Evaluation of Safety of Stereotactic Body Radiotherapy for the Treatment of Patients With Multiple Metastases: Findings From the NRG-BR001 Phase 1 Trial.

IMPORTANCE: Stereotactic body radiotherapy (SBRT) for oligometastases is hypothesized to improve survival and is increasingly used. Little evidence supports its safe use to treat patients with multiple metastases. OBJECTIVE: To establish safety of SBRT dose schedules in patients with 3 to 4 metastases or 2 metastases in close proximity to each other. DESIGN, SETTING, AND PARTICIPANTS: This phase 1 trial opened on August 4, 2014, and closed to accrual on March 20, 2018. Metastases to 7 anatomic locations were included: bone/osseous (BO), spinal/paraspinal (SP), peripheral lung (PL), central lung (CL), abdominal-pelvic (AP), mediastinal/cervical lymph node (MC), and liver (L). Six patients could be enrolled per anatomic site. The setting was a consortium of North American academic and community practice cancer centers participating in NRG Oncology trials. Patients with breast, prostate, or non-small cell lung cancer with 3 to 4 metastases or 2 metastases in close proximity (≤5 cm) amenable to SBRT were eligible for this phase 1 study. Statistical analyses were performed from December 31, 2017, to September 19, 2019. INTERVENTIONS: The starting dose was 50 Gy in 5 fractions (CL, MC), 45 Gy in 3 fractions (PL, AP, L), and 30 Gy in 3 fractions (BO, SP). MAIN OUTCOMES AND MEASURES: The primary end point was dose-limiting toxicity (DLT) defined by the Common Terminology Criteria for Adverse Events, version 4.0, as specific adverse events (AEs) of grades 3 to 5 (definite or probable per the protocol DLT definition) related to SBRT within 180 days of treatment. Dose levels were considered safe if DLTs were observed in no more than 1 of 6 patients per location; otherwise, the dose at that location would be de-escalated. RESULTS: A total of 42 patients enrolled, 39 were eligible, and 35 (mean [SD] age, 63.1 [14.2] years; 20 men [57.1%]; 30 White patients [85.7%]) were evaluable for DLT. Twelve patients (34.3%) had breast cancer, 10 (28.6%) had non-small cell lung cancer, and 13 (37.1%) had prostate cancer; there was a median of 3 metastases treated per patient. Median survival was not reached. No protocol-defined DLTs were observed. When examining all AEs, 8 instances of grade 3 AEs, most likely related to protocol therapy, occurred approximately 125 to 556 days from SBRT initiation in 7 patients. CONCLUSIONS AND RELEVANCE: This phase 1 trial demonstrated the safety of SBRT for patients with 3 to 4 metastases or 2 metastases in close proximity. There were no treatment-related deaths. Late grade 3 AEs demonstrate the need for extended follow-up in long-surviving patients with oligometastatic disease. Treatment with SBRT for multiple metastases has been expanded into multiple ongoing randomized phase 2/3 National Cancer Institute-sponsored trials (NRG-BR002, NRG-LU002). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02206334.

Assessment of interfractional variation of the breast surface following conventional patient positioning for whole-breast radiotherapy.

The purpose of this study was to quantify the variability of the breast surface position when aligning whole-breast patients to bony landmarks based on MV portal films or skin marks alone. Surface imaging was used to assess the breast surface position of 11 whole-breast radiotherapy patients, but was not used for patient positioning. On filmed fractions, AlignRT v5.0 was used to capture the patient's surface after initial positioning based on skin marks (28 "preshifts" surfaces), and after treatment couch shifts based on MV films (41 "postshifts" surfaces). Translations and rotations based on surface captures were recorded, as well as couch shifts based on MV films. For nonfilmed treatments, "daily" surface images were captured following positioning to skin marks alone. Group mean and systematic and random errors were calculated for all datasets. Pearson correlation coefficients, setup margins, and 95% limits of agreement (LOA) were calculated for preshifts translations and MV film shifts. LOA between postshifts surfaces and the filmed treatment positions were also computed. All the surface captures collected were retrospectively compared to both a DICOM reference surface created from the planning CT and to an AlignRT reference surface. All statistical analyses were performed using the DICOM reference surface dataset. AlignRT reference surface data was only used to calculate the LOA with the DICOM reference data. This helped assess any outcome differences between both reference surfaces. Setup margins for preshifts surfaces and MV films range between 8.3-12.0 mm and 5.4-13.4 mm, respectively. The largest margin is along the left-right (LR) direction for preshift surfaces, and along craniocaudal (CC) for films. LOA ranges between the preshifts surfaces and MV film shifts are large (12.6-21.9 mm); these decrease for postshifts surfaces (9.8-18.4 mm), but still show significant disagreements between the two modalities due to their focus on different anatomical landmarks (patient's topography versus bony anatomy). Pearson's correlation coefficients further support this by showing low to moderate correlations in the anterior-posterior (AP) and LR directions (0.47-0.69) and no correlation along CC (< 0.15). The use of an AlignRT reference surface compared to the DICOM reference surface does not significantly affect the LOA. Alignment of breast patients based solely on bony alignment may lead to interfractional inconsistencies in the breast surface position. The use of surface imaging tools highlights these discrepancies, and allows the radiation oncology team to better assess the possible effects on treatment quality.

Calculation and prediction of the effect of respiratory motion on whole breast radiation therapy dose distributions.

The standard treatment technique used for whole-breast irradiation can result in undesirable dose distributions in the treatment site, leading to skin reaction/fibrosis and pulmonary and cardiac toxicities. Hence, the technique has evolved from conventional wedged technique (CWT) to segment intensity-modulated radiation therapy (SIMRT) and beamlet IMRT (IMRT). However, these newer techniques feature more highly modulated dose distributions that may be affected by respiration. The purpose of this work was to conduct a simple study of the clinical impact of respiratory motion on breast radiotherapy dose distributions for the three treatment planning techniques. The ultimate goal was to determine which patients would benefit most from the use of motion management. Eight patients with early-stage breast cancer underwent a free-breathing (FB) computed tomography (CT) simulation, with medial and lateral markers placed on the skin. Two additional CT scans were obtained at the end of inspiration (EI) and the end of expiration (EE). The FB-CT scan was used to develop treatment plans using each technique. Each plan was then applied to EI and EE-CT scans. Compared with the FB CT scan, the medial markers moved up to 1.8 cm in the anterior-superior direction at the end of inspiration (EI-scan), and on average 8 mm. The CWT and SIMRT techniques were not "sensitive" to respiratory motion, because the % clinical target volume (CTV) receiving 95% of the prescription dose (V(95%)) remained constant for both techniques. For patients that had large respiratory motion indicated by marker movement >0.6 cm, differences in coverage of the CTV at the V100% between FB and EI for beamlet IMRT plans were on the order of >10% and up to 18%. A linear model was developed to relate the dosimetric coverage difference introduced by respiration with the motion information. With this model, the dosimetric coverage difference introduced by respiratory motion could be evaluated during patient CT simulation. An appropriate treatment method can be chosen after the simulation.