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.

Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001.

PURPOSE: Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS: This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS: Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [P = .049] and 16.4% v 33.3% [P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue (P = .04), less difficulty with remembering things (P = .01), and less difficulty with speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008) and fewer cognitive symptoms (P = .01). CONCLUSION: HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Effective treatment of the brachial plexus syndrome in breast cancer patients by early detection and control of loco-regional metastases with radiation or systemic therapy.

BACKGROUND: In breast cancer (BC) patients the brachial plexus syndrome (BPS) has been reported to be due to loco-regional metastases or radiation plexopathy. Associated arm edema is considered more suggestive of the latter. Radiation therapy is the only effective treatment for BPS reported. METHODS: The charts of all BC patients who presented to our clinic from 1982 to 2006 with homolateral arm pain and neurological deficits, without humerus, cervical spine, or brain metastases, were reviewed. RESULTS: There were 28 patients fulfilling these criteria for BPS. Supraclavicular, axillary or chest wall metastases developed synchronously with the BPS in 26 patients; in 21 they were recurrences, found 6-94 months (median 34 months) after primary BC treatment, while in 5 others they were progressing inoperable primary tumors and nodes. Arm edema first occurred at the same time as loco-regional metastases in 19 patients. Treatment for the BPS was administered to 22 patients; it was directed at their locoregional metastases. The BPS was initially treated with radiation (8 patients) or chemo- or endocrine therapy (14 patients); 19 (86%) had partial or complete remission of pain and neurologic deficits, with an 8-month median duration. CONCLUSION: The BPS in BC patients is due to loco-regional metastases and is often associated with arm edema. Chemo- or endocrine therapy induced the remission of pain and deficits as frequently as radiation therapy.

Partial breast brachytherapy as the primary treatment for breast cancer diagnosed after mantle radiation therapy for Hodgkin's disease.

PURPOSE: Mastectomy is the most widely accepted treatment for managing breast cancer in patients who have previously received mantle radiation therapy (RT). With accumulating evidence supporting partial breast irradiation, we treated newly diagnosed breast cancer among lymphoma survivors who had history of RT with lumpectomy and breast brachytherapy. METHODS: Five patients, with history of Hodgkin disease (HD) underwent lumpectomy and sentinel lymphadenectomy +/- axillary dissection followed by low dose rate Ir-192 interstitial brachytherapy. A multicatheter technique was used and all patients received 45 Gy to the target volume over 4 to 5 day time interval. Adjuvant systemic therapy when indicated was administered after completion of brachytherapy. RESULTS: The median time from the treatment of the HD to the diagnosis of breast cancer was 242 months (range: 68-322 months). The median T-size of the invasive breast cancer is 0.7 cm. The range of follow up after brachytherapy is 5 to 67 months. All 5 patients have an intact breast and are without evidence of relapse. No patients developed an infection. No skin toxicity > or =grade 2 was observed. All patients have an excellent cosmetic result. No excessive fibrosis or necrosis has been observed. CONCLUSION: The preliminary experience using partial breast brachytherapy (PBB) in patients with previous history of mantle RT suggests low complication rates, and acceptable cosmetic results. The excellent local control and freedom from mastectomy for local recurrence warrants further investigation to establish brachytherapy as an acceptable alternative to mastectomy for early stage breast cancer among HD survivors with history of prior RT.