3, and 2% were T4, 8% were node positive. 77 patients (37%) received either ACEI (26%) or ARB (11%) therapy during SBRT. 25 patients developed grade 1 pneumonitis (12%), 20 patients developed grade 2 pneumonitis (10%), 14 patients developed grade 3 pneumonitis (7%), 5 patients developed grade 4 pneumonitis (2%), and 2 patients developed grade 5 pneumonitis (1%). In total 32% of patients developed pneumonitis of any grade. Significantly fewer patients developed any grade of RP if ACEI or ARB were taken during SBRT compared to those who did not - 16.6% vs. 38.4% at 1 year, and 25.6% vs. 39.6% at 2 years (p<=0.005). ACEI or ARB use was associated with higher 5-year overall survival rates, 44.5% vs. 28.5% (HR 0.60, p=0.042). On subset univariate analysis in patients receiving either 3, 4 or 5 fraction SBRT, 5 fraction SBRT was associated with higher rates of any grade RP compared to those treated with 3 or 4 fraction SBRT (HR 2.15, p=0.029). On subset multivariable analysis ACEI/ARB use was significant for lower rates of any grade RP (HR 0.41, p=0.003), and; 5 fraction SBRT and age >65 years were associated with higher rates of any grade RP (HR 2.5, p=0.01, HR 1.92, p=0.049 respectively). ACEI or ARB use during SBRT was associated with significantly greater freedom from any grade RP, and higher likelihood of 5-year survival. ACEI or ARB use during SBRT should be prospectively evaluated.

Reasons for Screen Failure among Patients Identified as Candidates for a Phase 2 Study of 5-fraction Stereotactic Body Radiation Therapy (SBRT) for Oligometastatic Cancer

The term oligometastatic (OM) was introduced to describe patients with a limited number of clinically detectable metastases for which local ablative therapy could potentially provide improved disease-free survival or even cure. The incidence of an oligometastatic disease distribution is difficult to estimate. The purpose of this analysis was to describe the reasons precluding trial participation in our trial of SBRT for oligometastatic cancer. We retrospectively audited all patients who were screened for participation in a single-arm phase II trial designed for patients with OM cancer (up to 5 sites of extra-cranial metastases). Study participants received local ablative therapy to all known sites of disease and at least one index lesion was treated with 5 fraction SBRT (study intervention). Eligibility criteria required baseline computed tomography (CT) ≤1 month prior to enrolment, and all cases were discussed at peer-review rounds to confirm eligibility. Between Mar 7 2013 and Nov 17 2017, 236 patients were screened and 145 (61%) enrolled to the study. The reasons for screen failure included patients declining study participation in 4% (9/236) [n = 9; 4 with <5 mets, and 5 with uncertain number] and 12% (29/236) having >5 metastases upon restaging baseline scans. Of the remaining 53 patients who had ≤5 metastases but were not enrolled, reasons for screen failure included uncertainty that the primary tumor was controlled (n=9), lesions where alternative ablative therapy was recommended (n=10), not suitable for SBRT (n=18; size n=3, non-SBRT strategy preferred n=8, toxicity risk n=4, previous RT field overlap n=3), high subjective risk of systemic relapse (n=9; progressive disease during restaging scans n=4, not suitable for comprehensive ablative therapy n=1, plan for systemic therapy n=4) or other reasons (n=7; e.g. index lesion resolution, index lesion was a primary tumor, presence of cranial metastases). In our review of a cohort of patients flagged to be potential candidates for enrollment in a clinical trial of SBRT for OM cancer, 87% of patients were confirmed to have <5 metastases. The screen failure rate was high. The most common reason for exclusion was detection of >5 metastases (12%) while a small group of patients (5%) were deemed to be at high risk of systemic relapse based on clinical factors and peer review rounds. Reporting of the characteristics of screen failed patients are important in the interpretation of trial results.